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To explore the deep sliding instability mechanism of a soil slope, taking the subgrade slope instability at K1219+000 of the downward line of the Beijing-Guangzhou railway as an example, the deformation and failure characteristics, geomechanical process and instability causes of the soil slope are detailedly studied. The results show that the width and depth of cracks on the surface of the subgrade slope gradually become shallow and narrow from the top of the slope to the toe of the slope, and the deformation has a certain rotation, with obvious traction characteristics, which belongs to deep sliding and splitting instability. The soil slope has experienced three geomechanical processes: the redistribution of the stress field and seepage field caused by slope toe excavation and pumping, the increasing sliding force caused by rainwater infiltration softening and the deepening of the sliding surface, and the failure of retaining structure resistance. The mechanism of slope instability includes the stage of shallow sliding, the stage of shallow sliding surface moving to the deep layer, and the stage of deep sliding instability triggered by the dynamic load.On this basis, the position of the sliding surface is comprehensively determined and the mechanical parameters of the slip surface are determined by the inversion method. The regulation scheme of rigid frame double row anti-slide piles is adopted. Through theoretical calculation and numerical analysis, the deformation of slope and anti-slide piles are consistent with the deformation monitoring results, which indicates that the theoretical analysis of deep instability of soil slope is accurate and the calculation of mechanical parameters is scientific, and the measures are proven stable and reliable.

Objectives Many factors should be taken into consideration in the selection of a fin stabilizer for a polar cruise ship, such as environmental adaptation and device performance, and it should not be chosen via subjective judgment. To this end, a comprehensive fin stabilizer selection and evaluation method based on a combined weighting-TOPSIS (technique for order preference by similarity to ideal solution) method is proposed. Methods The selection principle of a fin stabilizer for a polar cruise ship with a gross tonnage of 8 035 is confirmed according to the PC6 guidelines for polar class ships, and the initial area of the fin stabilizer is calculated using the experimental mathematical model. Three design schemes are put forward for the fin stabilizer. A selection and evaluation index system is built by consulting experts, including five primary indexes and fourteen secondary indexes. The weights of the indexes are determined using the analytic hierarchy process (AHP) and entropy weight method (EWM), and the TOPSIS method is introduced to calculate the degree of closeness between the alternative and ideal solutions. Results According to the ranking results, Design Scheme 1 (Aquarius A100 fin stabilizer) is selected as the optimal fin stabilizer for meeting the decision-makers' requirements. Conclusions The method proposed in this study has valuable guiding significance for the selection of fin stabilizers for polar cruise ships by reducing the blindness of the shipbuilders and decision-makers.

Summary: Glioblastoma (GBM) is identified to share common signal pathways between glioma and immune cells. Here, we find that T cell immunoglobulin domain and mucin domain protein 3 (TIM-3) is one of the most common co-inhibitory immune checkpoints in GBM shared by tumor and non-tumor cells. Glioma cell-intrinsic TIM-3 is involved in not only regulating malignant behaviors of glioma cells but also inducing macrophage migration and transition to anti-inflammatory/pro-tumorigenic phenotype by a TIM-3/interleukin 6 (IL6) signal. In mechanism, as one of the major regulators of IL6, TIM-3 regulates its expression through activating NF-κB. Blocking this feedback loop by Tocilizumab, an IL6R inhibitor, inhibited the above effects and repressed the tumorigenicity of GBM in vivo. Our work identifies glioma cell-intrinsic functions of TIM-3/IL6 signal mediating the crosstalk feedback loop between glioma cells and tumor-associated macrophages (TAMs). Blocking this feedback loop may provide a novel therapeutic strategy for GBM.

Background: Heterogeneous phenotypes that display distinct common characteristics of osteoarthritis (OA) are not well defined and will be helpful in identifying more customized therapeutic options for OA. Circular RNAs (circRNAs) have attracted more and more attention due to their role in the progression of OA. Investigating the role of circRNAs in the pathogenesis of OA will contribute to the phenotyping of OA and to individualized treatment.Methods: Small extracellular vesicles (sEV) were isolated from serum samples from patients with OA of different stages and sEV-derived circPARD3B was determined using RT-qPCR analysis. CircPARD3B expression in a stimulated coculture that included OA fibroblast-like synoviocytes (OA-FLS) as well as human dermal microvascular endothelial cells (HDMECs), plus the effects of circPARD3B on the expression of vascular endothelial growth factor (VEGF) long with angiogenic activity, were evaluated in vitro. Based on bioinformatics analysis and luciferase reporter assay (LRA), MiR-326 and sirtuin 1 (SIRT1) were found to be interactive partners of circPARD3B. Mesenchymal stem cells (SMSCs) overexpressing circPARD3B were constructed and SMSCs-derived sEV with overexpressed circPARD3B (OE-circPARD3B-SMSCs-sEV) were obtained to explore the effect of the intervention of circPARD3B combined with SMSCs-sEV-based therapy in vitro and in a OA model induced by collagenase in vivo.Results: Serum sEV-linked circPARD3B was indentified to be significantly decreased in the inflammatory phenotype of OA. Overexpression of circPARD3B was found to inhibit the expression of VEGF, as well as the angiogenesis induced by VEGF in a IL-1β stimulated the co-culture of OA-FLS as well as HDMECs. CircPARD3B is directly bound to miR-326. SIRT1 was considered a novel miR-326 target gene. OE-circPARD3B-SMSCs-sEV significantly reduced VEGF expression in coculture of OA-FLS and HDMECs. Injection of OE-circPARD3B-SMSCs-sEV could also reduce synovial VEGF; additionally, it could further ameliorate OA in the mouse model of OA in vivo.Conclusion: Serum sEV circPARD3B is a potential biomarker that enables the identification of the inflammatory phenotype of patients with OA. Correspondingly, intracellular transfer of circPARD3B through OE-circPARD3B-SMSCs-sEV could postpone disease progression through a functional module regulated angiogenesis of circPARD3B-miR-326-SIRT1, providing a novel therapeutic strategy for OA.

Increasingly, the melting of Arctic ice due to global warming has provided opportunities for commercial shipping between Asia and Europe. Given the vulnerability of the Arctic environment, especially due to emissions of short-lived pollutants from shipping activities, a more effective propulsion system with a comprehensive control strategy is required to reduce fuel consumption, thus potentially mitigating the impacts of shipping activities on the northern sea route (NSR). In this paper, a shipboard DC hybrid system powered by a combination of diesel generator sets and batteries is proposed and analysed in terms of its application on a ship in the NSR. The specific fuel consumption and various losses in the power sources were analysed to develop an efficiency-optimisation control strategy for the proposed DC hybrid power system. To evaluate the performance of the hybrid power system with the proposed optimisation control strategy, lab-scale experiments have been conducted in the Shanghai Marine Diesel Engine Research Institute to compare the proposed system with a conventional hybrid system. The experimental results indicate that the proposed DC hybrid power plant with the energy optimisation control contributes a 5.35% fuel saving compared with the DC fixed-speed diesel electric configuration during a scaled-down NSR scenario.

ObjectiveIntraoperative hemorrhage represents a major risk during endoscopic intraventricular surgery. There are very few publications describing the maintenance of hemostasis during conventional endoscopic intraventricular surgery. Here, we designed a new mini-tubular port to combine intra- and extra-endoscopic techniques for endoscopic intraventricular surgery. With this new methodology, complicated techniques can be performed more efficiently with improved bleeding control.MethodsThe new mini-tubular port consists of an outer sheath and an obturator. The sheath is a thin-walled transparent cylinder that is 0.35 mm thick, 10 mm in diameter, and 90 mm in length. In this report, we describe the use of the mini-tubular port on 36 patients receiving endoscopic intraventricular surgery.ResultsThe study enrolled 36 patients, with a median age of 45 years (range: 0–72 years), of which 19 were male and 17 were female. Pure ETV (endoscopic third ventriculostomy) was performed in 20 patients and pure biopsy was performed in 2. ETV and biopsy were performed in five patients, ETV and the removal of cysticerci were performed in five, cyst fenestration was performed in one, ETV and cyst fenestration were performed in two, and ETV and shunt removal were performed in one patient. Two patients received microscopic surgery following endoscopic surgery during the same operation. A total of 17 patients (47%) underwent extra-endoscopic techniques. The median Karnofsky Performance Status (KPS) score of the patients prior to surgery was 50, while the median KPS score of the patients after one month of surgery was 80; these scores were significantly different (P

Seizures are a common symptom of craniocerebral diseases, and epilepsy is one of the comorbidities of craniocerebral diseases. However, how to rationally use anti-seizure medications (ASMs) in the perioperative period of craniocerebral surgery to control or avoid seizures and reduce their associated harm is a problem. The China Association Against Epilepsy (CAAE) united with the Trauma Group of the Chinese Neurosurgery Society, Glioma Professional Committee of the Chinese Anti-Cancer Association, Neuro-Oncology Branch of the Chinese Neuroscience Society, and Neurotraumatic Group of Chinese Trauma Society, and selected experts for consultancy regarding outcomes from evidence-based medicine in domestic and foreign literature. These experts referred to the existing research evidence, drug characteristics, Chinese FDA-approved indications, and expert experience, and finished the current guideline on the application of ASMs during the perioperative period of craniocerebral surgery, aiming to guide relevant clinical practice. This guideline consists of six sections: application scope of guideline, concepts of craniocerebral surgery-related seizures and epilepsy, postoperative application of ASMs in patients without seizures before surgery, application of ASMs in patients with seizures associated with lesions before surgery, emergency treatment of postoperative seizures, and 16 recommendations.

Abstract Background Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. GNG5, which is part of the G-protein family, has been associated with different malignant tumors, though the role of GNG5 in glioma has not been studied. Therefore, we aimed to identify the relationship between GNG5 and glioma prognosis and identify a new biomarker for the diagnosis and treatment of gliomas. Methods We used data on more than a thousand gliomas from multiple databases and clinical data to determine the expression of GNG5 in glioma. Based on clinical data and CGGA database, we identified the correlation between GNG5 and multiple molecular and clinical features and prognosis using various analytical methods. Co-expression analysis and GSEA were performed to detect GNG5-related genes in glioma and possible signaling pathways involved. ESTIMATE, ssGSEA, and TIMER were used to detect the relationship between GNG5 and the immune microenvironment. Functional experiments were performed to explore the function of GNG5 in glioma cells. Results GNG5 is highly expressed in gliomas, and its expression level is positively correlated with pathological grade, histological type, age, and tumor recurrence and negatively correlated with isocitrate dehydrogenase mutation, 1p/19 co-deletion, and chemotherapy. Moreover, GNG5 as an independent risk factor was negatively correlated with the overall survival time. GSEA revealed the potential signaling pathways involved in GNG5 function in gliomas, including cell adhesion molecules signaling pathway. The ssGSEA, ESTIMATE, and TIMER based analysis indicated a correlation between GNG5 expression and various immune cells in glioma. In vivo and in vitro experiments showed that GNG5 could participate in glioma cell proliferation and migration. Conclusions Based on the large data platform and the use of different databases to corroborate results obtained using various datasets, as well as in vitro and in vivo experiments, our study reveals for the first time that GNG5, as an oncogene, is overexpressed in gliomas and can inhibit the proliferation and migration of glioma cells and lead to poor prognosis of patients. Thus, GNG5 is a potential novel biomarker for the clinical diagnosis and treatment of gliomas.

Abstract Background XRCC2, a homologous recombination-related gene, has been reported to be associated with a variety of cancers. However, its role in glioma has not been reported. This study aimed to find out the role of XRCC2 in glioma and reveal in which glioma-specific biological processes is XRCC2 involved based on thousands of glioma samples, thereby, providing a new perspective in the treatment and prognostic evaluation of glioma. Methods The expression characteristics of XRCC2 in thousands of glioma samples from CGGA and TCGA databases were comprehensively analyzed. Wilcox or Kruskal test was used to analyze the expression pattern of XRCC2 in gliomas with different clinical and molecular features. The effect of XRCC2 on the prognosis of glioma patients was explored by Kaplan–Meier and Cox regression. Gene set enrichment analysis (GSEA) revealed the possible cellular mechanisms involved in XRCC2 in glioma. Connectivity map (CMap) was used to screen small molecule drugs targeting XRCC2 and the expression levels of XRCC2 were verified in glioma cells and tissues by RT-qPCR and immunohistochemical staining. Results We found the overexpression of XRCC2 in glioma. Moreover, the overexpressed XRCC2 was associated with a variety of clinical features related to prognosis. Cox and meta-analyses showed that XRCC2 is an independent risk factor for the poor prognosis of glioma. Furthermore, the results of GSEA indicated that overexpressed XRCC2 could promote malignant progression through involved signaling pathways, such as in the cell cycle. Finally, doxazosin, quinostatin, canavanine, and chrysin were identified to exert anti-glioma effects by targeting XRCC2. Conclusions This study analyzed the expression pattern of XRCC2 in gliomas and its relationship with prognosis using multiple datasets. This is the first study to show that XRCC2, a novel oncogene, is significantly overexpressed in glioma and can lead to poor prognosis in glioma patients. XRCC2 could serve as a new biomarker for glioma diagnosis, treatment, and prognosis evaluation, thus bringing new insight into the management of glioma.

Hippocampal sclerosis (HS) is one of the most common pathological type of intractable temporal lobe epilepsy (TLE), often characterized by hippocampal atrophy, neuronal apoptosis, and gliogenesis. However, the molecular mechanisms of neuronal apoptosis in patients with HS are still not fully understood. We therefore conducted a pilot study focusing on the neuronal apoptosis ceRNA network in the sclerotic hippocampus of intractable TLE patients. In this research, RNA sequencing (RNA-seq) was utilized to quantify the expression levels of lncRNAs, miRNAs, and mRNAs in TLE patients with HS (HS-TLE) and without HS (non-HS-TLE), and reverse transcription-quantitative PCR (qRT-PCR). The interactions of differential expression (DE) lncRNAs-miRNAs or DEmiRNAs-mRNAs were integrated by StarBase v3.0, and visualized using Cytoscape. Subsequently, we annotate the functions of lncRNA-associated competitive endogenous RNA (ceRNA) network through analysis of their interactions with mRNAs. RNA-seq analyses showed 381 lncRNAs, 42 miRNAs, and 457 mRNAs were dysregulated expression in HS-TLE compared to non-HS-TLE. According to the ceRNA hypothesis, 5 HS-specific ceRNA network were constructed. Among them, the core ceRNA regulatory network involved in neuronal apoptosis was constituted by 10 DElncRNAs (CDKN2B-AS1, MEG3, UBA6-AS1, etc.), 7 DEmiRNAs (hsa-miR-155-5p, hsa-miR-195-5p, hsa-miR-200c-3p, etc.), and 3 DEmRNAs (SCN2A, DYRK2, and MAPK8), which belonging to apoptotic and epileptic terms. Our findings established the first ceRNA network of lncRNA-mediated neuronal apoptosis in HS-TLE based on transcriptome sequencing, which provide a new perspective on the disease pathogenesis and precise treatments of HS.

CAR T-cell therapy efficacy in solid tumors is limited by inadequate T-cell migration and/or persistence in tumour microenvironment. Here, the authors show that the activity of tumour-antigen specific CAR T cells, in multiple preclinical mouse models, can be enhanced by co-expression of two IL-8 receptors that mediate their migration into the tumor microenvironment when IL-8 production in tumor is naturally expressed or enhanced by radiation.

Glioblastoma is the most common and lethal brain cancer globally. Clinically, this cancer has heterogenous molecular and clinical characteristics. Studies have shown that UBE2S is highly expressed in many cancers. But its expression profile in glioma, and the correlation with clinical outcomes is unknown. RNA sequencing data of glioma samples was downloaded from the Chinese Glioma Genome Atlas and The Cancer Genome Atlas. A total of 114 cases of glioma tissue samples (WHO grades II-IV) were used to conduct protein expression assays. The molecular and biological characteristics of UBE2S, and its prognostic value were analyzed. The results showed that high UBE2S expression was associated with a higher grade of glioma and PTEN mutations. In addition, UBE2S affected the degree of malignancy of glioma and the development of chemo-radiotherapy resistance. It was also found to be an independent predictor of worse survival of LGG patients. Furthermore, we identified five UBE2S ubiquitination sites and found that UBE2S was associated with Akt phosphorylation in malignant glioblastoma. The results also revealed that UBE2S expression was negatively correlated with 1p19q loss and IDH1 mutation; positively correlated with epidermal growth factor receptor amplification and PTEN mutation. This study demonstrates that UBE2S expression strongly correlates with glioma malignancy and resistance to chemo-radiotherapy. It is also a crucial biomarker of poor prognosis.

BackgroundIgG4-related disease (IgG4-RD) is a recently recognized systemic fibro-inflammatory disease of unknown cause involving many organs including pancreas, salivary glands, and lymph nodes. Chronic tuberculosis (TB) infection has been reported in IgG4-RD, but the prevalence of TB infection has not been evaluated in IgG4-RD.MethodsCharacterization of a patient with IgG4-RD by physical examination, laboratory tests, magnetic resonance imaging (MRI) and histological examination. TB infection was evaluated by medical history, radiological examinations, sputum examinations, tubercular skin test (TST) and interferon gamma (IFN-γ) release assay test (IGRA). Medical records of IgG4-RD patients were reviewed in our institute from February 2015 to September 2020 to explore the prevalence of TB infection in IgG4-RD.ResultsWe described a 40-year-old Chinese man presented with headache and diplopia. Physical examination revealed bitemporal hemianopsia and limited abduction of both eyes. MRI revealed uniformly enhancing mass overlying clivus with dural tail sign. Laboratory data revealed elevation of IgG4 (1.9g/L), and TB-IGRA demonstrated significantly elevated IFN-γ (414.21 pg/ml). The clivus lesion was subtotally removed and IgG4 was strongly positive on immunohistochemical staining. The diagnosis of IgG4-RD was established, and the patient received treatment of corticosteroids, methotrexate, and cyclophosphamide with isoniazid prophylaxis. Consequently, the mass shrank remarkably within 3 months. A similar concurrence of TB disease or latent TB infection (LTBI) and IgG4-RD was present in 17/47 (36.2%) patients in our institute.ConclusionHigh frequency of TB/LTBI presented in patients with IgG4-RD. Patients with IgG4-RD and LTBI should be closely monitored for resurgence of TB. Whether TB represents a risk for IgG4-RD should be further investigated in prospective cohort.

Glioblastoma multiform (GBM) is a malignant central nervous system cancer with dismal prognosis despite conventional therapies. Scientists have great interest in using immunotherapy for treating GBM because it has shown remarkable potential in many solid tumors, including melanoma, non-small cell lung cancer, and renal cell carcinoma. The gene expression patterns, clinical data of GBM individuals from the Cancer Genome Atlas database (TCGA), and immune-related genes (IRGs) from ImmPort were used to identify differentially expressed IRGs through the Wilcoxon rank-sum test. The association between each IRG and overall survival (OS) of patients was investigated by the univariate Cox regression analysis. LASSO Cox regression assessment was conducted to explore the prognostic potential of the IRGs of GBM and construct a risk score formula. A Kaplan–Meier curve was created to estimate the prognostic role of IRGs. The efficiency of the model was examined according to the area under the receiver operating characteristic (ROC) curve. The TCGA internal dataset and two GEO external datasets were used for model verification. We evaluated IRG expression in GBM and generated a risk model to estimate the prognosis of GBM individuals with seven optimal prognostic expressed IRGs. A landscape of 22 types of tumor-infiltrating immune cells (TIICs) in glioblastoma was identified, and we investigated the link between the seven IRGs and the immune checkpoints. Furthermore, there was a correlation between the IRGs and the infiltration level in GBM. Our data suggested that the seven IRGs identified in this study are not only significant prognostic predictors in GBM patients but can also be utilized to investigate the developmental mechanisms of GBM and in the design of personalized treatments for them.

Osteoporosis is a kind of brittle bone disease, which is characterized by a reduction in bone mineral density (BMD). In recent years, a number of genes and pathophysiological mechanisms have been identified for osteoporosis. However, the genes associated with BMD remain to be explored. Toward this end, we integrated multiple osteoporosis microarray datasets to identify and systematically characterize BMD-related genes. By integrating the differentially expressed genes from three osteoporosis microarray datasets, 152 genes show differentially expressed between high and low BMD osteoporosis samples in at least two of the three datasets. Among them, 88 were up-regulated in high BMD samples and 64 were up-regulated in low BMD samples. The expression of ZFP36, JUNB and TMEM8A were increased at high BMD samples in all three datasets. Hub genes were further identified by co-expression network analysis. Functional enrichment analysis showed that the gene up-regulated in high BMD were enriched in immune-related functions, suggesting that the immune system plays an important role in osteoporosis. Our study explored BMD-related genes based on the integration of osteoporosis microarray data, providing guidance to other researchers from a new perspective.

We generated two humanized interleukin-13 receptor α2 (IL-13Rα2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13Rα2, but not IL-13Rα1. Hu08BBz also recognized canine IL-13Rα2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial (ClinicalTrials.gov: NCT02209376). The Hu08BBz demonstrated a 75% reduction in orthotopic tumor growth using low-dose CAR T cell infusion. Using combination therapy with immune checkpoint blockade, humanized IL-13Rα2 CAR T cells performed significantly better when combined with CTLA-4 blockade, and humanized EGFRvIII CAR T cells’ efficacy was improved by PD-1 and TIM-3 blockade in the same mouse model, which was correlated with the levels of checkpoint molecule expression in co-cultures with the same tumor in vitro. Humanized IL-13Rα2 CAR T cells also demonstrated benefit from a self-secreted anti-CTLA-4 minibody in the same mouse model. In addition to a canine glioma cell line (J3T), canine osteosarcoma lung cancer and leukemia cell lines also express IL-13Rα2 and were recognized by Hu08BBz. Canine IL-13Rα2 CAR T cell was also generated and tested in vitro by co-culture with canine tumor cells and in vivo in an orthotopic model of canine glioma. Based on these results, we are designing a pre-clinical trial to evaluate the safety of canine IL-13Rα2 CAR T cells in dog with spontaneous IL-13Rα2-positive glioma, which will help to inform a human clinical trial design for glioblastoma using humanized scFv-based IL-13Rα2 targeting CAR T cells. Keywords: glioblastoma, chimeric antigen receptor, CAR, IL-13Rα2, minibody, canine, immune checkpoint blockade, PD-1, CTLA-4, TIM-3

Background: Interferon treatment, as an important approach of anti-tumor immunotherapy, has been implemented in multiple clinical trials of glioma. However, only a small number of gliomas benefit from it. Therefore, it is necessary to investigate the clinical role of interferons and to establish robust biomarkers to facilitate its application. Materials and methods: This study reviewed 1,241 glioblastoma (GBM) and 1,068 lower grade glioma (LGG) patients from six glioma cohorts. The transcription matrix and clinical information were analyzed using R software, GraphPad Prism 7 and Medcalc, etc. Immunohistochemical (IHC) staining were performed for validation in protein level. Results: Interferon signaling was significantly enhanced in GBM. An interferon signature was developed based on five interferon genes with prognostic significance, which could reflect various interferon statuses. Survival analysis showed the signature could serve as an unfavorable prognostic factor independently. We also established a nomogram model integrating the risk signature into traditional prognostic factors, which increased the validity of survival prediction. Moreover, high-risk group conferred resistance to chemotherapy and high IFNB1 expression levels. Functional analysis showed that the high-risk group was associated with overloaded immune response. Microenvironment analysis and IHC staining found that high-risk group occupied a disorganized microenvironment which was characterized by an enrichment of M0 macrophages and neutrophils, but less infiltration of activated nature killing (NK) cells and M1 type macrophages. Conclusion: This interferon signature was an independent indicator for unfavorable prognosis and showed great potential for screening out patients who will benefit from chemotherapy and interferon treatment.

Background: Malignant gliomas are heterogeneous brain tumors with the potential for aggressive disease progression, as influenced by suppressive immunoediting. Given the success and enhanced potential of immune-checkpoint inhibitors in immunotherapy, we focused on the connections between genetic alterations affected by IDH1 mutations and immunological landscape changes and PDL-1 expression in gliomas.Methods: Paired surgically resected tumors from lower-grade gliomas (LGGs) and glioblastomas (GBM) were investigated, and a genetic analysis of patients' primary tumor samples culled from TCGA datasets was performed.Results: The results demonstrate that when compared with IDH1-mutant tumors, IDH1 wildtype tumors represent an immunosuppression landscape and elevated levels of PD-L1 expression. DNA hypo-methylation of the PD-L1 gene, as well as high gene and protein expressions, were observed in the wildtype tumors. We also found that quantitative levels of IDH1 mutant proteins were positively associated with recurrence-free survival (RFS). A key product of the IDH1 mutation (2-hydroxyglutarate) was found to transiently increase DNA methylation and suppress PD-L1 expression.Conclusions: IDH1 mutations impact the immune landscape of gliomas by affecting immune infiltrations and manipulating checkpoint ligand PD-L1 expression. Applications of immune checkpoint inhibitors may be beneficial for chemoradiation-insensitive IDH1-wildtype gliomas.

BackgroundAngiogenesis and immune cell infiltration are key features of gliomas and their manipulation of the microenvironment, but their prognostic significance remains indeterminate. We evaluate the interconnection between tumor-infiltrating lymphocyte (TIL) and tumor blood-vasculatures in the context of glioma progression.MethodsPaired tumor tissues of 44 patients from three tumor-recurrent groups: diffuse astrocytomas (DA) recurred as DA, DA recurred as glioblastomas (GBM), and GBM recurred as GBM were evaluated by genetic analysis, immunohistochemistry for tumor blood vessel density, TIL subsets, and clinical outcomes. These cells were geographically divided into perivascular and intratumoral TILs. Associations were examined between these TILs, CD34+ tumor blood vessels, and clinical outcomes. To determine key changes in TIL subsets, microarray data of 15-paired tumors from patients who failed antiangiogenic therapy- bevacizumab, and 16-paired tumors from chemo-naïve recurrent GBM were also evaluated and compared.ResultsUpon recurrence in primary gliomas, similar kinetic changes were found between tumor blood vessels and each TIL subset in all groups, but only CD4+ including Foxp3+ TILs, positively correlated with the density of tumor blood vessels. CD4 was the predominant T cell population based on the expression of gene-transcripts in primary GBMs, and increased activated CD4+ T cells were revealed in Bevacizumab-resistant recurrent tumors (not in chemo-naïve recurrent tumors). Among these TILs, 2/3 of them were found in the perivascular niche; Foxp3+ T cells in these niches not only correlated with the tumor vessels but were also an independent predictor of shortened recurrence-free survival (RFS) (HR = 4.199, 95% CI 1.522–11.584, p = 0.006).ConclusionThe minimal intratumoral T cell infiltration and low detection of CD8 transcripts expression in primary GBMs can potentially limit antitumor response. CD4+ and perivascular Foxp3+ TILs associate with tumor angiogenesis and tumor progression in glioma patients. Our results suggest that combining antiangiogenic agents with immunotherapeutic approaches may help improve the antitumor efficacy for patients with malignant gliomas.

Objective To review the clinical diagnosis and treatment of 5 epileptic patients with failure of epilepsy surgery, to explore causes of failure, and to summerize related experiences and lessons. Methods Five cases (4 males and one female, age from 2 years and 7 months to 24 years) of epilepsy [3 cases with dysembryoplastic neuroepithelial tumor (DNT) and 2 cases with hippocampal sclerosis associated with cortical dysplasia (CD)] were reported. Failure of epilepsy surgery in 5 cases were retrospectively analysed. Results The causes of failed surgery for epilepsy in 5 patients were confirmed by reoperation. The causes of failure were related to incomplete removal of the lesion and (or) epileptogenic zone in 3 cases, incomplete removal of medial temporal lobe structure in one case, and epileptogenic zone localized wrong or not accurate in one case. Outcomes of reoperation with gama-knife treatment were satisfactory. Four cases achieved Engel I, and one case with Engel III. By the evaluation of Tan Qifu's standard, 4 cases were satisfactory, and only one case showed moderate improvement. Conclusion The causes of failed epilepsy surgery may be related to incomplete resection of epileptogenic lesion. After failure it is necessary to present second preoperative evaluation and to perform reoperation which may produce satisfactory effect. DOI：10.3969/j.issn.1672-6731.2011.04.009

In this study, we examined the effect of chronic administration of simvastatin immediately after status epilepticus (SE) on rat brain with temporal lobe epilepsy (TLE). First, we evaluated cytokines expression at 3 days post KA-lesion in hippocampus and found that simvastatin-treatment suppressed lesion-induced expression of interleukin (IL)-1β and tumor necrosis factor-α (TNF-α). Further, we quantified reactive astrocytosis using glial fibrillary acidic protein (GFAP) staining and neuron loss using Nissl staining in hippocampus at 4-6 months after KA-lesion. We found that simvastatin suppressed reactive astrocytosis demonstrated by a significant decrease in GFAP-positive cells, and attenuated loss of pyramidal neurons in CA3 and interneurons in dentate hilar (DH). We next assessed aberrant mossy fiber sprouting (MFS) that is known to contribute to recurrence of spontaneous seizure in epileptic brain. In contrast to the robust MFS observed in saline-treated animals, the extent of MFS was restrained by simvastatin in epileptic rats. Attenuated MFS was related to decreased neuronal loss in CA3 and DH, which is possibly a mechanism underlying decreased hippocampal susceptibility in animal treated with simvastatin. Electronic encephalography (EEG) was recorded during 4 to 6 months after KA-lesion. The frequency of abnormal spikes in rats with simvastatin-treatment decreased significantly compared to the saline group. In summary, simvastatin treatment suppressed cytokines expression and reactive astrocytosis and decreased the frequency of discharges of epileptic brain, which might be due to the inhibition of MFS in DH. Our study suggests that simvastatin administration might be a possible intervention and promising strategy for preventing SE exacerbating to chronic epilepsy.

Abstract Osteoarthritis (OA) is a common degenerative joint disease that can cause severe pain, motor dysfunction, and even disability. A growing body of research indicates that gut microbiota and their associated metabolites are key players in maintaining bone health and in the progression of OA. Short-chain fatty acids (SCFAs) are a series of active metabolites that widely participate in bone homeostasis. Gold nanoparticles (GNPs) with outstanding anti-bacterial and anti-inflammatory properties, have been demonstrated to ameliorate excessive bone loss during the progression of osteoporosis (OP) and rheumatoid arthritis (RA). However, the protective effects of GNPs on OA progression are not clear. Here, we observed that GNPs significantly alleviated anterior cruciate ligament transection (ACLT)-induced OA in a gut microbiota-dependent manner. 16S rDNA gene sequencing showed that GNPs changed gut microbial diversity and structure, which manifested as an increase in the abundance of Akkermansia and Lactobacillus. Additionally, GNPs increased levels of SCFAs (such as butyric acid), which could have improved bone destruction by reducing the inflammatory response. Notably, GNPs modulated the dynamic balance of M1/M2 macrophages, and increased the serum levels of anti-inflammatory cytokines such as IL-10. To sum up, our study indicated that GNPs exhibited anti-osteoarthritis effects via modulating the interaction of “microbiota-gut-joint” axis, which might provide promising therapeutic strategies for OA.