Applying the en-bloc technique in corpus callosum glioblastoma surgery contributes to maximal resection and better prognosis: a retrospective study.

BACKGROUND: Corpus callosum glioblastoma (ccGBM) is a specific type of GBM and has worse outcomes than other non-ccGBMs. We sought to identify whether en-bloc resection of ccGBMs based on T2-FLAIR imaging contributes to clinical outcomes and can achieve a satisfactory balance between maximal resection and preservation of neurological function. METHODS: A total of 106 adult ccGBM patients (including astrocytoma, WHO grade 4, IDH mutation, and glioblastoma) were obtained from the Department of Neurosurgery in Nanfang Hospital between January 2008 and December 2018. The clinical data, including gender, age, symptoms, location of tumor, involvement of eloquent areas, extent of resection (EOR), pre- and postoperative Karnofsky Performance Status (KPS) scales, and National Institute of Health stroke scale (NIHSS) scores were collected. Propensity score matching (PSM) analysis was applied to control the confounders for analyzing the relationship between the en-bloc technique and EOR, and the change in the postoperative KPS scales and NIHSS scores. RESULTS: Applying the en-bloc technique did not negatively affect the postoperative KPS scales compared to no-en-bloc resection (P = 0.851 for PSM analysis) but had a positive effect on preserving or improving the postoperative NIHSS scores (P = 0.004 for PSM analysis). A positive correlation between EOR and the en-bloc technique was identified (r = 0.483, P < 0.001; r = 0.720, P < 0.001 for PSM analysis), indicating that applying the en-bloc technique could contribute to enlarged maximal resection. Further survival analysis confirmed that applying the en-bloc technique and achieving supramaximal resection could significantly prolong OS and PFS, and multivariate analysis suggested that tumor location, pathology, EOR and the en-bloc technique could be regarded as independent prognostic indicators for OS in patients with ccGBMs, and pathology, EOR and the en-bloc technique were independently correlated with patient's PFS. Interestingly, the en-bloc technique also provided a marked reduction in the risk of tumor recurrence compared with the no-en-bloc technique in tumors undergoing TR, indicating that the essential role of the en-bloc technique in ccGBM surgery (HR: 0.712; 95% CI: 0.535-0.947; P = 0.02). CONCLUSIONS: The en-bloc technique could contribute to achieving an enlarged maximal resection and could significantly prolong overall survival and progression-free survival in patients with ccGBMs.

Supramaximal resection based on en-bloc technique reduces tumor burden and prolongs survival in primary supratentorial lobar glioblastoma.

PURPOSE: Resection beyond the contrast-enhanced zone contributed to reduce tumor burden and prolong survival in glioblastomas. The optimal extent of resection (EOR) and how to achieve it are worthy of continuous investigation for obtaining a satisfactory balance between maximal resection and the preservation of neurological function. METHODS: A total of 340 adult supratentorial lobar glioblastomas (included astrocytoma, WHO 4, IDH mutation and glioblastoma) were retrospectively evaluated. The clinical data, EOR, technique of resection, postoperative complications, overall survival (OS) and progression-free survival (PFS) were assessed by univariate, multivariate and propensity score matched analysis. Histological staining was performed to comprehend the effect of the membranous structures and the cell distribution in tumoral and peritumoral regions. RESULTS: Supramaximal resection (SMR) was confirmed as resection with 100% EORCE and > 50% EORnCE in glioblastomas by Cox proportional hazards model. Histological results showed SMR reduced the cell density of surgical edge compared to total resection. En-bloc technique based on membranous structures, which had blocking effect on tumoral invasion, contributed to achieve SMR. Moreover, applying en-bloc technique and achieving SMR did not additionally deteriorate neurological function and had similarly effects on the improvement of neurological function. Multivariate analysis confirmed that IDH1 status, technique of resection and EOR were independently correlated with PFS, and > 64 years old, IDH1 status, technique of resection, EOR and preoperative NIHSS were independently correlated with OS. CONCLUSIONS: Applying en-bloc technique and achieving SMR, which could reduce tumor burden and did not increase additional complications, both had remarkedly positive effects on clinical outcomes in patients with primary supratentorial lobar glioblastomas.

A Four-Gene Panel for the Prediction of Prognosis and Immune Cell Enrichment in Gliomas.

BACKGROUNDS: Gliomas is a deadly disease without effective therapy. Although immunotherapy has provided novel choices for glioma treatment, the curative efficacy is unsatisfactory due to the complex immune micro-environment and the heterogeneity of the disease. Therefore, it is urgent to identify effective biomarkers and therapeutic targets. METHODS: Overall survival, gene ontology (GO), Kyoto Encyclopedia of Genes, and Genomes (KEGG) enrichment analysis, Gene Set Enrichment Analysis (GSEA) and immune infiltration were analyzed by bioinformatics software with The Cancer Genome Atlas (TCGA) database. RESULTS: Based on the TCGA database and protein-protein interaction (PPI) analysis revealed a four-gene panels [DNA topoisomerase II alpha (TOP2A); ribonucleotide reductase regulatory subunit M2 (RRM2); kinesin family member 20 A (KIF20A) and DLG associated protein 5 (DLGAP5)], which correlated with poor prognosis, including overall survival (OS), disease specific survival (DSS) and progress free interval (PFI), mitosis, cell cycle, Th2 cells and macrophages enrichment. The four-gene panels correlates with the biomarkers of Th2 cells, macrophages tumor-associated macrophages (TAMs) and the immune checkpoint molecules in gliomas. CONCLUSION: The four-gene panels represented a novel prognostic indicator and potential therapeutic target for the treatment of glioma. In addition, the four-gene panels might contribute to enhance the efficacy of immunotherapy in glioma.

Identification of Necroptosis-related Molecular Subtypes and Construction of Necroptosis-related Gene Signature for Glioblastoma Multiforme.

Background Necroptosis is a highly regulated and genetically controlled process, and therefore, attention has been paid to the exact effects of this disorder on a variety of diseases, including cancer. An in-depth understanding of the key regulatory factors and molecular events that trigger necroptosis can not only identify patients at risk of cancer development but can also help to develop new treatment strategies. Aims This study aimed to increase understanding of the complex role of necroptosis in glioblastoma multiforme (GBM) and provide a new perspective and reference for accurate prediction of clinical outcomes and gene-targeted therapy in patients with GBM. The objective of this study was to analyze the gene expression profile of necroptosis regulatory factors in glioblastoma multiforme (GBM) and establish a necroptosis regulatory factor-based GBM classification and prognostic gene signature to recognize the multifaceted impact of necroptosis on GBM. Method The necroptosis score of the glioblastoma multiforme (GBM) sample in TCGA was calculated by ssGSEA, and the correlation between each gene and the necroptosis score was calculated. Based on necroptosis score-related genes, unsupervised consensus clustering was employed to classify patients. The prognosis, tumor microenvironment (TME), genomic changes, biological signal pathways and gene expression differences among clusters were analyzed. The gene signature of GBM was constructed by Cox and LASSO regression analysis of differentially expressed genes (DEGs). Result Based on 34 necroptosis score-related genes, GBM was divided into two clusters with different overall survival (OS) and TME. A necroptosis-related gene signature (NRGS) containing 8 genes was developed, which could stratify the risk of GBM in both the training set and verification set and had good prognostic value. NRGS and age were both independent prognostic indicators of GBM, and a nomogram developed by the integration of both of them showed a better predictive effect than traditional clinical features. Conclusion In this study, patients from public data sets were divided into two clusters and the unique TME and molecular characteristics of each cluster were described. Furthermore, an NRGS was constructed to effectively and independently predict the survival outcome of GBM, which provides some insights for the implementation of personalized precision medicine in clinical practice.

Silencing ATF4 inhibits JMJD3-dependent JUNB/ETS1 axis and mitigates cerebral ischemic injury.

Activating transcription factor 4 (ATF4) is known to play an important role in cerebral ischemia through apoptosis and neuron regulation. Histone demethylase JMJD3, specifically removing the methylation of H3K27me3, is highlighted to attenuate cerebral ischemic injury. However, few studies have explored the interaction between ATF4 and JMJD3 in this disease. Thus, we intended to explore the effect of ATF4 on cerebral ischemia. We first constructed a mouse model of middle cerebral artery occlusion (MCAO) and cultured PC12 cells. Specifically, the regulatory function of ATF4 and demethylase JMJD3 on the ischemic injury was explored via using ectopic expression and depletion by determination of modified neurologic severity score, blood-brain barrier, brain water content, apoptosis, infarct size, oxidative stress, and inflammation. Moreover, the interaction among ATF4, JUNB, JMJD3, and ETS1 was assessed by western blot analysis, immunofluorescence, immunoprecipitation, and dual-luciferase reporter gene assay. These data showed that ATF4 and JMJD3 were upregulated in the MCAO model and PC12 cells. In addition, ectopic expression of ATF4 aggravated the ischemic injury through demethylation of JMJD3. Meanwhile, JMJD3 upregulated JUNB expression by inhibiting H3K21me2/3 enrichment and promoted ETS1 expression as well. Altogether, ATF4 could exacerbate cerebral ischemic injury through JMJD3-dependent upregulation of JUNB/ETS1 expression, suggesting a potential theoretical basis of treatment for cerebral ischemic injury.

Classification of unilateral thalamic gliomas predicts tumor resection and patient's survival: a single center retrospective study.

BACKGROUND: To propose our classification about unilateral thalamic gliomas, and to describe relationship between the classification and clinical characteristics including symptoms, surgical approaches and survival, which should contribute to the treatment and the prognostic prediction of unilateral thalamic gliomas. METHODS: A total of 66 adult unilateral thalamic glioma patients with pathologic confirmation between January 2010 and December 2018 were retrospectively investigated. RESULTS: Unilateral thalamic gliomas could be divided into quadrigeminal cistern and ventricle extension type (Type Q), lateral type (Type L) and anterior type (Type A) according to tumor location, extensive polarity and location of ipsilateral posterior limb of internal capsule. Each subtype of QLA classification could match with one kind of corresponding approach. Preoperative symptoms including headache, dyskinesia, aphasia, hydrocephalus and KPS scores, and pathological features including H3K27M mutation and P53 expression were correlated with QLA classification. Further analysis confirmed that Type Q tumors had a higher rate of total resection and a significantly longer survival time compared to Type L and Type A tumors, with similar improved and deteriorated rates of symptoms. Univariate and multivariate analysis demonstrated QLA classification was remarkedly associated with overall survival and could be considered as an independent prognostic factor in patients with unilateral thalamic gliomas. CONCLUSIONS: Unilateral thalamic glioma could be divided into 3 subtypes by imaging characteristics, symptoms and survival. QLA classification could predict tumor resection and the prognosis and could contribute to the planning of therapeutic strategy in patients with unilateral thalamic gliomas.

Overexpression of ORX or MCH Protects Neurological Function Against Ischemic Stroke.

In recent years, orexin (ORX) and melanin-concentrating hormone (MCH) have been demonstrated to exert neuroprotective roles in cerebral ischemia. Hence, this study investigated the regulatory function of ORX and MCH in neurological function following ischemic stroke and explored the molecular mechanism underlying these functions. A rat model of ischemic stroke was developed by middle cerebral artery occlusion (MCAO), and Longa scoring was employed to evaluate the degree of neurological function deficit. The expression patterns of ORX and MCH were examined by real-time polymerase chain reaction in the brain tissues of rats with ischemic stroke induced by middle cerebral artery occlusion (MCAO). Moreover, electroencephalography (EEG) analysis and high-performance liquid chromatography (HPLC) were respectively performed to detect rapid-eye movement (REM) sleep, the glutamate (Glu) uptake, and the expression of γ-aminobutyric acid B receptor (GABAB). Immunoblotting was performed to test the levels of autophagic markers LC3, BECLIN-1, and p62. Immunohistochemistry (IHC) staining and TUNEL assays were respectively used to assess the autophagy and neuronal apoptosis. Results demonstrated that ORX and MCH were lowly expressed in brain of rats with ischemic stroke. ORX or MCH overexpression decreased neuronal apoptosis and autophagy, and improved the sleep architecture of post-stroke rats, while rescuing Glu uptake and GABA expression. ORX or MCH upregulation exerted protective effects on neurological function. Taken together, ORX and/or MCH protect against ischemic stroke in a rat model, highlighting their value as targets for the clinical treatment of ischemic stroke.

Ventricle wall resection contributes to supramaximal resection and prognosis in SVZ-involved frontal gliomas: A single center retrospective study.

BACKGROUND: Frontal glioma frequently invaded the subventricular zone (SVZ), which existed glioma stem cells and might be involved in the development of primary and recurrent gliomas. We attempted to identify whether ventricle wall resection contributed to the maximal extent of resection (EOR) and increased the patient's survival during frontal glioma resection. METHODS: A total of 151 adult patients with primary SVZ-involved frontal gliomas were obtained between January 2012 and December 2018. We analyzed clinical data, EOR, complications and survival profiles between the ventricle wall group and the ventricle intact/opening group. RESULTS: Applying ventricle wall removal had similar effect on the improvement of neurological function compared to applying ventricle intact/opening and did not increase the incidence of new neurological deficits, hydrocephalus, and ependymal dissemination in SVZ-involved frontal gliomas. A positive correlation was identified between EOR and the ventricle wall handling (r = 0.487, P < 0.001), which indicated that ventricle wall resection could contribute to achieve supramaximal resection. Applying supramaximal resection and ventricle wall resection could significantly prolong overall survival and progression free survival. Ventricle wall resection could be regarded as an independent prognostic indicator for both overall survival and progression free survival in patients with SVZ-involved frontal gliomas. CONCLUSIONS: Ventricle wall resection in SVZ-involved frontal gliomas could contribute to achieve supramaximal resection and could significantly prolong overall survival and progression free survival.

Establishing a papillary craniopharyngioma cell line by SV40LT-mediated immortalization.

BACKGROUND: Craniopharyngioma represents a troublesome tumor of the intracranial sellar region. There are currently no available well-characterized craniopharyngioma cell lines. This lack of reliable, immortal cell lines is a major reason for the slow progress in fundamental research related to craniopharyngioma. METHODS: We describe the development of an immortal papillary craniopharyngioma (PCP) cell line by transfecting primary PCP cells with the pLenti-simian virus 40 large T antigen(SV40LT). RESULTS: Three clones have been cultured for more than 14 months so far, while non-transfected cells ceased proliferation within three months of isolation. The established immortal PCP cell lines were identified to have BRAFV600E mutations, while no mutations in tumor suppressor genes were found in primary cells or immortal cells. Immortal cells had higher proliferation rates and formed tumors when implanted in the bran of nude mice. BRAF inhibition in immortal PCP cells altered cell morphology, inhibited cell proliferation and promoted apoptosis. CONCLUSION: We successfully developed PCP cell lines by SV40LT-mediated immortalization. These cell lines represent a powerful tool for fundamental and therapeutical studies on craniopharyngioma.

Correction to: A complex mechanism for HDGF-mediated cell growth, migration, invasion, and TMZ chemosensitivity in glioma.

In the original publication, there are errors in Fig. 3D and Fig. 5C and are corrected as follows.

Membrane Structures Between Craniopharyngioma and the Third Ventricle Floor Based on the QST Classification and Its Significance: A Pathological Study.

The aim of this study was to clarify the relationship between craniopharyngiomas (CP) and the third ventricle floor by analyzing the membranes between them. Eight fetal specimens were first examined by hematoxylin and eosin and immunofluorescence staining to determine optimal markers for identifying membrane structures in the sellar region. Then, 17 CP with third ventricle floor involvement that had been removed by total en bloc resection through a transsphenoidal approach were examined. We found that the dura mater, arachnoid membrane, and pia mater could be seen to separate type Q tumors from the third ventricle floor. The arachnoid membrane and pia mater could be seen between type S tumors and the third ventricle floor. Pia mater could be seen between type T tumors and the third ventricle floor; however, at the origin point of the tumor, pia mater could be loosened or replaced by the tumor. Although some type T tumors compressed the third ventricle, the ependymal layer remained intact. Based on these embryonic and pathological data, we suggest that CP are nonneuroepithelial, epi-pia mater, and epi-third ventricle tumors.

Flow evaluation of STA-MCA bypass using quantitative ultrasonography: An alternative to standard angiography for follow up of bypass graft.

PURPOSE: To date, digital subtraction angiography (DSA) has been considered as the gold imaging modality for assessing graft patency after extracranial-intracranial bypass. The utility of a noninvasive and quantitative method of assessing graft flow postoperatively was evaluated by using quantitative ultrasonography. METHOD: All STA-MCA bypass surgery performed over a 5-year period at a single institution were reviewed. Measured by duplex ultrasonography, pre-operative (day1) and post-operative (day1, day7, 3month and 6 month) graft blood flow rates were recorded and analyzed. Results were correlated to Matsushima grade determined by DSA performed within 24 h when ultrasonography was conducted to confirm the graft function. RESULTS: 100 patients with 131 operated hemispheres were included in this study. The mean flow rates in the STA graft on pre-operative day1, post-operative day 1 and 7, at 3- and 6-month postoperatively were 24.1, 106.7, 112.6, 97.4 and 79.7 ml/min respectively. The mean post-operative flow in the STA graft graded as A/B/C were significantly different (168.0 ± 34.8 ml/min, 91.0 ± 15.5, 42.1 ± 17.2 ml/min, respectively, p = 0.000). 124.5 ml/min and 65.5 ml/min are good cut-off value for predicting post-operative graft Matsushima grade. The analysis also showed excellent agreement between ultrasonography and DSA for assessing bypass function (κ = 0.78). CONCLUSIONS: The patency of the STA grafts can be assessed noninvasively by quantitative ultrasonography, which results are comparable to those of conventional DSA. This, therefore, suggest that quantitative ultrasonography may be an alternative method to standard DSA for serial follow up of STA grafts.

Long intergenic non-protein coding RNA 00475 silencing acts as a tumor suppressor in glioma under hypoxic condition by impairing microRNA-449b-5p-dependent AGAP2 up-regulation.

OBJECTIVE: Long non-coding RNAs have been demonstrated to be involved in the progression of a variety of cancers, including glioma. Through microarray analyses, long intergenic non-protein coding RNA 00475 (LINC00475) was identified in the glioma development. However, its potential role remains incompletely understood. This study aimed to elucidate the effect of LINC00475 on the development of glioma under hypoxic conditions. METHODS: Glioma cells underwent hypoxic treatment and were collected. The functional role of LINC00475 and AGAP2 in glioma was determined using ectopic expression, depletion, and reporter assay experiments. Then, the expression of LINC00475, microRNA (miR)-449b-5p, AGAP2, FAK, and HIF-1α was determined. In addition, cell migration and invasion were examined. Finally, a tumor xenograft was carried out in nude mice to explore the role of LINC00475 on oxidation in vivo. RESULTS: LINC00475 was identified to be overexpressed in hypoxic glioma samples, which was further observed to bind to and down-regulate miR-449b-5p, and negatively targeted AGAP2. Moreover, we also revealed a positive correlation between LINC00475 and AGAP2 expression in glioma. In addition, silencing of LINC00475 decreased the extent of FAK phosphorylation and reduced the expression of HIF-1α and AGAP2. It was also observed that LINC00475 silencing suppressed glioma cell proliferation, migration, and invasion, and promoted cell apoptosis. Moreover, oxidation of nude mice was promoted by LINC00475 silencing. CONCLUSION: Taken together, LINC00475 silencing exerted an inhibitory effect on glioma under hypoxic conditions by down-regulating AGAP2 via up-regulation of miR-449b-5p.

A Hybrid Strategy for Patients With Complex Cerebral Aneurysm: STA-MCA Bypass in Combination With Endovascular Embolization.

Objective: This work aims to present our experience of patients with complex cerebral aneurysm treated with a hybrid approach: superficial temporal artery-middle cerebral artery (STA-MCA) bypass in combination with endovascular exclusion of the aneurysm. Method: Patients with aneurysms deemed unclippable and uncoilable were included. All patients were treated with a hybrid approach. After STA-MCA bypass, the parent artery was temporarily occluded. If the intraoperative motor evoked potential (MEP) and somatosensory evoked potential (SEP) waveforms remain normal and last for 30 min, the aneurysm and te parent artery will be embolized permanently with detachable balloons or coils. Results: A total of 20 patients with 22 aneurysms were included in this study. There were 13 women and 7 men, with an average age of 42.5 years. Intraoperative angiography showed the good patency of all the STA grafts, and neither SEP nor MEP abnormalities were detected. After the parent artery and the aneurysm were occluded, the intraoperative angiography showed an immediately successful exclusion of the aneurysm in 20 aneurysms and immediate contrast stasis in two. All patients recovered uneventfully without ischemic or hemorrhagic complication. Angiography at 6-month follow-up showed the total obliteration in 20 aneurysms. Two aneurysms showed residuals and were recoiled. All STA grafts showed a good patency, and the mean graft flow was 124.2 ml/min. Conclusion: STA-MCA bypass in combination with endovascular exclusion is an appropriate option for patients with complex cerebral aneurysms that are not amenable to direct surgical clipping or endovascular embolization.

Exosomes derived from microRNA-199a-overexpressing mesenchymal stem cells inhibit glioma progression by down-regulating AGAP2.

Accumulating evidence has implied that microRNAs (miRNAs) are implicated in glioma progression, and genetically engineered mesenchymal stem cells can help to inhibit tumor growth of glioma. Herein we hypothesized that miR-199a could be delivered by mesenchymal stem cells to glioma cells through exosomes and thus prevent the glioma development by down-regulating ArfGAP with GTPase domain, ankyrin repeat and PH domain 2 (AGAP2). The expression pattern of miR-199a and AGAP2 was characterized in glioma tissues and cells using RNA polymerase chain reaction quantification, immunohistochemical staining and Western blot assays. Mesenchymal stem cells transfected with miR-199a mimic or their derived exosomes were co-cultured with U251 cells. The biological behaviors as well as chemosensitivity of U251 cells were assessed to explore the involvement of miR-199a/AGAP2 in glioma. MiR-199a was poorly expressed in glioma tissue and cells while AGAP2 was highly expressed. Mesenchymal stem cells delivered miR-199a to the glioma cells via the exosomes, which resulted in the suppression of the proliferation, invasion and migration of glioma cells. Besides, mesenchymal stem cells over-expressing miR-199a enhanced the chemosensitivity to temozolomide and inhibited the tumor growth in vivo. Taken together, mesenchymal stem cell-derived exosomal miR-199a can inhibit the progression of glioma by down-regulating AGAP2.

Identification of tumor stem-like cells in admanatimomatous craniopharyngioma and determination of these cells' pathological significance.

OBJECTIVE: Nuclear ß-catenin, a hallmark of active canonical Wnt signaling, can be histologically detected in a subset of cells and cell clusters in up to 94% of adamantinomatous craniopharyngioma (ACP) samples. However, it is unclear whether nuclear ß-catenin-containing cells within human ACPs possess the characteristics of tumor stem cells, and it is unknown what role these cells have in ACP. METHODS: Primary ACP cells were cultured from 12 human ACP samples. Adamantinomatous CP stem cell-like cells (CSLCs) showing CD44 positivity were isolated from the cultured primary ACP cells by performing magnetic-activated cell sorting. The tumor sphere formation, cell cycle distribution, stemness marker expression, and multidifferentiation potential of the CD44- cells and the CSLCs were analyzed. RESULTS: Compared with the CD44- cells, the cultured human CSLCs formed tumor spheres and expressed CD44 and CD133; moreover, these cells demonstrated nuclear translocation of ß-catenin. In addition, the CSLCs demonstrated osteogenic and adipogenic differentiation capacities compared with the CD44- cells. The CSLCs also displayed the capacity for tumor initiation in human-mouse xenografts. CONCLUSIONS: These results indicate that CSLCs play an important role in ACP development, calcification, and cystic degeneration.

LncRNA SNHG6 functions as a ceRNA to regulate neuronal cell apoptosis by modulating miR-181c-5p/BIM signalling in ischaemic stroke.

Long non-coding RNAs (lncRNAs) play important roles in the pathogenesis of brain and neurodegenerative disorders. As far as we know, the functions and potential mechanisms of small nucleolar RNA host gene 6 (SNHG6) in ischaemic stroke have not been explored. This study aimed to examine the functional role of SNHG6 in the ischaemic stroke. Middle cerebral artery occlusion (MCAO) in mice and the oxygen glucose deprivation (OGD)-induced injury in neuronal cells were applied to mimic ischaemic stroke. TTC staining, quantitative real-time PCR, cell apoptosis assay, caspase-3 activity assay, Western blot, RNA immunoprecipitation and luciferase reporter assay were performed to evaluate the function and possible mechanisms of SNHG6 in the pathogenesis of ischaemic stroke. The results show that SNHG6 expression was significantly increased both OGD-induced neuronal cells and MCAO model mice. In vitro results showed that inhibition of SNHG6 increased cell viability, inhibited cell apoptosis and caspase-3 activity in OGD-induced neuronal cells. Consistently, knockdown of SNHG6 reduced brain infarct size and improved neurological scores in the MCAO mice. Mechanistic study further revealed that SNHG6 functioned as a competing endogenous RNA (ceRNA) for miR-181c-5p, which in turn repressed its downstream target of Bcl-2 interacting mediator of cell death (BIM) and inhibiting cell apoptosis. This study revealed a novel function of SNHG6 in the modulating neuronal apoptosis in the ischaemic stroke model, and the role of SNHG6 in the regulating of neuronal apoptosis was at least partly via targeting miR-181c-5p/BIM signalling pathway.

Acquired temozolomide resistance in MGMT-deficient glioblastoma cells is associated with regulation of DNA repair by DHC2.

The acquisition of temozolomide resistance is a major clinical challenge for glioblastoma treatment. Chemoresistance in glioblastoma is largely attributed to repair of temozolomide-induced DNA lesions by O6-methylguanine-DNA methyltransferase (MGMT). However, some MGMT-deficient glioblastomas are still resistant to temozolomide, and the underlying molecular mechanisms remain unclear. We found that DYNC2H1 (DHC2) was expressed more in MGMT-deficient recurrent glioblastoma specimens and its expression strongly correlated to poor progression-free survival in MGMT promotor methylated glioblastoma patients. Furthermore, silencing DHC2, both in vitro and in vivo, enhanced temozolomide-induced DNA damage and significantly improved the efficiency of temozolomide treatment in MGMT-deficient glioblastoma. Using a combination of subcellular proteomics and in vitro analyses, we showed that DHC2 was involved in nuclear localization of the DNA repair proteins, namely XPC and CBX5, and knockdown of either XPC or CBX5 resulted in increased temozolomide-induced DNA damage. In summary, we identified the nuclear transportation of DNA repair proteins by DHC2 as a critical regulator of acquired temozolomide resistance in MGMT-deficient glioblastoma. Our study offers novel insights for improving therapeutic management of MGMT-deficient glioblastoma.

Utility of CT assessment in hematology patients with invasive aspergillosis: a post-hoc analysis of phase 3 data.

BACKGROUND: Pulmonary computed tomography (CT) scans are commonly used as part of the clinical criteria in diagnostic workup of invasive fungal diseases like invasive aspergillosis, and may identify radiographic abnormalities, such as halo signs or air-crescent signs. We assessed the diagnostic utility of CT assessment in patients with hematologic malignancies or those who had undergone allogeneic hematopoietic stem cell transplantation in whom invasive aspergillosis was suspected. METHODS: This post-hoc analysis assessed data from a prospective, multicenter, international trial of voriconazole (with and without anidulafungin) in patients with suspected invasive aspergillosis (IA; proven, probable, or possible, using 2008 European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria) [NCT00531479]. Eligible patients received at least one baseline lung CT scan. RESULTS: Of 395 patients included in this post-hoc analysis, 240 patients (60.8%) had 'confirmed' proven (9/240, 3.8%) or probable (231/240, 96.3%) invasive aspergillosis (cIA) and 155 patients (39.2%) had 'non-confirmed' invasive aspergillosis (all nIA; all possible IA (de Pauw et al., Clin Infect Dis 46:1813-21, 2008)). Mean age was 52.3 and 50.5 years, 56.3 and 60.0% of patients were male, and most patients were white (71.7 and 71.0%) in the cIA and nIA populations, respectively. Median baseline galactomannan was 1.4 (cIA) and 0.2 (nIA), mean Karnofsky score was 65.3 (cIA) and 66.8 (nIA), and mean baseline platelet count was 48.0 (cIA) and 314.1 (nIA). Pulmonary nodules (46.8% of all patients), bilateral lung lesions (37.5%), unilateral lung lesions (28.4%), and consolidation (24.8%) were the most common radiographic abnormalities. Ground-glass attenuation (cIA: 24.2%; nIA: 11.6%; P < 0.01) and pulmonary nodules (cIA: 52.5%; nIA: 38.1%; P < 0.01) were associated with cIA. Other chest CT scan abnormalities (including halo signs and air-crescent signs) at baseline in patients with hematologic malignancy or hematopoietic stem cell transplantation, and suspected IA, were not associated with cIA. CONCLUSIONS: These findings highlight the limitations in the sensitivity of chest CT scans for the diagnosis of IA, and reinforce the importance of incorporating other available clinical data to guide management decisions on individual patients, including whether empirical treatment is reasonable, pending full evaluation. TRIAL REGISTRATION: NCT00531479 (First posted on ClinicalTrials.gov on September 18, 2007).

Pathological Relationship Between Adamantinomatous Craniopharyngioma and Adjacent Structures Based on QST Classification.

The aim of this study was to clarify pathological and anatomical relationships between adamantinomatous craniopharyngiomas (ACP) and their surrounding structures. We previously established a QST classification scheme based on the apparent anatomic origin of the tumors. According to this classification, 13 type Q tumors, 6 type S tumors, and 42 type T ACPs were analyzed. Type Q tumors, which are most likely to involve the pituitary gland, did not invade the area of contact with the adenohypophysis. Instead, tumor invasion was observed in areas where the tumor contacted the neurohypophysis. Type S tumors primarily involved the pituitary stalk; the arachnoid remained present between these tumors and normal structures. Type T tumors were located beneath the basal arachnoid membrane and outside the pia mater. The pia mater was disrupted and finger-like invasions were found in the neural layer of the third ventricle floor along the invasive front. Tumors were never observed to break through the ependymal layer of the third ventricle. The QST classification has important implications for understanding the growth pattern of tumors and can be used to guide surgical procedures.