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.

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.

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.

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.

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.

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.

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).

Risk score for the prediction of severe obesity in pediatric craniopharyngiomas: relative to tumor origin.

BackgroundWe aimed to develop a risk score to improve the prediction of severe obesity in pediatric craniopharyngiomas (PCs).MethodsOverall, 612 consecutive PCs were prospectively enrolled from six hospitals. Data from 404 participants were analyzed. Participants from three of the six hospitals (n=290) were used to develop a risk score. External validation of the developed risk score was conducted using the participants from the other three hospitals (n=114). Sequential logistic regression was used to develop and validate the risk score. The c statistic and a calibration plot were used to assess the discrimination and calibration of the proposed risk score.ResultsThe overall frequency of severe obesity was 16.1% (65/404). The risk score employed a scale of 0-16 and demonstrated good discriminative power, with an optimism-corrected c statistic of 0.820. Similar results were obtained from external validation, with a c statistic of 0.821. The risk score showed good calibration, with no apparent over- or under-prediction observed in the calibration plots.ConclusionsThis novel risk score is a simple tool that can help clinicians assess the risk of severe obesity in PCs, thereby helping to plan and initiate the most appropriate disease management for these patients in time.

Preliminary Study on Composition and Microstructure of Calcification in Craniopharyngiomas.

To analyze the element composition and microstructure of calcification in craniopharyngiomas and to explore the differences among differing degrees of calcification, 50 consecutive patients with craniopharyngioma were selected. X-ray diffraction analysis and energy-dispersive X-ray spectroscopy analysis were performed on the calcified plaques isolated from the tumor specimens. All calcified plaques were constituted of hydroxyapatite crystals and some amorphous materials. The main elements for the analysis were calcium, phosphate, carbon, and oxygen. There were significant differences among groups of differing degrees of calcification in the percentage composition of calcium, phosphorus, and carbon (P < 0.05), in which the element content of calcium and phosphorus had a positive correlation with the extent of calcification (rp = 0.745 and 0.778, respectively, P < 0.01), while the element content of carbon had a negative correlation with the extent of calcification (rp =-0.526, P <0.01). The calcium, phosphorus, and carbon content are different in calcified plaques with different extents of calcification. The element content of calcium, phosphorus, and carbon influences the degree of calcification.

Alpha-enolase as a potential cancer prognostic marker promotes cell growth, migration, and invasion in glioma.

BACKGROUND: The success of using glycolytic inhibitors for cancer treatment relies on better understanding the roles of each frequently deregulated glycolytic genes in cancer. This report analyzed the involvement of a key glycolytic enzyme, alpha-enolase (ENO1), in tumor progression and prognosis of human glioma. METHODS: ENO1 expression levels were examined in glioma tissues and normal brain (NB) tissues. The molecular mechanisms of ENO1 expression and its effects on cell growth, migration and invasion were also explored by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, Transwell chamber assay, Boyden chamber assay, Western blot and in vivo tumorigenesis in nude mice. RESULTS: ENO1 mRNA and protein levels were upregulated in glioma tissues compared to NB. In addition, increased ENO1 was associated disease progression in glioma samples. Knocking down ENO1 expression not only significantly decreased cell proliferation, but also markedly inhibited cell migration and invasion as well as in vivo tumorigenesis. Mechanistic analyses revealed that Cyclin D1, Cyclin E1, pRb, and NF-κB were downregulated after stable ENO1 knockdown in glioma U251 and U87 cells. Conversely, knockdown of ENO1 resulted in restoration of E-cadherin expression and suppression of mesenchymal cell markers, such as Vimentin, Snail, N-Cadherin, ß-Catenin and Slug. Furthermore, ENO1 suppression inactivated PI3K/Akt pathway regulating the cell growth and epithelial-mesenchymal transition (EMT) progression. CONCLUSION: Overexpression of ENO1 is associated with glioma progression. Knockdown of ENO1 expression led to suppressed cell growth, migration and invasion progression by inactivating the PI3K/Akt pathway in glioma cells.

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

HDGF is overexpressed in gliomas as compared to normal brain. We therefore analyzed the molecular mechanisms of HDGF action in gliomas. HDGF was downregulated in normal brain tissue as compared to glioma specimens at both the mRNA and the protein levels. In glioma samples, increased HDGF expression was associated with disease progression. Knocking down HDGF expression not only significantly decreased cellular proliferation, migration, invasion, and tumorigenesis, but also markedly enhanced TMZ-induced cytotoxicity and apoptosis in glioma cells. Mechanistic analyses revealed that CCND1, c-myc, and TGF-ß were downregulated after stable HDGF knockdown in the U251 and U87 glioma cells. HDGF knockdown restored E-cadherin expression and suppressed mesenchymal cell markers such as vimentin, ß-catenin, and N-cadherin. The expression of cleaved caspase-3 increased, while Bcl-2 decreased in each cell line following treatment with shHDGF and TMZ, as compared to TMZ alone. Furthermore, RNAi-based knockdown study revealed that HDGF is probably involved in the activation of both the PI3K/Akt and the TGF-ß signaling pathways. Together, our data suggested that HDGF regulates glioma cell growth, apoptosis and epithelial-mesenchymal transition (EMT) probably through the Akt and the TGF-ß signaling pathways. These results provide evidence that targeting HDGF or its downstream targets may lead to novel therapies for gliomas.

Radical resection of nongerminomatous pineal region tumors via the occipital transtentorial approach based on arachnoidal consideration: experience on a series of 143 patients.

BACKGROUND: The role of radical resection for nongerminomatous pineal region tumors is still controversial. The purpose of this study was to present the surgical results in a large series and evaluate the feasibility of radical surgical strategy. METHODS: We retrospectively reviewed the records of 143 patients with nongerminomatous pineal region tumors surgically treated via an occipital transtentorial approach between 2000 and 2011. The tumor was small (<2 cm) in 14.7 % of patients, medium (2-4 cm) in 52.4 %, and large (>4 cm) in 32.9 %. RESULTS: Gross total tumor removal was achieved in 91.6 % of patients, subtotal in 7.0 %, and partial in 1.4 %. Histological diagnosis was nongerminomatous germ cell tumor in 41.3 %, pineal parenchymal tumor in 14.7 %, glial tumors in 28.7 %, and miscellaneous in 15.4 %. The overall complication and mortality rate was 18.2 % and 0.7 %, respectively. Permanent morbidity occurred in 5.6 % of patients, including hemianopsia in 3.5 % and Parinaud syndrome in 2.1 %. Hydrocephalus was resolved in 82.1 % without surgery for the CSF diversion. Sixty-eight patients with malignant tumors underwent radiotherapy; 35 also received adjuvant chemotherapy. One hundred thirty patients were successfully followed up with a mean duration of 43 months. Finally, 86.9 % of the patients achieved a favorable functional outcome (mRS ≤ 2), 3.1 % had an mRS score of 3, 1.5 % had an mRS score of 4, and 8.5 % had died (mRS = 6). CONCLUSIONS: Radical surgery was recommended as the optimal treatment for nongerminomatous pineal region tumors. Favorable results could be achieved by experienced neurosurgeons. Hydrocephalus could be cured by radical tumor removal in the majority of cases. The occipital transtentorial approach was indicated for most pineal region tumors, but surgeon's preference and experience should also be considered. New understanding of the arachnoid membranes of this region may be helpful for tumor resection.

Topographic variations of the optic chiasm and the pituitary stalk: a morphometric study based on midsagittal T2-weighted MR images.

PURPOSE: This study was conducted to characterize topographic variations of the optic chiasm (OC) and the pituitary stalk (PS) in situ based on MR images. METHODS: Normal T2-weighted midsagittal MR images were obtained in 157 children and 323 adults. The height of OC (PC) and the inclination angle of PS (PS-AP angle) were measured in each case. All chiasms were classified into prefixed, normal and postfixed types, and low, medium and high types, respectively. All stalks were performed classification (prefixed, centered and postfixed PS) and grading (Grade 1-3 according to the relationship between PS and the dorsum sellae), respectively. RESULTS: PC averaged 4.33 ± 1.59 mm. Adults had a greater PC (P = 0.023) than children. There were 80 (16.7 %) prefixed, 354 (73.8 %) normal and 46 (9.6 %) postfixed chiasms, and 112 (23.3 %), 295 (61.5 %) and 73 (15.2 %) cases with low, medium and high OC, respectively. High OC was more frequent in adults than in children (P = 0.001). The mean PS-AP angle of the whole group was 59.47 ± 8.62º. Children had a greater PS-AP angle than adults (P = 0.012). Adults had a greater percentage of postfixed (P = 0.000) and grade 3 (P = 0.000) PS than children, whereas centered (P = 0.002) and grade 1 (P = 0.001) PS were more prevalent in children than in adults. CONCLUSIONS: The classifications of OC and PS based on MR images reflect the topographic variations of their real position in vivo. It would be helpful to identify and characterize the anomalies involving OC and PS and understand the anatomical and physiological influence in pathological situations.

The Relationship Between Jugular Foramen Schwannoma and Surrounding Membrane Structures and Its Surgical Application.

BACKGROUND AND OBJECTIVES: Surgical resection of jugular foramen (JF) schwannomas with minimal neurological complications is challenging because of their difficult-to-access location and complex relationships with surrounding neurovascular structures, even for experienced neurosurgeons. In this article, we elucidate the membranous anatomy of JF schwannomas, with the aim of reducing iatrogenic injury to the lower cranial nerves (LCNs) during surgery. METHODS: The clinical data of 31 consecutive patients with JF schwannomas were reviewed. The relationship between the tumor and the surrounding membranous structures was observed during dissection. Samples were analyzed using Masson's trichrome and immunofluorescence staining to study the membranous characteristics. Histological-radiographic correlations were also summarized. RESULTS: In this series, we found that all 3 type B, 2 type C, and 8 type D tumors (according to the Kaye-Pellet grading system) were entirely extradural in location, whereas the 18 type A tumors could be subdural (9 cases) or extradural (9 cases), which frequently could not be predicted preoperatively based on whether the tumor had intraforaminal extension. The dural capsule, when present, could be used as an insulating layer to protect LCNs. With this subcapsular dissection technique, postoperative LCN dysfunction occurred in 10 patients (32.3%), which was usually temporary and mild. CONCLUSION: The different relationships between the tumor and membranous structures of the JF is related to the distinct point of tumor origin and the complex anatomy of the meningeal dura within the JF. Subcapsular dissection technique is recommended for better preservation of LCNs when the dural capsule is identified.

Downregulation of miR-130a contributes to cisplatin resistance in ovarian cancer cells by targeting X-linked inhibitor of apoptosis (XIAP) directly.

MicroRNAs (miRNAs) are short, highly conserved small non-coding RNA molecules, which post-transcriptionally regulate genes expression and play crucial roles in diverse biological processes. Recent studies have shown that dysregulation of miRNAs might modulate the resistance of cancer cells to chemotherapeutic agents. To investigate the possible role of miR-130a in the development of cisplatin resistance in human ovarian cancer cell line A2780, we evaluated the expression of microRNA-130a (miR-130a) in the cells by the quantitative real-time reverse transcription-polymerase chain reaction. The results showed that miR-130a was significantly down-regulated in cisplatin-resistant ovarian cancer cells. MTT assay and flow cytometry (FCM) results showed that over-expression of miR-130a regulated apoptotic activity, and thereby cisplatin chemosensitivity, in ovarian cancer cells. Furthermore, we found that miR-130a can directly target XIAP, and participate in the regulation of apoptosis. The up-regulation of miR-130a led to a significant decrease in the XIAP mRNA levels and protein levels. XIAP plays an important role in cisplatin resistance in ovarian cancer cell line A2780. Our findings suggested that miR-130a could play a role in the development of cisplatin resistance in ovarian cancer cell line A2780, at least in part by modulation of apoptosis via targeting XIAP.

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.

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.

The impact of the site of origin and rate of tumour growth on clinical outcome in children with craniopharyngiomas.

OBJECTIVES: Data on many predictors of hypothalamic-pituitary axis dysfunction associated with childhood craniopharyngioma (CP) are rather inconsistent, probably reflecting the variable but as yet unclarified growth pattern of these tumours. The aim of this study was to define the determinative role of tumour growth pattern on hypothalamic-pituitary axis function and outcomes for childhood CPs. PATIENTS AND METHODS: The authors retrospectively analysed the records of 81 consecutive children with primary CP who underwent a uniform treatment paradigm of attempted radical resection performed by a single surgeon. The patients were divided into two subgroups based on tumour location and growth patterns: group A (infra-diaphragmatic sellar tumours: 34 cases) and group B [third ventricular floor (3rd VF) tumours: 47 cases]. The children's pre- and postsurgical endocrinological and hypothalamic disturbances were compared. Pituitary function and hypothalamic statues were quantitatively assessed using classification systems proposed in the previous studies. RESULTS: Preoperative pituitary function was more severely compromised in patients in group A than those in group B and deteriorated significantly following resection in both groups. (Average pituitary function scores increased from 2·19 ± 0·83 to 3·31 ± 0·74, P < 0·001). At the last follow-up, children with 3rd VF tumours had more prevalent weight gain (median body mass index: 23·1 kg/m(2) in group B vs 19·7 kg/m(2) in group A, P < 0·001) and increased hypothalamic dysfunction (average hypothalamic status scores: 2·04 ± 0·97 in group B vs 1·29 ± 0·57 in group A, P < 0·001). Children with 3rd VF tumours had a significantly lower probability of recurrence-free survival than those with sellar tumours (at 5 years: 74%vs 49%, respectively; at 10 years: 66%vs 32%, respectively; P = 0·02). CONCLUSIONS: Substantial differences in the outcome of childhood CP with different tumour growth patterns and locations were found, which suggested that diverse therapeutic considerations, especially endocrinological substitution, might be emphasized.