Impact of metabolic syndrome on postoperative outcomes of transsphenoidal pituitary surgery: analysis of U.S. nationwide inpatient sample data 2005-2018.

Introduction: Transsphenoidal surgery (TSS) is the preferred surgical method for most pituitary adenomas owing to high efficacy and low mortality. This study aimed to evaluate the influence of metabolic syndrome (MetS) on postoperative outcomes of TSS for pituitary adenoma. Methods: This population-based, retrospective observational study extracted data of adults 20-79 y receiving TSS for pituitary adenoma from the US Nationwide Inpatient Sample (NIS) between 2005-2018. Primary outcomes were pituitary-related complications, poor outcomes (i.e., in-hospital mortality or unfavorable discharge), prolonged length of stay (LOS), and patient safety indicators (PSIs). Univariate and multivariate regressions were performed to determine the associations between study variables and outcomes. Results: 19,076 patients (representing a 93,185 US in-patient population) were included, among which 2,109 (11.1%) patients had MetS. After adjustment, pre-existing MetS was not significantly associated with presence of pituitary-related complications and poor outcomes. In contrast, MetS was significantly associated with an increased risk for prolonged LOS (adjusted OR (aOR) = 1.19; 95% CI: 1.05-1.34), PSIs (aOR = 1.31; 95% CI: 1.07-1.59) and greater hospital costs (adjusted ß = 8.63 thousand USD; 95% CI: 4.98-12.29). Among pituitary-related complications, MetS was independently associated with increased risk of cerebrospinal fluid (CSF) rhinorrhea (aOR = 1.22, 95% CI: 1.01, 1.47) but lowered diabetes insipidus (aOR = 0.83, 95% CI: 0.71, 0.97). Discussion: MetS does not pose excessive risk of in-hospital mortality or unfavorable discharge. However, MetS independently predicted having PSIs, prolonged LOS, greater hospital costs, and CSF rhinorrhea. Study findings may help clinicians achieve better risk stratification before TSS.

Psoriatic arthritis increases the risk of venous thromboembolism following degenerative lumbar spine surgery: An analysis of U.S. Nationwide Inpatient Sample 2005-2018.

Background: This retrospective study aimed to determine the risk of venous thromboembolism (VTE) in patients with PsA after surgery for lumbar degenerative disease (LDD). Methods: The study data of adults aged ≥20 years admitted to U.S. hospitals with diagnoses of LDD and undergoing spinal decompression or fusion between 2005 and 2018 were extracted from the National Inpatient Sample (NIS) database. Patients were further divided into two groups based on a diagnosis of PsA or not via codes ICD-9: 696.0 and ICD-10: L40.50. Patients with missing information were excluded. Propensity score matching (PSM) was employed to enhance comparability between groups. Logistic regression was used to determine associations between PsA and various outcomes, including complications, unfavorable discharge, and prolonged length of stay (LOS). Results: Data on 471,283 patients with LDD was extracted from the NIS database.from 2005 to 2018. Before propensity score matching, patients with PsA had higher proportions of overall morbidity (8.8 % vs. 6.9 %), VTE (1.4 % vs. 0.7 %), and unfavorable discharge (20.8 % vs. 16.9 %). After matching, patients with PsA still had higher VTE incidence and unfavorable discharge proportions. After adjustments, multivariable regression analysis indicated that patients with PsA had a higher risk of unfavorable discharge (aOR: 1.26, 95 % CI: 1.03-1.55) and VTE (aOR: 1.99, 95 % CI: 1.05-3.75). Conclusions: Among patients undergoing surgery for LDD, pre-existing PsA may be associated with increased risks of unfavorable discharge and VTE occurrence. The findings may benefit preoperative risk stratifications before LDD surgeries.

Psychometric properties and structural validity of traditional Chinese version of the Richards-Campbell Sleep Questionnaire in intensive care unit patients without physical restraint.

BACKGROUND: Sleep assessment in the intensive care unit (ICU) is difficult and often unreliable. The most commonly used questionnaire for assessing ICU sleep, the Richards-Campbell Sleep Scale (RCSQ), has not been tested for reliability and construct validity in the Mandarin-Taiwanese speaking population. OBJECTIVE: The objective of this study was to test the construct validity and criterion validity of the traditional Chinese version of RCSQ (TC-RCSQ) in critically ill patients without physical restraint. METHODS: We adopted a cross-sectional study design. Adults aged 20 years and above were recruited from a plastic surgery ICU of a medical center. The Cronbach's alpha was used to test internal consistency; the validity testing included content validity, criterion validity, and construct validity. Criterion validity was analysed by testing the association of TC-RCSQ with the Chinese version of Verran and Snyder-Halpern Sleep Questionnaire and sleep parameter of actigraphy using the Pearson correlation coefficient; construct validity was analysed using exploratory factor analysis. RESULTS: A total of 100 patients were included with a mean age of 49.78 years. Internal consistency reliability suggested Cronbach's alpha of 0.93. Moderate to strong correlations of TC-RCSQ with Verran-Snyder-Halpern Sleep Questionnaire were identified (r = 0.36 to 0.80, P < 0.05). We found significant correlations of actigraphic sleep efficiency with difficulty of falling sleep, awakening times, sleep quality, and total score of the TC-RCSQ (r = 0.23, 0.23, 0.20, and 0.23, P < 0.05). One factor (named as overall sleep quality) was extracted by exploratory factor analysis with a total variance explained of 78.40 %, which had good construction validity. CONCLUSIONS: The TC-RCSQ yields satisfactory reliability and validity in critically ill patients. Actigraphic sleep efficiency may be a single index for objectively sleep assessment of sleep quality in patients without physical restraint. Both the TC-RCSQ and actigraphy can aid nurses to evaluate the sleep quality in critically ill patients without physical restraint.

Predictors for delayed awakening in adult glioma patients receiving awake craniotomy under monitored anesthesia care.

PURPOSE: Delayed awakening after anesthetic discontinuation during awake craniotomy is associated with somnolence during functional brain mapping. However, predictors of delayed awakening in patients receiving monitored anesthesia care for awake craniotomy are unknown. METHODS: This retrospective cohort study analyzed 117 adult patients with supratentorial glioma in or near eloquent areas who received monitored anesthesia care for awake craniotomy between July 2020 and January 2023 at Linkou Chang Gung Memorial Hospital. These patients were divided into two groups according to their time to awakening (ability to speak their names) after propofol cessation: longer or shorter than 20 min (median duration). Because propofol was solely used anesthetic from skin incision to dural opening, parameters in Schnider model for propofol target-controlled infusion, such as age, sex, and BMI, were adjusted or propensity-matched to compare their anesthetic, surgical, and histopathological profiles. RESULTS: After propensity-matched comparisons of age and BMI, significant predictors of delayed awakening included IDH1 wild-type tumors and repeated craniotomies. Subgroup analysis revealed that older age and larger T2 volume were predictors in patients undergoing the first craniotomy, while lower preoperative Karnofsky performance scale scores and depression were predictors in repeated craniotomy cases. Delayed awakening was also associated with somnolence and a lower gross total resection rate. CONCLUSION: Our retrospective analysis of patients receiving monitored anesthesia care for awake craniotomy revealed that delayed awakening after propofol discontinuation occurred more often in patients with IDH1 wild-type tumors and repeated craniotomies. Also, delayed awakening was associated with somnolence during functional mapping and a lower gross total resection rate.

Neuropsychological impairment in primary malignant brain tumor patients with awake craniotomy: a hospital-based registration study.

PURPOSE: Neuroplasticity is an ability to maintain neural circuit function when facing damages. It is one of the reasons that making brain tumors notorious. Therefore, we evaluated the characteristics of patients with primary brain tumors, compared neuropsychological deficits between patients who had awake craniotomy with left- or right-sided tumors, and analyzed the association between white matter tracts and neuropsychological deficits in patients with right-sided tumors. METHODS: Using the registration dataset of Chang Gung Memory Hospital between 2014 and 2020, this study included a total of 698 adult patients who received craniotomy for primary brain tumors (538 of conventional craniotomy; 160 of awake craniotomy). Neuropsychological assessments were arranged in patients as preoperative evaluation for awake craniotomies. RESULTS: A lower proportion of right-sided tumors was noted in patient who had awake craniotomy than those who had conventional craniotomy (33.8% and 51.5%, p < 0.001). In awake craniotomy, 88.7% of patients with left-sided tumors and 77.8% of patients with right-sided tumors had neuropsychological impairment. Patients with left-sided tumors had worse preoperative performance compared to those with right-sided tumors in global function (36.2% and 8.0%, p < 0.001), language domain (57.6% and 22.2%, p < 0.001), and attention (36.0% and 18.5%, p = 0.02). Furthermore, in those with right-sided low-grade gliomas, patients involving pathway of superior longitudinal fasciculus (SLF) I had a higher risk of deficits than those without involvement in verbal memory (p = 0.001, Odd ratio = 11.2, 95% CI = 1.8 ~ 71.4) and visual memory (p = 0.048, Odd ratio = 10.5, 95% CI = 1.0 ~ 111). CONCLUSION: In awake craniotomy, patients with left-sided brain tumors had worse cognitive function than those with right-sided tumors in terms of global function, language, and attention. 77% of patients with right-sided tumors had neuropsychological impairment. Therefore, a comprehensive neuropsychological evaluation and awake craniotomy are necessary for patients with brain tumors.

Acrolein produced by glioma cells under hypoxia inhibits neutrophil AKT activity and suppresses anti-tumoral activities.

Acrolein, which is the most reactive aldehyde, is a byproduct of lipid peroxidation in a hypoxic environment. Acrolein has been shown to form acrolein-cysteine bonds, resulting in functional changes in proteins and immune effector cell suppression. Neutrophils are the most abundant immune effector cells in circulation in humans. In the tumor microenvironment, proinflammatory tumor-associated neutrophils (TANs), which are termed N1 neutrophils, exert antitumor effects via the secretion of cytokines, while anti-inflammatory neutrophils (N2 neutrophils) support tumor growth. Glioma is characterized by significant tissue hypoxia, immune cell infiltration, and a highly immunosuppressive microenvironment. In glioma, neutrophils exert antitumor effects early in tumor development but gradually shift to a tumor-supporting role as the tumor develops. However, the mechanism of this anti-to protumoral switch in TANs remains unclear. In this study, we found that the production of acrolein in glioma cells under hypoxic conditions inhibited neutrophil activation and induced an anti-inflammatory phenotype by directly reacting with Cys310 of AKT and inhibiting AKT activity. A higher percentage of cells expressing acrolein adducts in tumor tissue are associated with poorer prognosis in glioblastoma patients. Furthermore, high-grade glioma patients have increased serum acrolein levels and impaired neutrophil functions. These results suggest that acrolein suppresses neutrophil function and contributes to the switch in the neutrophil phenotype in glioma.

Vascular risk factors and astrocytic marker for the glymphatic system activity.

OBJECTIVES: Glymphatic system maintains brain fluid circulation via active transportation of astrocytic aquaporin-4 in perivascular space. The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) is an established method measuring perivascular glymphatic activity, but comprehensive investigations into its influential factors are lacking. METHODS: Community-dwelling older adults underwent brain MRI scans, neuropsychiatric, and multi-domain assessments. Blood biomarker tests included glial fibrillary acidic protein (GFAP) for astrocyte injury. RESULTS: In 71 enrolled participants, the DTI-ALPS index was associated with modifiable factors, including lipid profile (high-density lipoprotein, r = 0.396; very-low-density lipoprotein, r = - 0.342), glucose intolerance (diabetes mellitus, standardized mean difference (SMD) = 0.7662; glycated hemoglobin, r = - 0.324), obesity (body mass index, r = - 0.295; waist, r = - 0.455), metabolic syndrome (SMD = - 0.6068), cigarette-smoking (SMD = - 0.6292), and renal clearance (creatinine, r = - 0.387; blood urea nitrogen, r = - 0.303). Unmodifiable associative factors of DTI-ALPS were age (r = - 0.434) and sex (SMD = 1.0769) (all p < 0.05). A correlation of DTI-ALPS and blood GFAP was noticed (r = - 0.201, one-tailed t-test for the assumption that astrocytic injury impaired glymphatic activity, p = 0.046). Their cognitive correlations diverged, domain-specific for DTI-ALPS (Facial Memory Test, r = 0.272, p = 0.022) but global cognition-related for blood GFAP (MoCA, r = - 0.264, p = 0.026; ADAS-cog, r = 0.304, p = 0.010). CONCLUSION: This correlation analysis revealed multiple modifiable and unmodifiable association factors to the glymphatic image marker. The DTI-ALPS index correlated with various metabolic factors that are known to increase the risk of vascular diseases such as atherosclerosis. Furthermore, the DTI-ALPS index was associated with renal indices, and this connection might be a link of water regulation between the two systems. In addition, the astrocytic biomarker, plasma GFAP, might be a potential marker of the glymphatic system; however, more research is needed to confirm its effectiveness.

Augmented Reality Surgical Navigation System Integrated with Deep Learning.

Most current surgical navigation methods rely on optical navigators with images displayed on an external screen. However, minimizing distractions during surgery is critical and the spatial information displayed in this arrangement is non-intuitive. Previous studies have proposed combining optical navigation systems with augmented reality (AR) to provide surgeons with intuitive imaging during surgery, through the use of planar and three-dimensional imagery. However, these studies have mainly focused on visual aids and have paid relatively little attention to real surgical guidance aids. Moreover, the use of augmented reality reduces system stability and accuracy, and optical navigation systems are costly. Therefore, this paper proposed an augmented reality surgical navigation system based on image positioning that achieves the desired system advantages with low cost, high stability, and high accuracy. This system also provides intuitive guidance for the surgical target point, entry point, and trajectory. Once the surgeon uses the navigation stick to indicate the position of the surgical entry point, the connection between the surgical target and the surgical entry point is immediately displayed on the AR device (tablet or HoloLens glasses), and a dynamic auxiliary line is shown to assist with incision angle and depth. Clinical trials were conducted for EVD (extra-ventricular drainage) surgery, and surgeons confirmed the system's overall benefit. A "virtual object automatic scanning" method is proposed to achieve a high accuracy of 1 ± 0.1 mm for the AR-based system. Furthermore, a deep learning-based U-Net segmentation network is incorporated to enable automatic identification of the hydrocephalus location by the system. The system achieves improved recognition accuracy, sensitivity, and specificity of 99.93%, 93.85%, and 95.73%, respectively, representing a significant improvement from previous studies.

The impact of patient factors and tumor characteristics on language neuroplasticity in left hemispheric diffuse gliomas prior to surgical resection.

PURPOSE: Language networks are reorganized during glioma growth, leading to varying language performance in patients with gliomas located in or around language-eloquent areas. Therefore, pre-treated language performance reflects the neuroplasticity potential. Different domains of language processing, such as speech expression, repetition, and comprehension, involving different neural networks. We analyzed the effects of patient factors and tumor characteristics on the pre-treated performance to investigate neuroplastic potential of different language domains. METHODS: Patient age, sex, education level, tumor grade, language pathway involvement, T1 contrast enhanced (C+), and FLAIR (T2) volume were selected as variables. The correlation with abnormal language performance was verified using univariate and multivariate logistic regression. RESULTS: In total, 104 left hemispheric glioma patients were enrolled in this study. 44% of patients had repetitive abnormalities, 34.9% had comprehensive abnormalities, and 32.1% had expressive abnormalities. The proportion of normal language performance was 60% in grade 2 and 3 gliomas and 16% in grade 4 gliomas. Tumor grade (p = 0.006) and T2 volume (p = 0.008) were associated with abnormal performance in the expressive domain, education level (p = 0.004) and T1 C+ volume (p = 0.049) in the repetitive domain, and education level (p = 0.013), T2 volume (p = 0.011), and tumor grade (p = 0.089) in the comprehensive domain. CONCLUSION: Different clinical and radiological factors affected the abnormal performance of the three language domains, indicating their functional connectivity and neuroplastic potential are inherently varied. The dynamic interactions between patient factors, tumor characteristics, and language processing should be considered when resecting left hemispheric gliomas.

Bioengineered Bacteriophage-Like Nanoparticles as RNAi Therapeutics to Enhance Radiotherapy against Glioblastomas.

Since glioblastomas (GBMs) are radioresistant malignancies and most GBM recurrences occur in radiotherapy, increasing the effectiveness of radiotherapy by gene-silencing has recently attracted attention. However, the difficulty in precisely tuning the composition and RNA loading in nanoparticles leads to batch-to-batch variations of the RNA therapeutics, thus significantly restricting their clinical translation. Here, we bioengineer bacteriophage Qß particles with a designed broccoli light-up three-way junction (b-3WJ) RNA scaffold (contains two siRNA/miRNA sequences and one light-up aptamer) packaging for the silencing of genes in radioresistant GBM cells. The in vitro results demonstrate that the cleavage of de novo designed b-3WJ RNA by Dicer enzyme can be easily monitored in real-time using fluorescence microscopy, and the TrQß@b-3WJLet-7gsiEGFR successfully knocks down EGFR and IKKα simultaneously and thereby inactivates NF-κB signaling to inhibit DNA repair. Delivery of TrQß@b-3WJLet-7gsiEGFR through convection-enhanced delivery (CED) infusion followed by 2Gy X-ray irradiation demonstrated that the median survival was prolonged to over 60 days compared with the 2Gy X-ray irradiated group (median survival: 31 days). Altogether, the results of this study could be critical for the design of RNAi-based genetic therapeutics, and CED infusion serves as a powerful delivery system for promoting radiotherapy against GBMs without evidence of systemic toxicity.

Sensory Symptoms and Effects on Health-related Quality of Life of Patients Undergoing Lumbar Spine Surgery.

BACKGROUND: Patients with lumbar degenerative spine diseases (LDSDs) commonly report sensory symptoms before and after lumbar spine surgery. AIM: To explore the changing patterns of sensory symptoms-namely pain, numbness, stinging, itching, and burning-and investigate the influences of sensory symptom changes on the health-related quality of life (HRQoL) of patients who experienced lumbar spine surgery. METHODS: All sensory symptoms (i.e., pain, numbness, paresthesia) were measured using a visual analog scale. The Chinese versions of the Oswestry Disability Index, Pittsburgh Sleep Quality Index, Clinically Useful Depression Outcome Scale, and EuroQol-five dimensions (EQ-5D) Scale were used to assess patients 1 week prior to surgery and 6 weeks and 6 months after surgery. A generalized estimating equation was used for data analysis. RESULTS: A total of 101 patients with mean age of 58.38 years were included. All sensory symptoms declined significantly over time (all p < .05) with the exception of itching (feeling on toes and thighs). Patients experiencing moderate-to-severe pain had poorer QoL over time, even after controlling for other sensory symptoms and potential confounders. CONCLUSIONS: Sensory symptoms gradually declined after surgery, but itching symptom did not. Moderate-to-severe pain was the only sensory symptom that influenced HRQoL over time in patients with LDSDs.

Outcome predictors and clinical presentation of syringomyelia.

BACKGROUND: The prognosis of syringomyelia is not yet established. Syringomyelia derived from different etiologies contributes to similar symptoms. OBJECTIVE: Assess the syringomyelia in our medical institutes and describe the etiologies and clinical appearance of the disorder. And identify the predictors of a good outcome and to find the most suitable timing of surgical intervention according to our results. METHODS: This retrospective cohort study used databases in our hospitals to analyze 70 cases of syringomyelia between 1997 and 2014. All available information was obtained from medical records and radiological reports. We used American Spinal Injuries Association disability scores (ASIA scores), the modified Nurick classification system, and recorded the number of days the patient was hospitalized, for neurological and functional assessment. Univariate and multivariate analyses were used to evaluate the relationship between clinical factors and outcomes. RESULTS: Non-communicating syringomyelia was the most common type of syringomyelia. In univariate analysis, autonomic dysfunction and motor impairment were strong predictors of poor neurological and functional outcomes. In addition to the above factors, syrinxes at the cervical level predicted better functional outcomes than at any spinal level in multivariate analysis. CONCLUSIONS: Motor impairment, which is commonly seen in patients with syringomyelia in Taiwan, is a strong predictor to poor neurological and functional outcomes. Our study indicates that patients without autonomic dysfunction or motor impairment should receive timely surgical intervention to prevent symptomatic deterioration. We also found that cervical syringomyelia in particular has the potential for good functional recovery after adequate intervention.

Sleep disturbance in adults with untreated primary brain tumors: prevalence and impact on quality of life.

Purpose: To investigate the frequency of sleep disturbance and its effects on quality of life in adults with untreated primary brain tumors. Methods: This cross-sectional study recruited 68 and 35 patients with newly diagnosed benign and malignant brain tumors, respectively. All participants completed the Chinese versions of the Athens Insomnia Scale, Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, Brief Fatigue Inventory, and EORTC-QLQ-BN20 for quality-of-life assessment. An actigraph was used to measure sleep parameters [e.g., dichotomy index (I < O)], for at least 3 consecutive days in untreated status. Results: The majority of the patients with benign and malignant tumors had meningioma (57.4%) and glioblastoma (40%), respectively. The prevalence of insomnia, poor sleep quality, and excessive daytime sleepiness was 59.2%, 77.7%, and 4.9%, respectively. The prevalence rates of sleep disturbances were not affected by tumor locations (suprasellar vs. non-suprasellar tumors) and tumor types (benign vs. malignant tumors). Only 36 participants completed actigraphy assessments (I < O = 95.4) due to having a tight schedule, actigraph malfunction, or not having the habit of wearing a wristwatch; 61% of them experienced circadian rhythm disruption (I < O ≤ 97.5). Insomnia was the only sleep parameter that significantly affected quality of life after controlling for potential confounders (B = 0.54, p = 0.03, adjusted R2 = 0.60). Conclusion: More than 60% of the patients with primary malignant and benign brain tumors experienced insomnia, poor sleep quality, and circadian rhythm disruption. Insomnia was independently correlated with quality of life in untreated status. Health-care providers can apply these findings to design effective interventions targeting sleep disturbance to improve quality of life in this population. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-022-00436-y.

Augmented Reality Surgical Navigation System for External Ventricular Drain.

Augmented reality surgery systems are playing an increasing role in the operating room, but applying such systems to neurosurgery presents particular challenges. In addition to using augmented reality technology to display the position of the surgical target position in 3D in real time, the application must also display the scalpel entry point and scalpel orientation, with accurate superposition on the patient. To improve the intuitiveness, efficiency, and accuracy of extra-ventricular drain surgery, this paper proposes an augmented reality surgical navigation system which accurately superimposes the surgical target position, scalpel entry point, and scalpel direction on a patient's head and displays this data on a tablet. The accuracy of the optical measurement system (NDI Polaris Vicra) was first independently tested, and then complemented by the design of functions to help the surgeon quickly identify the surgical target position and determine the preferred entry point. A tablet PC was used to display the superimposed images of the surgical target, entry point, and scalpel on top of the patient, allowing for correct scalpel orientation. Digital imaging and communications in medicine (DICOM) results for the patient's computed tomography were used to create a phantom and its associated AR model. This model was then imported into the application, which was then executed on the tablet. In the preoperative phase, the technician first spent 5-7 min to superimpose the virtual image of the head and the scalpel. The surgeon then took 2 min to identify the intended target position and entry point position on the tablet, which then dynamically displayed the superimposed image of the head, target position, entry point position, and scalpel (including the scalpel tip and scalpel orientation). Multiple experiments were successfully conducted on the phantom, along with six practical trials of clinical neurosurgical EVD. In the 2D-plane-superposition model, the optical measurement system (NDI Polaris Vicra) provided highly accurate visualization (2.01 ± 1.12 mm). In hospital-based clinical trials, the average technician preparation time was 6 min, while the surgeon required an average of 3.5 min to set the target and entry-point positions and accurately overlay the orientation with an NDI surgical stick. In the preparation phase, the average time required for the DICOM-formatted image processing and program import was 120 ± 30 min. The accuracy of the designed augmented reality optical surgical navigation system met clinical requirements, and can provide a visual and intuitive guide for neurosurgeons. The surgeon can use the tablet application to obtain real-time DICOM-formatted images of the patient, change the position of the surgical entry point, and instantly obtain an updated surgical path and surgical angle. The proposed design can be used as the basis for various augmented reality brain surgery navigation systems in the future.

SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma.

BACKGROUND: The mechanism by which glioblastoma evades temozolomide (TMZ)-induced cytotoxicity is largely unknown. We hypothesized that mitochondria plays a role in this process. METHODS: RNA transcriptomes were obtained from tumor samples and online databases. Expression of different proteins was manipulated using RNA interference or gene amplification. Autophagic activity and mitochondrial metabolism was assessed in vitro using the respective cellular and molecular assays. In vivo analysis were also carried out in this study. RESULTS: High SH3GLB1 gene expression was found to be associated with higher disease grading and worse survival profiles. Single-cell transcriptome analysis of clinical samples suggested that SH3GLB1 and the altered gene levels of oxidative phosphorylation (OXPHOS) were related to subsets expressing a tumor-initiating cell signature. The SH3GLB1 protein was regulated by promoter binding with Sp1, a factor associated with TMZ resistance. Downregulation of SH3GLB1 resulted in retention of TMZ susceptibility, upregulated p62, and reduced LC3B-II. Autophagy inhibition by SH3GLB1 deficiency and chloroquine resulted in attenuated OXPHOS expression. Inhibition of SH3GLB1 in resistant cells resulted in alleviation of TMZ-enhanced mitochondrial metabolic function, such as mitochondrial membrane potential, mitochondrial respiration, and ATP production. SH3GLB1 modulation could determine tumor susceptibility to TMZ. Finally, in animal models, resistant tumor cells with SH3GLB1 knockdown became resensitized to the anti-tumor effect of TMZ, including the suppression of TMZ-induced autophagy and OXPHOS. CONCLUSIONS: SH3GLB1 promotes TMZ resistance via autophagy to alter mitochondrial function. Characterizing SH3GLB1 in glioblastoma may help develop new therapeutic strategies against this disease in the future.

A manzamine-derived compound as a potential therapeutic agent for glioma by inducing apoptosis and cell cycle arrest.

Glioma is a severe disease with a poor prognosis despite aggressive surgical resection and traditional chemotherapies. Therefore, new anti-neoplastic drugs are urgently needed. Bioactive compounds from natural products are potential sources of antiproliferative molecules, among which manzamine compounds extracted from the Formosan marine sponge Haliclona sp. have shown considerable promise as anticancer drugs. In the present study, the anti-neoplastic effect and mechanism of the manzamine derivative 1-(9'-propyl-3'-carbazole)-1, 2, 3, 4-tetrahydro-ß-carboline (PCTC) were investigated using in vitro cell lines and an in vivo subcutaneous animal model. Both cytotoxic and anti-proliferative effects were shown in human and murine glioma cell lines (A172, U87MG, and GL261), together with enhanced expressions of apoptotic enzymes and intracellular reactive oxygen species, and blockage of the G1/S phase of the cell cycle. In addition, combined treatment of GL261 cells with PCTC and temozolomide had a synergic antiproliferative effect. Significant safety, efficacy, and survival benefits were also demonstrated with PCTC treatment in the murine subcutaneous GL261 model. In conclusion, PCTC could effectively promote cell death through apoptosis and cell cycle arrest in glioma cell lines, and provide survival benefits in the animal model. Therefore, PCTC may be a clinically beneficial therapy for glioblastoma.

Primary intracranial malignant melanomas in solitary type: a tertiary center experience.

PURPOSE: Solitary type primary intracranial malignant melanoma (PIMM) is extremely rare but fatal. The optimal treatment algorithm according to clinical relevance of symptoms and outcomes is unclear. This series emphasized the prognostic factors of solitary PIMM and established the treatment algorithm for this rare disease. METHODS: Patients with solitary PIMMs were pathologically verified and treated with neurosurgical tumor resection. All solitary PIMMs recruited at our institute received multidisciplinary team care. We analyzed the clinical findings and prognostic factors. RESULTS: The study cohort included 10 patients. PIMMs in solitary type impacted middle-aged populations with male predominance in Taiwan. Most patients (80%) presented a single tumor initially. Six patients had progressed to multiplicity after the initial treatment. Rates of tumor bleeding and leptomeningeal metastasis seeding (LS) are high in solitary PIMMs. Patients who had gross-total resection (GTR) had better survival than those who had incomplete resection, with median overall survival (OS) rates of 170.4 months vs. 5.23 months (p = 0.004). Multiplicity, eloquent area involvement, initial tumor bleeding, LS, hydrocephalus, and Karnofsky Performance Score < 80 at diagnosis were associated with negative outcomes in progression-free survival and OS. Adjuvant radiotherapy for patients who had LS and for those who cannot undergo grossly total tumor removal resulted in a good outcome. CONCLUSIONS: GTR demonstrated better outcomes for solitary PIMM. For recurrent tumors, aggressively repeated surgical resection remained beneficial for selected cases. Adjuvant radiotherapy was a treatment option for LS following operation. We proposed a possible treatment algorithm for solitary PIMM.

Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation.

BACKGROUND: Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown. METHODS: RNA-Seq and mass spectrometry were used to analyze gene expression and metabolites amounts in paired GBM specimens (primary vs. recurrent) and in paired GBM cells (sensitive vs. resistant). ω-3/6 fatty acid and arachidonic acid (AA) metabolism in GBM patients were analyzed by targeted metabolome. Mitochondrial functions were determined by Seahorse XF Mito Stress Test, RNA-Seq, metabolome and substrate utilization for producing ATP. Therapeutic options targeting prostaglandin (PG) E2 in TMZ-resistant GBM were validated in vitro and in vivo. RESULTS: Among the metabolic pathways, Sp1 increased the prostaglandin-endoperoxide synthase 2 expression and PGE2 production in TMZ-resistant GBM. Mitochondrial genes and metabolites were obviously increased by PGE2, and these characteristics were required for developing resistance in GBM cells. For inducing TMZ resistance, PGE2 activated mitochondrial functions, including fatty acid ß-oxidation (FAO) and tricarboxylic acid (TCA) cycle progression, through PGE2 receptors, E-type prostanoid (EP)1 and EP3. Additionally, EP1 antagonist ONO-8713 inhibited the survival of TMZ-resistant GBM synergistically with TMZ. CONCLUSION: Sp1-regulated PGE2 production activates FAO and TCA cycle in mitochondria, through EP1 and EP3 receptors, resulting in TMZ resistance in GBM. These results will provide us a new strategy to attenuate drug resistance or to re-sensitize recurred GBM.

HDAC6 involves in regulating the lncRNA-microRNA-mRNA network to promote the proliferation of glioblastoma cells.

BACKGROUND: Glioblastoma (GBM) is the most aggressive and lethal brain tumor. Although the histone deacetylase (HDAC)/transcription factor axis promotes growth in GBM, whether HDACs including HDAC6 are involved in modulating long non-coding RNAs (lncRNAs) to affect GBM malignancy remains obscure. METHODS: Integrative analysis of microarray and RNA-seq was performed to identify lncRNAs governed by HDAC6. Half-life measurement and RNA-protein pull-down assay combined with isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis were conducted to identify RNA modulators. The effect of LINC00461 on GBM malignancy was evaluated using animal models and cell proliferation-related assays. Functional analysis of the LINC00461 downstream networks was performed comprehensively using ingenuity pathway analysis and public databases. RESULTS: We identified a lncRNA, LINC00461, which was substantially increased in stem-like/treatment-resistant GBM cells. LINC00461 was inversely correlated with the survival of mice-bearing GBM and it was stabilized by the interaction between HDAC6 and RNA-binding proteins (RBPs) such as carbon catabolite repression-negative on TATA-less (CCR4-NOT) core exoribonuclease subunit 6 and fused in sarcoma. Targeting LINC00461 using azaindolylsulfonamide, an HDAC6 inhibitor, decreased cell-division-related proteins via the lncRNA-microRNA (miRNA)-mRNA networks and caused cell-cycle arrest, thereby suppressing proliferation in parental and drug-resistant GBM cells and prolonging the survival of mice-bearing GBM. CONCLUSIONS: This study sheds light on the role of LINC00461 in GBM malignancy and provides a novel therapeutic strategy for targeting the HDAC6/RBP/LINC00461 axis and its downstream effectors in patients with GBM.