NUDT5 promotes the growth,metastasis,and Warburg effect of IDH wild-type glioblastoma multiforme cells by upregulating TRIM47

Objective:To explore the regulatory mechanism of NUDT5 in glioblastoma multiforme(GBM).Methods:GEPIA database was used to predict the expressions of NUDT5 and tripartite motif family proteins 47(TRIM47)in GBM patients.RT-qPCR and Western blot analyses were performed to examine NUDT5 expression in GBM cells.LN-229 cell proliferation,migration as well as invasion were estimated by CCK-8,colony formation,wound healing,and Transwell assays following interference with NUDT5.ECAR assay,L-lactic acid kit,glucose detection kit,and ATP detection kit were applied for the detection of glycolysis-related indexes.Co-immunoprecipitation experiment was carried out to verify the relationship between NUDT5 and TRIM47.Results:GEPIA database showed that NUDT5 expression was significantly increased in GBM patients.Inhibiting the expression of NUDT5 in GBM cells significantly suppressed the viability,proliferation,invasion,migration,and glycolysis of GBM cells.Moreover,TRIM47 was highly expressed in GBM cells and interacted with NUDT5.Overexpression of TRIM47 partially reversed the inhibitory effect of NUDT5 downregulation on the proliferation,metastasis,and glycolysis of GBM cells.Conclusions:NUDT5 promotes the growth,metastasis,and Warburg effect of GBM cells by upregulating TRIM47.Both NUDT5 and TRIM47 can be used as targets for GMB treatment.

Nanosensitizers for sonodynamic therapy for glioblastoma multiforme: current progress and future perspectives

Glioblastoma multiforme(GBM) is the most common primary malignant brain tumor, and it is associated with poor prognosis. Its characteristics of being highly invasive and undergoing heterogeneous genetic mutation, as well as the presence of the blood–brain barrier(BBB), have reduced the efficacy of GBM treatment. The emergence of a novel therapeutic method, namely, sonodynamic therapy(SDT), provides a promising strategy for eradicating tumors via activated sonosensitizers coupled with low-intensity ultrasound. SDT can provide tumor killing effects for deep-seated tumors, such as brain tumors. However, conventional sonosensitizers cannot effectively reach the tumor region and kill additional tumor cells, especially brain tumor cells. Efforts should be made to develop a method to help therapeutic agents pass through the BBB and accumulate in brain tumors. With the development of novel multifunctional nanosensitizers and newly emerging combination strategies, the killing ability and selectivity of SDT have greatly improved and are accompanied with fewer side effects. In this review, we systematically summarize the findings of previous studies on SDT for GBM, with a focus on recent developments and promising directions for future research.

Glioblastoma multiforme:Diagnosis, treatment, and invasion

Glioblastoma multiforme(GBM) is an essentially incurable brain tumor, which has been explored for approximately a century. Nowadays, surgical resection, chemotherapy, and radiation therapy are still the standardized therapeutic options. However, due to the intrinsic invasion and metastasis features and the resistance to chemotherapy, the survival rate of glioblastoma patients remains unsatisfactory. To improve the current situation, much more research is needed to provide comprehensive knowledge of GBM. In this review, we summarize the latest updates on GBM treatment and invasion. Firstly, we review the traditional and emerging therapies that have been used for GBM treatment. Given the limited efficiency of these therapies, we further discuss the role of invasion in GBM recurrence and progression, and present current research progress on the mode and mechanisms of GBM invasion.

Exploring Chemovar-Specific Cannabis Extracts Quantification and Evaluation of Cytotoxic Compounds for Targeting Glioblastoma Multiforme

Glioblastoma Multiforme (GBM) represents one of the most aggressive and metastatic brain tumors, with a dismal success rate of less than three percent after five years, particularly in tumors with active immune checkpoints. This necessitates the development of targeted endogenous agents for precise GBM treatment. Previous experiments utilizing Chemovar Specific Cannabis Extractions (CSCEs), fractionated with polar solvents and quantified using Liquid and Gas Column Chromatography combined with Mass Spectrometry (LC/GCMS), have shown reduced viability and motility in human GBM cell lines. However, the complexity of the botanical substance has hindered the personalization of standard cannabis medicines for GBM due to unknown synergistic effects of multiple compounds. To address this limitation, our study focuses on exposing AM251 cells to chemovar fractions extracted using a non-polar solvent, thereby isolating a broader spectrum of constituents. By employing LC/GCMS in conjunction with Nuclear Magnetic Resonance (NMR), we have identified and quantified nine* compounds present in the non-polar CSCE that exhibit significant efficacy (0.1 μM) in inducing cytotoxicity* in GBM tumor cells. Conversely, the polar fraction in our experiment did not demonstrate efficacy against UM251 cells. The quantification of individual compounds within a cannabis extraction that selectively induces cell death in brain tumors holds promise for guiding future research and facilitating the development of a standardized CSCE for GBM therapy.

IKIP downregulates THBS1/FAK signaling to suppress migration and invasion by glioblastoma cells

Background:Inhibitor of NF-κB kinase-interacting protein(IKIP)is known to promote proliferation of glioblastoma(GBM)cells,but how it affects migration and invasion by those cells is unclear.Methods:We compared levels of IKIP between glioma tissues and normal brain tissue in clinical samples and public databases.We examined the effects of IKIP overexpression and knockdown on the migration and invasion of GBM using transwell and wound healing assays,and we compared the transcriptomes under these different conditions to identify the molecular mechanisms involved.Results:Based on data from our clinical samples and from public databases,IKIP was overexpressed in GBM tumors,and its expression level correlated inversely with survival.IKIP overexpression in GBM cells inhibited migration and invasion in transwell and wound healing assays,whereas IKIP knockdown exerted the opposite effects.IKIP overexpression in GBM cells that were injected into mouse brain promoted tumor growth but inhibited tumor invasion of surrounding tissue.The effects of IKIP were associated with downregulation of THBS1 mRNA and concomitant inhibition of THBS1/FAK signaling.Conclusions:IKIP inhibits THBS1/FAK signaling to suppress migration and invasion of GBM cells.

Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo

Tumor cell proliferation, infiltration, migration, and neovascularization are known causes of treatment resistance in glioblastoma multiforme(GBM). The purpose of this study was to determine the effect of radiation on the growth characteristics of primary human GBM developed in a nude rat. Primary GBM cells grown from explanted GBM tissues were implanted orthotopically in nude rats. Tumor growth was confirmed by magnetic resonance imaging on day 77(baseline) after implantation. The rats underwent irradiation to a dose of 50 Gy delivered subcuratively on day 84 postimplantation(n = 8), or underwent no radiation(n = 8). Brain tissues were obtained on day 112(nonirradiated) or day 133(irradiated). Immunohistochemistry was performed to determine tumor cell proliferation(Ki-67) and to assess the expression of infiltration marker(matrix metalloproteinase-2, MMP-2) and cell migration marker(CD44). Tumor neovascularization was assessed by microvessel density using von-Willebrand factor(vWF) staining. Magnetic resonance imaging showed well-developed, infiltrative tumors in 11 weeks postimplantation. The proportion of Ki-67-positive cells in tumors undergoing radiation was(71 ± 15)% compared with(25 ± 12)% in the nonirradiated group(P = 0.02). The number of MMP-2-positive areas and proportion of CD44-positive cells were also high in tumors receiving radiation, indicating great invasion and infiltration. Microvessel density analysis did not show a significant difference between nonirradiated and irradiated tumors. Taken together, we found that subcurative radiation significantly increased proliferation, invasion, and migration of primary GBM. Our study provides insights into possible mechanisms of treatment resistance following radiation therapy for GBM.

A Phase II Study of Antineoplastons A10 and AS2-1 in Adult Patients with Recurrent Glioblastoma Multiforme: Final Report (Protocol BT-21)

Treatment of recurrent glioblastoma multiforme (RGBM) creates one of the most difficult challenges to neuro-oncology. The purpose of this study is to evaluate the outcome of adults with high-grade glioma with special attention to RGBM patients treated with Antineoplastons (ANP) A10 and AS2-1 injections. The study was conducted according to Protocol BT-21, which accrued patients who failed standard radiation therapy (RT) and chemotherapy. There were 40 candidates registered in the study. Among the intent-to-treat (ITT) population, there were 30 cases of RGBM that progressed during and after prior treatment, 4 patients with anaplastic astrocytoma (AA), 1 with anaplastic mixed glioma (AMG), and 5 with persistent GBM. The aim of this paper is to evaluate the responses, survival and toxicity of all 40 patients, the efficacy in 30 patients with RGBM, and in 24 patients with RGBM who received at least 28 days of ANP (ERGBM). All RGBM patients were treated before with RT and chemotherapy, except one patient who only had surgery (patient refused radiation). In this group, 63% had one recurrence, 30% had two recurrences, and 7% had three recurrences. The median duration of ANP and ITT was 12 weeks and the median dosage of ANP A10 was 6.52 g/kg/d and ANP AS2-1 was 0.23 g/kg/d. Responses were assessed by gadolinium-enhanced magnetic resonance imaging (MRI) repeated every eight weeks. In the ITT population, objective responses (ORs) were determined in 10% of cases (complete response—CR, and partial response—PR in 5% each). Progression-free survival (PFS) in ITT at six months was 17.5%. Overall survival (OS) was 28.3% at one year, 2.6% at two years, five and ten years. In the RGBM population, objective responses (ORs) were determined in 13.3% of cases (CR and PR in 6.7% each). PFS in RGBM at six months was 16.7%. OS was 34.7% at one year, 3.47% at two years, five?and ten years. In the ERGBM population, ORs were determined in 16.7% of cases (CR and PR in?8.3% each). PFS in ERGBM at six months was 20.8%, OS was 39.3% at one year, 4.4% at two years, five and ten years. The treatment was well-tolerated with reversible Grades 3 and 4 toxicity in 17.5% of patients (7 patients who experienced multiple toxicities) and no chronic toxicity. In conclusion, the study reached efficacy endpoint. ANP is well-tolerated and compares favorably to the current treatment for RGBM.

Radiation and concomitant chemotherapy for patients with glioblastoma multiforme

Postoperative external beam radiotherapy was considered the standard adjuvant treatment for patients with glioblastoma multiforme until the advent of using the drug temozolomide(TMZ) in addition to radiotherapy. High-dose volume should be focal, minimizing whole brain irradiation. Modern imaging, using several magnetic resonance sequences, has improved the planning target volume definition. The total dose delivered should be in the range of 60 Gy in fraction sizes of 1.8-2.0 Gy. Currently, TMZ concomitant and adjuvant to radiotherapy has become the standard of care for glioblastoma multiforme patients. Radiotherapy dose-intensification and radiosensitizer approaches have not improved the outcome. In spite of the lack of high quality evidence, stereotactic radiotherapy can be considered for a selected group of patients. For elderly patients, data suggest that the same survival benefit can be achieved with similar morbidity using a shorter course of radiotherapy(hypofractionation). Elderly patients with tumors that exhibit methylation of the O-6-methylguanine-DNA methyltransferase promoter can benefit from TMZ alone.

Gliosarcoma:A rare variant of glioblastoma multiforme in paediatric patient:Case report and review of literature

Gliosarcoma is rare central nervous system tumour and a variant of glioblastoma multiforme with bimorphic histological pattern of glial and sarcomatous differentiation. It occurs in elderly between 5^(th) and 6^(th) decades of life and extremely rare in children. It is highly aggressive tumour and managed like glioblastoma multiforme. A 12-year-old female child presented with complaints of headache and vomiting from 15d and blurring of vision from 3d. Magnetic resonance imaging of brain shows heterogeneous mass in right parieto-occipital cortex. A right parieto-occipito-temporal craniotomy with complete excision of mass revealed a primary glioblastoma on histopathological investigation. Treatment consists of maximum surgical excision followed by adjuvant radiotherapy. The etiopathogenesis, treatment modalities and prognosis is discussed. The available literature is also reviewed.

Immunophenotypic signature of primary glioblastoma multiforme: A case of extended progression free survival

Glioblastoma-multiforme(GBM), the most aggressive glial tumor, has a worldwide age-adjusted incidence ranging from 0.59-3.69/100000 persons. Despite current multimodal-treatment approach, median-survival time and progression-free survival(PFS) remains short. Glioblastomas display a variety of molecular alterations, which necessitates determining which of these have a prognostic significance. This is a case of a 45-yearold patient who presented with progressive slurring of speech and features of raised intracranial pressure. Computed tomography(CT) scan revealed a large heterogeneously enhancing lesion in the left front-temporalperisylvian region with solid, cystic areas, suggestive of malignant glioma. Partial tumor-excision was followed by concurrent chemo-radiotherapy. Histopathologically, the tumor was astrocytoma grade-IV. Patient had an extended PFS of 12 mo, with an overall survival of 26 mo. Primary-GBM was confirmed using molecular markers and the immunophenotypic signature was defined by evaluating systemic expression of human telomerase reverse transcriptase, interleukin-6, neutrophil-lymphocyte ratio, tissue inhibitor of metalloproteinases-1, human chitinase-3-like-protein-1(YKL-40) and high mobility group-A1. Current findings suggest that this signature can identify worst outcomes, independent of clinical criteria.

Standards of care and novel approaches in the management of glioblastoma multiforme

Glioblastoma multiforme(GBM) is the most common malignant primary brain tumor in adults. Standard therapeutic approaches provide modest improvement in the progression-free and overall survival, necessitating the investigation of novel therapies. We review the standard treatment options for GBM and evaluate the results obtained in clinical trials for promising novel approaches, including the inhibition of angiogenesis, targeted approaches against molecular pathways, immunotherapies, and local treatment with low voltage electric fields.

Hypertensive-Nimodipine Therapy for Middle Cerebral Artery Vasospasm after Resection of Glioblastoma Multiforme: A Case Report and Literature Review

Delayed cerebral ischemia (DCI) due to post-brain tumor resection vasospasm is an often unrecognized yet debilitating complication. We present a patient with DCI after the resection of glioblastoma multiforme (GBM). To our knowledge, this is the first report on DCI after GBM resection. A 52-year-old female patient with headache for one month underwent subtotal resection of a left temporal GBM encasing the proximal middle cerebral artery (MCA). She was well during the immediate postoperative period but developed right upper limb dense monoparesis on postoperative day four with computed tomographic angiography confirming left MCA vasospasm. Symptoms were significantly alleviated with weeklong hypertensive therapy and nimodipine administration;however they recurred soon after cessation of treatment. A high index of clinical suspicion is needed for the diagnosis of post-tumor resection DCI. Any new postoperative neurological deficit that cannot be explained by hemorrhage, seizures or infection should be expeditiously investigated by angiography or transcranial Doppler sonography. Prompt initiation of hypertensive and nimodipine therapy can possibly reverse neurological deficit. Treatment should be guided by Doppler, angiographic or perfusion imaging studies and not by clinical improvement alone.

MRI Manif estions Correlate with Survival of Glioblastoma Multiforme Patients

Objective To identify the correlation between magnetic resonance manifestation and survival of patients with glioblastoma multiforme(GBM). Methods The magnetic resonance imaging(MRI) images of 30 glioblastoma patients were collected.Imaging features including degrees of contrasted area,edema surrounding the tumor,and intensity in T2-weighted imaging were selected to determine their correlation with patient survival.The relationship between imaging and survival time was studied using SPSS 19.0 software.KaplanMeier survival analysis and log-rank test were used to compare the survival curves. Results Patients with <5%contrasted enhancement area of tumor had longer overall survival(OS) than those with >5%contrasted enhancement area of tumor.Patients without edema surrounding the tumor had longer OS than those with edema.Patients with tumor of hyperintensity and/or isointensity in T2-weighted imaging had longer OS than those with hyperintensity and/or isointensity and hypointensity. Conclusions Some MR imaging features including degrees of contrasted area,edema surrounding the tumor,and intensity in T2- weighted imaging are correlated with the survival of patients with GBM.These features can serve as prognostic indicators for GBM patients.

Preliminary Findings on the Use of Targeted Therapy with Pazopanib and Other Agents in Combination with Sodium Phenylbutyrate in the Treatment of Glioblastoma Multiforme

The most common and aggressive type of brain tumor is glioblastoma multiforme (GBM). The prognosis for GBM remains poor with a five-year survival rate between 1% and 2%. The prospects for patients with recurrent GBM (RGBM) are much worse, with the majority dying within 6 months. This publication provides a brief description of the treatment of 11 GBM patients treated with sodium phenylbutyrate (PB) in combination with pazopanib, m-TOR inhibitors, and other agents. The treatment was associated with tolerable side effects and resulted in objective responses in 54.5% of cases (complete response 18.2%, partial response 36.3%) and 27.3% cases of stable disease. The preferable treatment regimen consisted of PB, pazopanib, dasatinib, everolimus, and bevacizumab (BVZ). For various reasons not all patients were compliant with the treatment regimen. In patients who strictly complied with the treatment plan, all responded as CR or PR. Based on preliminary findings, the authors propose further phase I/II clinical trials with PB in combination with pazopanib, dasatinib, everolimus, and BVZ in patients with RGBM who failed standard surgery, radiation therapy and chemotherapy. With proper dose reductions, the treatment appears to be well-tolerated. Molecular profiling of patient subgroups with favorable genomic signatures may help to select patients for future studies.

Recurrent Glioblastoma Multiforme—A Strategy for Long-Term Survival

Recurrent GBM (RGBM) has a highly unfavorable prognosis with majority of patients dying within 6 months and no standard treatments available. Antineoplaston (ANP) A10 and AS2-1 injections underwent Phase II trials in RGBM patients, which reported a long-term overall survival (OS) in a small percentage of patients. The additional Phase II studies BT-07, and BT-21 with ANP in GBM also revealed cases of a long-term OS. ANP shares active ingredients with metabolites of sodium phenylbutyrate (PB), which was used in private practice setting in combination of targeted and chemotherapeutic agents for the treatment of RGBM. The treatment contributed to cases of rapid complete response (CR) and significant OS. This paper provides case studies of three patients treated with ANP under Phase II protocols and two patients treated with PB in combination with targeted therapy, who obtained CR and long-term OS. Based on these studies and basic research on the effects of ANP and PB on the genome of GBM and review of results of preclinical and clinical research on targeted agents, the authors suggest a new strategy for successful treatment of RGBM. They propose Phase I/II clinical trials with ANP and PB in combination with targeted agents, bevacizumab (BVZ), pazopanib, dasatinib and everolimus in patients with RGBM after failure of standard surgery, radiation therapy (RT) and chemotherapy including temozolomide (TMZ) to be conducted to evaluate survival, response and toxicity in these patients.

Prognostic significance of annexin VII expression in glioblastomas multiforme in humans

OBJECT:Glioblastoma multiforme(GBM)is the most common and lethal primary brain tumor in adults.It isnearly uniformly fatal,with a median survival time of approximately l year,despite modem treatment modalities.Nevertheless,a range of survival times exists around this median.Efforts to understand why some patients livelonger or shorter than the average may provide insight into the biology of these neoplasms.The annexin VII(ANX7)gene is located on the human chromosome 10q21,a site long hypothesized to harbor tumor

Exploiting the inherent invasive property to treat glioblastoma multiforme

Glioblastoma multiforme(GBM)is the most malignant brain tumor with high infiltration.The routine surgical resection followed by radiation and chemotherapy only provides patients with a survival period ranging 12–15months.Here,I propose that the high invasiveness property of the GBM cells be exploited to treat this deadly disease.That is,instead of inhibiting the dissemination of GBM cells,we should take advantage of the high mobility of the disseminated GBM cells and directionally induce these cells to return to the center of surgical resection cavity of the primary neoplasm and subsequently kill them.This idea may provide a new promise to defeat this deadly disease.

Glioblastoma multiforme with metastasis to lung,bone,and chest wall:a case report

Glioblastoma multiforme(GBM)is a common brain tumor that rarely metastasizes extra-cranially.We present the case of a 40-year-old male with left temporal GBM who underwent craniotomy followed by radiotherapy and chemotherapy.Postoperative MRI scans at different time intervals demonstrated a good response.Eleven months after the initial diagnosis,there were no clinical or radiological signs suggesting recurrence.However,the tumor showed metastasis simultaneously to the chest wall,lungs,and bone,despite 2 cycles of chemotherapy.The patient developed paraplegia 14 months after the initial diagnosis and died due to systemic failure 19 months after diagnosis.Extracranial metastasis of GBM is extremely rare.We present the unusual case of a patient with GBM who showed simultaneous metastasis to the lungs,bone,and chest wall.The prognosis of patients with extracranial metastasis of glioblastomas is very poor,regardless of chemoradiotherapy.Newer approaches,such as immunotherapy and anti-angiogenic therapy,need to be further studied.

Molecular pathogenesis of glioblastoma multiforme: Nuances, obstacles, and implications for treatment

Glioblastoma multiforme(GBM), the literal apogee on the hierarchy of malignant brain tumors, remains one of the greatest therapeutic challenges in oncology andmedicine. Historically this may be contextualized in the fact that the medical and scientific communities have had a very elementary understanding of its intricate and complex pathophysiology. The last 10-15 years have yielded a number of studies that have elucidated much of the molecular and genetic complexities of GBM that underlie its pathogenesis. Excitingly, some of these discovered genetic mutations and molecular profiles in GBM have demonstrated value in prognostication and utility in predicting response to treatment. Despite this, however, treatment options for patients have remained somewhat limited. These treatment options are expected to expand with the availability of new data and with the transition of novel treatment modalities from animal to human studies. This paper will have a threefold objective: provide an overview of the traditional paradigm in understanding and treating GBM, describe recent discoveries in the molecular pathogenesis of GBM against this historical backdrop, and acquaint the reader with new treatment modalities that hold significant therapeutic potential for patients.

Protracted Adjuvant Temozolomide in Glioblastoma Multiforme

Purpose: Radiotherapy with concurrent temozolomide (TMZ), followed by 6 cycles of adjuvant TMZ, is the standard of care for newly diagnosed Glioblastoma Mulltiforme (GBM). However tumor progression is the role with median survival of almost 14 months. With lack of effective second line chemotherapy, many physicians and some guidelines advocate prolonged use of adjuvant TMZ more than 6 months. We conduct this study to test the efficacy of protracted adjuvant conventional dose TMZ over the standard 6 doses of adjuvant TMZ. Material and Methods: This phase II trial enrolled patients newly diagnosed as GBM, older than age 18 years, with a Karnofsky performance score (KPS) of ≥60, Neurological Performance Scale (NPS) of ≤3. Patients were randomly assigned to the standard concurrent chemoradiotherapy (CCRT) followed by 6 cycles of adjuvant TMZ or the same treatment with more than 6 cycles of adjuvant chemotherapy extended as long as the patient in good performance, with no unacceptable toxicity, no signs of disease progression. The primary end point was OS. Results: A total of 59 patients were recruited in the study and were randomized in two arms. 29 patients joined arm 1 aiming at receiving CCRT followed by adjuvant 6 cycles TMZ (6 cycles arm) and 30 joined arm 2 aiming at receiving the same treatment with more than 6 cycles of TMZ (>6 cycles). 16 patients managed to complete the adjuvant 6 cycles in arm 1. 19 patients in arm 2, completed the 6 cycles with additive more doses with a median of 11 cycles (range: 8 - 23 cycles). Median PFS was 12.1 months for (6 cycles) arm, and 18.8 months for (>6 cycles) arm, HR 0.88 (95% CI: 1.185 - 4.901) (P 0.015);the overall survival for (6 cycles) arm was 18.1 months, versus 24.1 months, HR 0.70 (95% CI: 1.007 - 4.037) (P 0.048). No significant added toxicity was notice and the 4 weekly TMZ was well tolerated. Conclusion: This study concluded that protracted adjuvant TMZ after concurrent chemoradiotherapy could be a feasible strategy for GBM. This strategy warrants a large phase III randomized trial.