Search

Glioma is a common primary nervous system malignant tumor with poor overall cure rate and low survival rate, yet successful treatment still remains a challenge. Here, we demonstrated that amantadine (AMT) exhibits the powerful anti-glioma effect by promoting apoptosis and autophagy in vivo and in vitro. Mechanistically, amantadine induces a large amount of reactive oxygen species (ROS) accumulation in glioma cells, and then triggers apoptosis by destroying mitochondria. In addition, amantadine induces the initiation of autophagy and inhibits the fusion of autophagosome and lysosome, consequently performing an anti-glioma role. Taken together, our findings suggest that amantadine could be a promising anti-glioma drug that inhibits glioma cells by inducing apoptosis and autophagy, which may provide a novel potential treatment option for patients., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval All animal studies were approved by the Institutional Ethics Committee of Lanzhou University Second Hospital., (© 2024. The Author(s).)

Glioblastoma multiforme (GBM) is a highly aggressive form of primary brain tumor in adults, which unfortunately has an abysmal prognosis and poor survival rates. The reason behind the poor success rate of several FDA-approved drug is mainly attributed to insufficient drug distribution to the tumor site across the blood-brain barrier (BBB) and induction of resistance. In this study, we have developed a novel nanotherapeutic approach to achieve our goal. PLGA-based nanoencapsulation of both Temozolomide (TMZ) and EGFR inhibitor 3,3'-diindoyl methane (DIM) in a combinatorial approach enhances the delivery of them together. Their synergistic mode of actions, significantly enhances the cytotoxic effect of TMZ in vitro and in vivo. Moreover, the dual-loaded nanoformulation works more efficiently on DNA damage and apoptosis, resulting in a several-fold reduction in tumor burden in vivo, systemic drug toxicity, and increased survival. These findings suggest the preclinical potential of this new treatment strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glioma, a common primary brain tumor, is highly infiltrative and invasive, often leading to drug resistance and recurrence. Therefore, the development of novel therapeutic agents is urgently needed. Pseudellone C is a novel marine triindole alkaloid. Screening of its antiproliferative activity against 55 cell lines revealed its anti-CNS cancer potential. A total of 42 derivatives of Pseudellone C were designed and synthesized, and their inhibitory activities against two human glioma cell lines (U-87MG and LN-229) were evaluated using the CCK-8 assay. Ten derivatives exhibited potent antiproliferative activity with IC 50 values below 10 μmol, which are 18- to 39- fold more potent than Pseudellone C. Among these, derivative 4o demonstrated favorable blood-brain barrier permeability. Mechanistic studies revealed that 4o induces apoptosis primarily by activating the downstream caspase 3 cascade via the TNF/TNFR pathway. Structure-activity relationship correlations were systematically analyzed, and a pharmacophore model for further rational design was constructed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

This study aims to explore the inhibitory effects of combined metformin and simvastatin therapy on the malignant progression of glioma. The research specifically examines how the maturation of SREBP2 as a transcription factor affects the expression of GLUT1 and GLUT6 in glioma cells. Additionally, it investigates the impact of this combination therapy on the biological functions and energy metabolism of glioma cells. To assess the functions of GLUT1/6, sh-GLUT1/6 plasmids were employed. The study determined the half-maximal inhibitory concentrations (IC50) of metformin and simvastatin using the CCK-8 assay. Subsequently, the effects of these drugs on glioma metabolism, proliferation, and apoptosis were explored in vitro and in vivo, using drug concentrations significantly lower than their respective IC50 values. The impact of drug treatment on GLUT1/6 and SREBP2 expression levels was also evaluated. The study elucidated the significant impact of GLUT1/6 on glioma cell functions, resulting in decreased glucose uptake. Moreover, it unveiled the regulatory role of SREBP2 in GLUT1 and GLUT6 transcription, alongside revealing differential expression of SREBP2 precursor and mature forms within gliomas. Following combined drug therapy, GLUT1/6 expression decreased, while the precursor form of SREBP2 increased, and mature SREBP2 reduced. This dual-drug treatment effectively modulated glioma cell energy metabolism. Subsequent in vivo experiments affirmed the augmented anti-tumor efficacy of combined drug therapy. Specifically, the synergistic action of metformin and simvastatin reshaped glioma metabolism, curbed malignant proliferation, promoted apoptosis, and demonstrated superior anti-tumor effects both in vitro and in vivo compared to individual administration of metformin or simvastatin. Importantly, the combination therapy achieved these effects at lower doses, rendering it a safer treatment option., (© 2024. The Author(s).)

Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of the currently approved drugs known to cross the blood-brain barrier can facilitate rapid clinical translation. Here, we assessed the role of catechol-O-methyltransferase (COMT), a key enzyme to degrade catecholamines and a drug target for Parkinson's disease, in glioma treatment. Analysis of The Cancer Genome Atlas data showed significantly higher COMT expression levels in both low-grade glioma and glioblastoma compared to normal brain tissues. Inhibition of COMT by genetic knockout or FDA-approved COMT inhibitors significantly sensitized glioma cells to RT in vitro and in vivo. Mechanistically, COMT inhibition in glioma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral double-stranded RNA sensing pathway and type I interferon (IFN) response. Elevated type I IFNs stimulated the phagocytic capacity of microglial cells, enhancing RT efficacy. Given the long-established safety record of the COMT inhibitors, these findings provide a solid rationale to evaluate them in combination with RT in patients with glioma. Significance: Inhibition of catechol-O-methyltransferase, a well-established drug target in Parkinson's disease, interferes with mitochondrial electron transport and induces mitochondrial double-stranded RNA leakage, activating type I interferon signaling and sensitizing glioma to radiotherapy., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold" and immunotherapy-refractory cancers., Methods: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor-associated macrophages/microglia (TAMs)., Results: FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4-mediated selective depletion of intratumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge., Conclusions: Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In this study, we focused on calcification and diffusion restriction, which sometimes appear around the resection cavity or periventricular white matter in patients with high-grade glioma (HGG) treated with bevacizumab (BVZ), as candidate imaging biomarkers for BVZ treatment efficacy. We investigated the timing of the appearance of diffusion restriction and calcification using magnetic resonance imaging and computed tomography in 35 patients with newly diagnosed or recurrent HGG treated with BVZ. In 17 (48.6%) patients, calcification was identified around the resection cavity or periventricular white matter at a median of 12 months after the initiation of BVZ treatment. Patients with calcification had significantly longer progression-free survival (16 vs. 7 months; p = 0.0023) and overall survival (36 vs. 12 months; p = 0.0006) than those without calcification. Histopathological examination revealed the presence of scattered microcalcifications within areas of necrosis, which suggested dystrophic calcification induced by BVZ. Diffusion-restricted lesions that appeared in patients with calcification had significantly lower apparent diffusion coefficients than those in patients without calcifications, indicating the presence of treatment-related necrosis but not hypercellularity. In conclusion, the radiological finding of diffusion restriction followed by calcification could be a potential imaging biomarker for favorable clinical course in patients with HGG treated with BVZ., (© 2024. The Author(s).)

Background/aim: This study aimed to investigate the effect and underlying mechanism of inhibiting glutamine synthetase (GS) on the vascular permeability of gliomas., Materials and Methods: C6 glioma rat models were randomly divided into control and L-methionine sulfoximine (MSO) treatment groups. MSO was intraperitoneally injected once every other day for a total of three injections in the MSO group. We assessed the effect of MSO on tumor vascular permeability by tail vein injection of Evans blue dye. GS activity, glutamate (Glu) concentration, glutamine (Gln) concentration, and arginine concentration in tumor tissues were measured using the corresponding kits. qPCR experiments were then conducted to examine the effect of glutamate concentration on N-methyl-D-aspartate (NMDA) receptor expression. Finally, the nitric oxide synthase (NOS) assay kit and the nitric oxide (NO) assay kit were employed to detect NOS activity and NO concentration changes, respectively., Results: Increased glioma tumor vascular permeability was observed after intraperitoneal injection of MSO; MSO acted as an inhibitor of GS, leading to a decrease in GS activity; increased glutamate levels caused activation of NMDA receptors and further activation of NOS; additionally, elevated NO levels were detected in association with an increase in arginine and NOS., Conclusion: Inhibiting GS results in increased vascular permeability in gliomas, which is associated with elevated NO levels and the vasodilatory effects of NO., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor group, currently regarded as a chronic disease. On 23 April 2024, the U.S. FDA approved a new type II RAF inhibitor, tovorafenib (OJEMDA TM ), previously known as DAY101, for the treatment of patients aged 6 months and older with relapsed or refractory (R/R) pLGG harboring a BRAF fusion or rearrangement, or BRAF V600E mutation., Areas Covered: This article aims to review the pharmacological properties of tovorafenib and evaluate its efficacy and safety in the treatment of R/R pLGG. We conducted a systematic search of PubMed and Web of Science databases for English-language publications related to tovorafenib, including journal articles and conference abstracts, up through 20 August 2024., Expert Opinion: As the first and only FDA-approved medicine for children with BRAF fusions or rearrangements, which are the most common molecular alteration in pLGG, tovorafenib shows superior central nervous system penetration without the paradoxical activation of the MAPK pathway reported for type I BRAF inhibitors. Phase 1 and the pivotal phase 2 trials have demonstrated that tovorafenib monotherapy is generally well-tolerated and exhibits encouraging signs of meaningful, rapid and sustained clinical activity in children and young adults with BRAF-altered pLGG.

The efficient and secure delivery of intravenous chemotherapeutic agents across the blood-brain barrier (BBB) to the precise location of a brain tumor is a crucial element in glioma treatment. Herein, we introduce a biomimetic nanoplatform (T7-M-C/S) comprising a core made up of irinotecan hydrochloride (CPT11) and its bioactive metabolite, 7-Ethyl-10-hydroxycamptothecin (SN38), surrounded by a layer of T7-peptide-modified macrophage membrane. CPT11 spontaneously assembles with SN38 into stable and water-dispersible nanoparticles (C/S), greatly enhancing the water solubility of SN38. The integration of the modified peptide with the inherent proteins expressed by macrophage cells confers the nanoplatform with enhanced bioavailability and robust glioma-targeting abilities, ultimately resulting in superior therapeutic outcomes. These discoveries highlight a drug delivery system characterized by a high drug loading capacity, leveraging the macrophage membrane, and promising significant potential for glioma treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The glioma is one of the most aggressive tumors in humans, which is difficult to eradicate clinically. Therefore, we devised a porphyrin-based metal-organic frameworks (MOFs) crosslinking hyaluronic acid (HA) hydrogel nanocomposite through double-network (Cu-MOF-S-S-HA-Gel, CSSH-Gel), which is tumor responsive for enhanced gas therapy and sonodynamic therapy (SDT). Firstly, the hydrogels show extraordinary injectability and biocompatibility, which enables intratumor administration to circumvent the danger associated with surgery. The Cu-MOF-Cys and HA-Cys are interconnected through ether and disulfide bonds to establish a dual-network gel structure. The overexpressed glutathione (GSH) in tumor microenvironment (TME) reacts with disulfide bonds to release of the nanosensitizer (Cu-MOF). Subsequently, Cu-MOF generates reactive oxygen species (ROS) upon ultrasound irradiation for SDT, and releases L-cysteine(L-Cys) catalyzed by 3-mercapto pyruvate sulfotransferase (3-MST) to generate H 2 S for gas therapy. The CSSH-Gel obtained excellent synergistic anti-tumor effects (82.34 % inhibition ratio in vivo), which holds tremendous promise for the advancement of minimally invasive glioma therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fibroblast growth factor (FGF) is involved in the progression of glioma, a most common type of brain tumor, and breast tumors. In this study, we aim to evaluate the effects of the inhibitor PP2 on cell proliferation and migration in glioma and breast tumor cells, and to characterize the molecular mechanisms involved in these processes. The inhibitory effect of PP2 on the tumorigenic potential of C6 glioma and MDA-MB-231 cells was examined by proliferation, migration, and invasion assays, and apoptotic analysis. The molecular mechanism behind the anti-glioma activity of PP2 was investigated by immunoblotting, immunoprecipitation, phosphoprotein assay, cellular thermal shift assay (CETSA), and molecular docking modeling. PP2 suppressed the proliferation and migration of C6 glioma and MDA-MB-231 cells via FGF2. Moreover, PP2 directly blocked the enzyme activity of FGF receptor 1 (FGFR1) and Src, subsequently affecting the nuclear factor-κB and activator protein-1 signaling pathways. CETSA analysis and the docking model indicated that the TK1 domains (Val 492 ad Glu 486) of FGFR2 could be binding sites of PP2. Collectively, therefore, our findings suggest that PP2 mediates antitumor effects by targeting both FGFR1 and Src and may have applications as a therapeutic inhibitor for the treatment of glioma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Temozolomide (TMZ) is the first-line chemotherapeutic drug for gliomas treatment. However, the clinical efficacy of TMZ in glioma patients was very limited. Therefore, it is urgently needed to discover a novel approach to increase the sensitivity of glioma cells to TMZ., Methods: Western blot, immunohistochemical staining, and qRT-PCR assays were used to explore the mechanisms underlying TMZ promoting DKK1 expression and andrographolide (AND) inhibiting DKK1 expression. HPLC was used to detect the ability of andrographolide (AND) to penetrate the blood-brain barrier. MTT assay, bioluminescence images, magnetic resonance imaging (MRI) and H&E staining were employed to measure the proliferative activity of glioma cells and the growth of intracranial tumors., Results: TMZ can promote DKK1 expression in glioma cells and brain tumors of an orthotopic model of glioma. DKK1 could promote glioma cell proliferation and tumor growth in an orthotopic model of glioma. Mechanistically, TMZ increased EGFR expression and subsequently induced the activation of its downstream MEK-ERK and PI3K-Akt pathways, thereby promoting DKK1 expression in glioma cells. Andrographolide inhibited TMZ-induced DKK1 expression through inactivating MEK-ERK and PI3K-Akt pathways. Andrographolide can cross the blood-brain barrier, the combination of TMZ and andrographolide not only improved the anti-tumor effects of TMZ but also showed a survival benefit in an orthotopic model of glioma., Conclusion: Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Glioma poses a serious threat to human health and has a high mortality rate. Therefore, developing natural anti-tumour drugs for cancer treatment is an urgent priority. Schizophyllum commune is an edible and medicinal fungus, with polysaccharides as its main active components, which may have anti-tumour properties. Herein, we characterised S. commune fruiting body polysaccharides (SCFP) structure and evaluated its anti-glioma activity in vitro and in vivo. UV and FTIR spectra, high-performance gel chromatography, and monosaccharide composition analyses demonstrated that SCFP was a heteropolysaccharide with a molecular weight of 290.92 kDa. Among the monosaccharide compositions, mannose, galactose, and glucose were the most abundant. SCFP significantly inhibited the survival of the glioma cell lines U251 and U-87MG. U251 xenograft tumours treated with SCFP via gavage showed a 47.39 % inhibition, with no significant toxic side effects observed. SCFP upregulated aplasia Ras homologue member I (ARHI) expression, thereby regulating PI3K/AKT signalling, inhibiting tumour migration, and inducing apoptosis, to inhibit tumour growth. Furthermore, SCFP treatment increased the relative abundance of beneficial bacteria, including Akkermansia muciniphila, Ligilactobacillus murinus, and Parabacteroides goldsteinii, in tumour-bearing mice and restored the gut microbiota structure to that of the normal group (NG group) mice without tumours. Thus, SCFP has the potential for application as a natural anticancer drug., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We declare that we do not have any commercial or related interests that conflict with our work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The risk of herpes zoster in patients treated with temozolomide is poorly defined in the literature. We aimed to evaluate the incidence of and risk factors for herpes zoster in individuals receiving temozolomide for glioma., Methods: A retrospective observational study was conducted on a series of patients treated with temozolomide for glioma at a single centre between 1 October 2018 and 30 September 2023., Results: 131 patients were treated with temozolomide for glioma with a median age of 55 years. 4 out of 131 patients (3.1 %) developed herpes zoster during temozolomide treatment. All cases of herpes zoster occurred in patients who had lymphocyte nadirs of less than 0.7 x 10 9 /L and were receiving corticosteroids concomitantly. The estimated herpes zoster incidence rates were 45.44 per 1000 person-years (95 % confidence interval (CI) 12.38-116.34 per 1000 person-years) in the overall study population and 224.97 per 1000 person-years (95 % CI 61.30-576.02 per 1000 person-years) in subjects who were treated with corticosteroids and had a lymphocyte nadir of less than 1.0 x 10 9 /L., Conclusion: Use of temozolomide, particularly in conjunction with lymphopaenia or corticosteroid use, poses a risk of herpes zoster. Further research into the benefits of prophylactic antiviral measures in this population is recommended., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: A dedicated magnetic resonance imaging simulation (MRsim) for radiation treatment (RT) planning in patients with high-grade glioma (HGG) can detect early radiologic changes, including tumor progression after surgery and before standard of care chemoradiation. This study aimed to determine the effect of using postoperative magnetic resonance imaging (MRI) versus MRsim as the baseline for response assessment and reporting pseudoprogression on follow-up imaging at 1 month (FU1) after chemoradiation., Methods and Materials: Histologically confirmed patients with HGG were planned for 6 weeks of RT in a prospective study for adaptive RT planning. All patients underwent postoperative MRI, MRsim, and follow-up MRI scans every 2 to 3 months. Tumor response was assessed by 3 independent blinded reviewers using Response Assessment in Neuro-Oncology criteria when baseline was either postoperative MRI or MRsim. Interobserver agreement was calculated using Light's kappa., Results: Thirty patients (median age, 60.5 years; IQR, 54.5-66.3) were included. Median interval between surgery and RT was 34 days (IQR, 27-41). Response assessment at FU1 differed in 17 patients (57%) when the baseline was postoperative MRI versus MRsim, including true progression versus partial response or stable disease in 11 (37%) and stable disease versus partial response in 6 (20%) patients. True progression was reported in 19 patients (63.3%) on FU1 when the baseline was postoperative MRI versus 8 patients (26.7%) when the baseline was MRsim (P = .004). Pseudoprogression was observed at FU1 in 12 (40%) versus 4 (13%) patients, when the baseline was postoperative MRI versus MRsim (P = .019). Interobserver agreement between observers was moderate (κ = 0.579; P < .001)., Conclusions: Our study demonstrates the value of acquiring an updated MR closer to RT in patients with HGG to improve response assessment, and accuracy in evaluation of pseudoprogression even at the early time point of first follow-up after RT. Earlier identification of patients with true progression would enable more timely salvage treatments including potential clinical trial enrollment to improve patient outcomes., (Copyright © 2024. Published by Elsevier Inc.)

Plasmonic photothermal therapy (PPTT) employing plasmonic gold nanorods (GNRs) presents a potent strategy for eradication of tumors including aggressive brain gliomas. Despite its promise, there is a pressing need for a more comprehensive evaluation of PPTT using sophisticated in vitro models that closely resemble tumor tissues, thereby facilitating the elucidation of therapeutic mechanisms. In this study, we exposed 3D glioma spheroids (tumoroids) to (16-mercaptohexadecyl)trimethylammonium bromide-functionalized gold nanorods (MTAB-GNRs) and a near-infrared (NIR) laser. We demonstrate that the photothermal effect can be fine-tuned by adjusting the nanoparticle concentration and laser power. Depending on the selected parameters, the laser can trigger either regulated or non-regulated cell death (necrosis) in both mouse GL261 and human U-87 MG glioma cell lines, accompanied by translocation of phosphatidylserine in the membrane. Our investigation into the mechanism of regulated cell death induced by PPTT revealed an absence of markers associated with classical apoptosis pathways, such as cleaved caspase 3. Instead, we observed the presence of cleaved caspase 1, gasdermin D, and elevated levels of NLRP3 in NIR-irradiated tumoroids, indicating the activation of pyroptosis. This finding correlates with previous observations of lysosomal accumulation of MTAB-GNRs and the known lysosomal pathway of pyroptosis activation. We further confirmed the absence of toxic breakdown products of GNRs using electron microscopy, which showed no melting or fragmentation of gold nanoparticles under the conditions causing regulated cell death. In conclusion, PPTT using coated gold nanorods offers significant potential for glioma cell elimination occurring through the activation of pyroptosis rather than classical apoptosis pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Glioma coined as 'butterfly tumor' exhibits intense heterogeneity at the molecular and cellular levels. Although, Temozolomide exerted a long-ranging and prevailing therapeutic effect against glioma, albeit it has provided modest survival outcome. Fucoidan, (marine brown algal derivative) has demonstrated potent anti-tumor effects including glioma. Nevertheless, there is paucity of studies conducted on Fucoidan to enhance the anti-glioma efficacy of Temozolomide. The present study aimed to explore the plausible synergistic anti-glioma efficacy of Fucoidan in combination with Temozolomide in an in vivo experimental model. The dual-drug combination significantly inhibited tumor growth in in vivo and prolonged the survival rate when compared with the other treatment and tumor-control groups, via down-regulation of inflammatory cascade- IL-6/T LR4 and JAK/STAT3 as per the immunohistochemistry findings. Furthermore, the ultrastructural analysis indicated that the combinatorial treatment had restored the normal neuronal architecture of glioma-induced rats. Overall, the dual-drug cocktail might enhance the therapeutic outcome in glioma patients.

Glioma is the most prevailing main malignant neoplasm of the central nervous system with a miserable prognosis. Temozolomide is the first-line chemotherapy drug for glioma, but its drug resistance reduces temozolomide's clinical efficacy and becomes the principal cause of the failure of glioma chemotherapy. Polyphyllin I (PPI), an active component in Rhizoma Paridis, demonstrates favorable therapeutic actions in diverse malignant neoplasms. Its effect on temozolomide-resistant glioma, however, has not yet been characterized. Here, we demonstrated that polyphyllin I inhibited the proliferation of temozolomide-resistant glioma cell in a concentration-dependent manner. Further, we found that polyphyllin I had a direct effect on temozolomide-resistant glioma tumor cells and promote reactive oxygen species (ROS)-dependent apoptosis and autophagy via mitogen-activated protein kinase (MAPK)-signaling (p38-JNK) pathway. Mechanistically, we showed that polyphyllin I downregulate the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway, indicating that polyphyllin I may be an expected therapeutic strategy for patients with temozolomide-resistant gliomas.

Background: Nicotinamide and tryptophan metabolism play important roles in regulating tumor synthesis metabolism and signal transduction functions. However, their comprehensive impact on the prognosis and the tumor immune microenvironment of glioma is still unclear. The purpose of this study was to investigate the association of nicotinamide and tryptophan metabolism with prognosis and immune status of gliomas and to develop relevant models for predicting prognosis and sensitivity to immunotherapy in gliomas., Methods: Bulk and single-cell transcriptome data from TCGA, CGGA and GSE159416 were obtained for this study. Gliomas were classified based on nicotinamide and tryptophan metabolism, and PPI network associated with differentially expressed genes was established. The core genes were identified and the risk model was established by machine learning techniques, including univariate Cox regression and LASSO regression. Then the risk model was validated with data from the CGGA. Finally, the effects of genes in the risk model on the biological behavior of gliomas were verified by in vitro experiments., Results: The high nicotinamide and tryptophan metabolism is associated with poor prognosis and high levels of immune cell infiltration in glioma. Seven of the core genes related to nicotinamide and tryptophan metabolism were used to construct a risk model, and the model has good predictive ability for prognosis, immune microenvironment, and response to immune checkpoint therapy of glioma. We also confirmed that high expression of TGFBI can lead to an increased level of migration, invasion, and EMT of glioma cells, and the aforementioned effect of TGFBI can be reduced by FAK inhibitor PF-573,228., Conclusions: Our study evaluated the effects of nicotinamide and tryptophan metabolism on the prognosis and tumor immune microenvironment of glioma, which can help predict the prognosis and sensitivity to immunotherapy of glioma., (© 2024. The Author(s).)

Brain tumors, particularly Glioblastoma Multiforme (GBM) and Low-Grade Gliomas (LGG), present significant clinical challenges due to their aggressive nature and resistance to conventional treatments. Traditional therapies such as surgery, chemotherapy, and radiation are often limited in efficacy, necessitating novel therapeutic strategies. Nanotechnology, particularly the use of silver nanoparticles (Ag NPs), offers a targeted and potentially more effective approach. This study focuses on the green synthesis of Ag NPs using Podocarpus macrophyllus leaf extract as a reducing agent. The synthesized Ag NPs were characterized for their physicochemical properties, demonstrating a controlled particle size of 13 nm as determined by scanning electron microscopy (SEM). Fourier-transform infrared (FTIR) spectroscopy confirmed the presence of functional groups, and energy-dispersive X-ray (EDX) spectroscopy revealed that silver constituted approximately 90% of the nanoparticle composition. The Ag NPs exhibited promising biological activity, including 90% free radical scavenging (antioxidant) activity, 99.15% inhibition of protein denaturation (anti-inflammatory activity), and 90.56% inhibition of alpha-amylase (anti-diabetic activity). Additionally, the nanoparticles displayed significant anti-hemolytic (89.9% inhibition) and antimicrobial activities, with a 20 mm inhibition zone against Staphylococcus species. Computational analyses further indicated that the NOTCH2 gene, which is upregulated in LGG and GBM, may interact with Ag NPs, suggesting their potential in brain cancer therapy. The green synthesis approach offers a sustainable and bioactive method for producing Ag NPs, underscoring their therapeutic promise for treating GBM and LGG., (© 2024. The Author(s).)

Self-assembled small peptide-based nanoparticles (NPs) constitute a major section of the biomimetic smart NPs owing to their excellent compatibility and minimal adverse effects in the biological system. Here, we have designed a modified L-carnosine dipeptide analog, "Fmoc-β-Ala-L-His-(Trt)- o -methyl formate", which was assembled along with a modified single amino acid, Fmoc-Arg-(Pbf)-OH and zinc ions to form stable and mono-dispersed L-carnosine analog NPs (CaNPs) with inherent anti-cancer properties. Furthermore, the CaNPs demonstrated an average size of ∼200 nm, making them suitable to invade the tumor site by following the enhanced permeability and retention (EPR) effect. Our studies depicted a remarkable cancer cell killing ability of the NPs of ∼82% in C6 glioma cells. Thereafter, cellular investigations were performed in C6 cells to analyze the influence of the NPs on cellular cytoskeleton integrity by using a phalloidin assay and anti-cancer efficacy by using calcein AM/PI, and an apoptosis assay further indicated their anti-cancer effect. Additionally, the NPs negatively impacted the ability of C6 cells to migrate across a premade scratch (∼44% wound closure) demonstrating their tendency to halt cancer cell migration and metastasis. Also, our NPs depicted ∼19.51 ± 0.17% permeability across the bEnd.3 transwell model establishing their BBB penetrability. Collectively, our results could positively implicate the successful anti-cancer potential of the minimalistic, biologically compliant, L-carnosine analog (Ca)-based nanostructures in glioma.

Background: Malignant gliomas represent a heterogenous group of brain cancers that are characterized by infiltrative growth that lacks a clearly identifiable tumor border. The lack of the possibility of radical surgical resection and targeted therapy results in a poor prognosis. Although Temozolomide (TMZ) is still the leading chemotherapeutic agent in glioma treatment, its efficacy is limited due to the development of tumor resistance. Therefore, there an urgent need to improve the diagnosis and treatment of these tumors. Finding and developing biomarkers that are specific to glioma could be useful for both identifying therapy targets and monitoring treatment as well as for constructing a personalized therapy. However, there are still no reliable markers that would change the quality of glioma treatment., Methods: In this study, differences in the expression of 84 cancer-related proteins in three glioma cell lines were analyzed using the dot-blot method: commercial T98G cells and two patient-derived cell lines. The influence of TMZ on changes in protein expression, cell morphology, and migration was also investigated (Proteome Profiler Human XL Oncology Array, LeviCell System, Microscopic imaging). The lines that were analyzed were characterized by a remarkably different plasticity of protein expression and the proteomic alterations that were induced by TMZ., Results: A dot-blot analysis revealed ten proteins that were common to all of the lines and five (Cathepsin b, FGF, Survivin, AXL, Osteopontin) that were modulated by the TMZ. As a result of the exposure of TMZ, the proteins that are involved in chemoresistance and invasion (TIE-2, Thrombospondin) were detected in both the HROG02 and T98G cell lines. In the control culture (not exposed to TMZ) of HROG17 cells, the proteins that are involved in metabolism were strongly suppressed., Conclusions: The presented data sheds new light on the modulatory effect of Temozolomide on the expression of a protein panel: Cathepsin b, fibroblast growth factor (FGF), Survivin, AXL, and Osteopontin that may suggest their potential as therapeutic targets or biomarkers to monitoring therapy effects. However, further high-throughput analysis and detection of the proteins in the body fluids are necessary., (© 2024 The Author(s). Published by IMR Press.)

Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors., Competing Interests: Declaration of interests The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Interleukin-18, a member of the interleukin - 1 family of cytokines, is upregulated in glioma. However, its effects on glioma remain unclear. This study aimed to explore the role and underlying mechanisms of interleukin-18 expression in glioma. Here, we demonstrated that interleukin-18 enhanced resistance to temozolomide by increasing proliferation and inhibiting apoptosis in cultured glioma cells. Further in vivo studies revealed that interleukin-18 promoted temozolomide resistance in BALB/c nude mice bearing tumor. Mechanical exploration indicated that interleukin-18 stimulation could activate the PI3K/AKT signaling pathway in glioma cells, and PI3K inhibition could reduce the temozolomide resistance promoted by interleukin-18. We found that interleukin-18 upregulated CD274 expression in glioma, revealing its potential effects on the microenvironment. Furthermore, we established a tumor xenograft model and explored the therapeutic efficacy of anti-interleukin-18 monoclonal antibody. Targeting interleukin-18 prolonged survival and attenuated CD274 expression in the mice bearing tumor. Combined treatment with anti-interleukin-18 and anti-PD-1 monoclonal antibody showed better efficacy in suppressing tumor growth than either treatment alone in mice bearing tumor. Collectively, these data present that interleukin-18 promotes temozolomide chemoresistance in glioma cells via PI3K/Akt activation and establishes an immunosuppressive milieu by modulating CD274. This study highlights the therapeutic value of interleukin-18 in glioma., (© 2024. The Author(s).)

Glioblastoma, a fatal brain cancer with limited treatments and poor prognosis, could benefit from targeting the L-type amino acid transporter I (LAT1). LAT1 is essential for cancer cells to acquire necessary amino acids. Tetrahydrocurcumin (THC), a key curcumin derivative, shows potential for glioblastoma treatment. However, its effectiveness is hindered by poor physicochemical and pharmacokinetic properties. Therefore, this study aims to improve the therapeutic efficacy of THC against glioblastoma by chemically modifying it to target LAT1. A novel series of THC-amino acid conjugates were synthesized by conjugating five amino acids: glycine, leucine, isoleucine, and phenylalanine to THC via carbamate bonds. The therapeutic efficacy of THC-amino acid conjugates was further examined in C6 glioma cells, including the role of LAT1 in their therapeutic effects. Among the conjugates tested, THC conjugated with two phenylalanines (THC-di-Phe) showed remarkably higher cytotoxicity against C6 glioma cells (35.8 μM) compared to THC alone (110.7 μM). THC-di-Phe induced cellular death via necrosis and apoptosis, outperforming THC. Additionally, THC-di-Phe inhibited C6 cell proliferation and migration more effectively than THC. Co-incubation of THC-di-Phe with the LAT1 inhibitor 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) further increased cellular death. THC-di-Phe also significantly inhibited the P70SK/S6 pathway, regulated by LAT1 inhibitors, more effectively than THC and displayed a similar binding mode with both JX-075 and BCH to the active site of LAT1. Findings suggest the potential role of THC-di-Phe as a LAT1 inhibitor and provide novel insight into its use as a potent antitumor agent in glioma with increased therapeutic efficacy.

H3K27M diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like and AC-like phenotypes and perform transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs in the different cellular states. We then define strategies to target metabolic vulnerabilities within specific tumor populations. We show that AC-like cells exhibit a mesenchymal phenotype and are sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulate cholesterol biosynthesis, have diminished mitochondrial oxidative phosphorylation (OXPHOS), and are accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors show efficacy and extend survival in preclinical orthotopic models established with stem-like H3K27M DMG cells. Together, this study demonstrates that cellular subtypes within DMGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain., (© 2024. The Author(s).)

Gliomas are one of the most frequent primary brain tumors and pose a serious threat to people's lives and health. Platelets, a crucial component of blood, have been applied as drug delivery carriers for disease diagnosis and treatment. In this study, we designed engineered nanoplatelets for targeted delivery of therapeutic miR-375 and temozolomide (TMZ, a first-line glioma treatment agent) to enhance glioma therapy. Nanoplatelets were prepared through mild ultrasound, TMZ and miR-375 were co-loaded through ultrasound and electrostatic interactions, respectively, to combine chemotherapy with gene therapy against glioma. To improve the blood brain barrier (BBB) crossing efficiency and glioma targeting ability, the nanoplatelets were modified with central nervous system-specific rabies viral glycoprotein peptide (RVG) through thiol-maleimide click reaction. The RVG modified nanoplatelets co-loaded TMZ and miR-375 (NR/TMZ/miR-375) not only inherited the good stability and remarkable biocompatibility of platelets, but also promoted the cellular uptake and penetration of glioma tissues, and effectively induced cell apoptosis to enhance the therapeutic effect of drugs. In vivo studies showed that NR/TMZ/miR-375 significantly increased the circulation time of TMZ, and exhibited superior combined antitumor effects. In summary, this multifunctional 'natural' nanodrug delivery system provides a potent, scalable, and safety approach for platelet-based combined cancer chemotherapy and gene therapy., (© 2024. The Author(s).)

Background: This case series describes the safety and efficacy of superselective intra-arterial (IA) cerebral infusion of teniposide for the treatment of patients with glioma, to provide new ideas and methods for the treatment of high grade gliomas., Methods: 12 patients with glioma who were previously treated with standard therapy were treated with superselective IA cerebral infusion of teniposide. Patients received at least two cycles of treatment (one cycle: 150 mg/time, used for 1 day, repeated at 28 day intervals) after blood-brain barrier disruption. Patients received individualized treatment on the tumor location. The ophthalmic artery was bypassed during the super-selective arterial infusion., Results: No significant differences in biochemical indexes and Karnofsky performance status (KPS) score were observed before and after treatment, and no evident adverse events occurred (P>0.05). In a recent response evaluation (August 2023), two (8%) patients presented with a complete response (16.7%), four had a partial response (33.3%), four had stable disease (33.3%), and two showed progressive disease (16.7%). The overall response rate and disease control rate were 50.0% and 83.3%, respectively. In addition, we described the detailed course of treatment in two patients. Case No 1 (recurrent tumor) and case No 2 (primary tumor) received six and three cycles of teniposide infusion, respectively. After treatment, the tumors of the patients were significantly reduced without evident adverse effects., Conclusion: This small series suggests that superselective IA cerebral infusion of teniposide may be a safe and effective therapy in the multimodal treatment of malignant glioma and warrants further study in larger prospective investigations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aggressive glioma exhibits a poor survival rate. Increased tumor aggression is linked to both tumor cells and tumor-associated macrophages (TAMs), which induce pro-aggression, invasion, and metastasis. Imperatively, for effective treatment, it is important to target both glioma cells and TAMs. Haloperidol, a neuropsychotic drug, avidly targets the sigma receptor (SR), which is expressed in higher levels in both the cell types. Herein, we present the development of a novel cationic lipid-conjugated reduced haloperidol (±RHPC8), which aims to mediate the SR-targeted antiglioma effect. Hypothetically, ±RHPC8 would act simultaneously as an SR-targeting ligand and anticancer agent. As the blood-brain barrier (BBB) obstructs direct targeting of in situ glioma, we used BBB-crossing glucose-based carbon nanospheres (CSPs) to deliver ±RHPC8 within the glioma tumor-bearing mouse brain. The resultant ±RHPC8-CSP nanoconjugate targeted SR-expressing glioma cells. In both orthotopic and subcutaneous mouse tumor models, ±RHPC8-CSP prolonged survival and regressed tumors compared to other treated groups. Notably, ±RHPC8-CSP was significantly taken up by SR-expressing TAMs thus resulting in macrophage polarization from M2 to M1, as exhibited by markedly reduced expression of immunosuppressive cytokines released by TAMs, including TGF-β, IL-10, and VEGF. In conclusion, the designed ±RHPC8-CSP nanoconjugate presented an effective nanodrug delivery system for brain cancer treatment.

Glioma is the most prevalent malignant brain tumor in adults. The development of engineered nanomaterials (ENMs) has led to the emergence of innovative therapeutic strategies for gliomas. Therefore, our aim is to investigate the therapeutic effect of CuO nanoparticles (NPs) on glioma and provide data support for future research. The therapeutic effect of CuO NPs on glioma rats was explored through the detection of inflammatory factors, oxidase, pathological sections, immunofluorescence, neurotransmitter, glioma biomarker proteins and genes, and rat behavioral tests. Additionally, the application prospect of CuO NPs was evaluated by treating U87MG human glioma cell line. In this study, it was found that CuO NPs can alleviate the inflammatory reaction in the hippocampus tissue of glioma rats, promote the production of ·OH and lead to the up-regulation of catalase (CAT) and superoxide dismutase (SOD) enzyme activities. Treatment with CuO NPs also inhibited the expression of matrix metalloproteinase-9 (MMP-9) biomarkers in model rats and glioma cells. Moreover, it enhanced the release of neurotransmitters, which subsequently improved spatial recognition and memory ability of glioma rats. In conclusion, CuO NPs is a potential glioma treatment for ENMs, but still needs modification and modification strategies to improve its biocompatibility and targeted delivery., (© 2024. The Author(s).)

Background: IDH-wild type (-wt) status is a prerequisite for the diagnosis of glioblastoma (GBM); however, IDH-wt gliomas with low-grade or anaplastic morphology have historically been excluded from GBM trials and may represent a distinct prognostic entity. While alkylating agent chemotherapy improves overall survival (OS) and progression-free survival (PFS) for IDH-wt GBM and also IDH-mutant gliomas, irrespective of grade, the benefit for IDH-wt diffuse histologic lower-grade gliomas is unclear., Methods: We performed a meta-analysis of randomized clinical trials for World Health Organization (WHO) grades 2-3 gliomas (2009 to present) to determine the effect of alkylating chemotherapy on IDH-wt and -mutant gliomas using a random-effects model with inverse-variance pooling., Results: We identified 6 trials with 1204 patients (430 IDH-wt, 774 IDH-mutant) that evaluated alkylating chemoradiotherapy versus radiotherapy alone, allowing us to perform an analysis focused on the value of adding alkylating chemotherapy to radiotherapy. For patients with IDH-wt tumors, alkylating chemotherapy added to radiotherapy was associated with improved PFS (HR:0.77 [95% CI: 0.62-0.97], P = .03) but not OS (HR:0.87 [95% CI: 0.64-1.18], P = .17). For patients with IDH-mutant tumors, alkylating chemotherapy added to radiotherapy improved both OS (HR:0.52 [95% CI: 0.42-0.64], P < .001) and PFS (HR = 0.47 [95% CI: 0.39-0.57], P < .001) compared to radiotherapy alone. The magnitude of benefit was similar for IDH-mutant gliomas with or without 1p19q-codeletion., Conclusions: Alkylating chemotherapy reduces mortality by 48% and progression by 53% for patients with IDH-mutant gliomas. Optimal management of IDH-wt diffuse histologic lower-grade gliomas remains to be determined, as there is little evidence supporting an OS benefit from alkylating chemotherapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The 2016 and 2021 World Health Organization 2021 Classification of central nervous system tumors have resulted in a major improvement in the classification of isocitrate dehydrogenase (IDH)-mutant gliomas. With more effective treatments many patients experience prolonged survival. However, treatment guidelines are often still based on information from historical series comprising both patients with IDH wild-type and IDH-mutant tumors. They provide recommendations for radiotherapy and chemotherapy for so-called high-risk patients, usually based on residual tumor after surgery and age over 40. More up-to-date studies give a better insight into clinical, radiological, and molecular factors associated with the outcome of patients with IDH-mutant glioma. These insights should be used today for risk stratification and for treatment decisions. In many patients with IDH-mutant grades 2 and 3 glioma, if carefully monitored postponing radiotherapy and chemotherapy is safe, and will not jeopardize the overall outcome of patients. With the INDIGO trial showing patient benefit from the IDH inhibitor vorasidenib, there is a sizable population in which it seems reasonable to try this class of agents before recommending radio-chemotherapy with its delayed adverse event profile affecting quality of survival. Ongoing trials should help to further identify the patients that are benefiting from this treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Vorasidenib (VORANIGO ® ; Servier) is an orally administered, first-in-class, highly brain-penetrant dual inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) enzymes being developed for use in IDH-mutant diffuse glioma. Vorasidenib received its first approval on 6 August 2024, in the USA, for the treatment of adult and pediatric patients aged 12 years and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery, including biopsy, sub-total resection, or gross total resection. Approval was based on results from the multinational phase III INDIGO trial, in which vorasidenib significantly improved progression-free survival and time to the next anticancer intervention relative to placebo. In the EU and other countries worldwide, regulatory review of vorasidenib in IDH-mutant glioma is currently underway. This article summarizes the milestones in the development of vorasidenib leading to this first approval for glioma., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Patients with brain tumours are motivated to participate in clinical trials involving repeat tissue sampling. Normalising the use of neoadjuvant and staged surgical trials necessitates collaboration among patients, regulatory agencies, and researchers. Initial and repetitive tissue sampling plays a crucial role in enhancing our understanding of resistance mechanisms and vulnerabilities in brain tumour therapy. Standardising biopsy techniques and ensuring technical uniformity across institutions are vital for effective interinstitutional collaboration. Although liquid biopsy technologies hold promise, they are not yet ready to replace tissue analysis. Clear communication about the risks and benefits of biopsies is essential, particularly regarding potential postoperative deficits. Changes in mindset and neurosurgical culture are imperative to achieve much needed breakthroughs in the development of new, effective therapies for brain tumours., Competing Interests: Declaration of interests MG declares research grant support from Evgen Pharm. KCS declares honoraria from Springworks Therapeutics and Novartis; declares research funding to her institution from Springworks Therapeutics; and serves on a data and safety monitoring board for Advarra. TFC is cofounder, major stock holder, consultant, and board member of Katmai Pharmaceuticals; holds stock for Erasca; is a member of the board and paid consultant for the 501c3 Global Coalition for Adaptive Research; holds stock in Chimerix and receives milestone payments and possible future royalties; is a member of the scientific advisory board for Break Through Cancer foundation and Cure Brain Cancer Foundation; has provided paid consulting services to Symbio, Mundipharma, Tango BlueRock, Vida Ventures, Lista Therapeutics, Stemline, Novartis, Roche, Sonalasense, Sagimet, Clinical Care Options, Ideology Health, Servier, Jubilant, Immvira, Gan & Lee, BrainStorm, Katmai, Sapience, Inovio, Vigeo Therapeutics, DNATrix, Tyme, SDP, Kintara, Bayer, Merck, Boehringer Ingelheim, VBL, Amgen, Kiyatec, AbbVie, VBI, Deciphera, Agios, Novocure, and Medscape; and has contracts with UCLA for the Brain Tumour Programme with Roche, VBI, Merck, Novartis, and Bristol Myers Squibb. The Regents of the University of California, TFC's employer, has licensed intellectual property co-invented by TFC to Katmai Pharmaceuticals. GL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics, IOBiotech, Immunocore, Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR, Pierre Fabre, and Regeneron. AC declares research funding and honoraria from AstraZeneca, Benevolent AI, Duke Street Bio, and Evgen Pharmaceuticals; and has received honoraria from Storm Therapeutics. MSA declares a grant from Seagen; declares consulting fees from Bayer, Kiyatec, Insightec, GSK, Xoft, Nuvation, SDP Oncology, Apollomics, Prelude, Janssen, Voyager Therapeutics, Viewray, Caris Lifesciences, Pyramid Biosciences, Varian Medical Systems, Cairn Therapeutics, Anheart Therapeutics, Theraguix, Menarini Ricerche, Sumitomo Pharma Oncology, Autem Therapeutics, GT Medical Technologies, Allovir, and Equillium Bio; is on the data and safety monitoring board for VBI Vaccines; is on the scientific advisory board of Modifi biosciences and Bugworks; and is a shareholder for Mimivax, Cytodyn, MedInnovate Advisors, and Trisalus Lifesciences. SB reports consulting fees from and is a member of the advisory boards of Telix, Servier, Bayer, and Novocure; and research grants from Incyte, GSK, Lilly, Kite, and Novocure. JdG reports being an advisory board member for Kintara Pharmaceuticals, Kazia, MundiPharma, Insightec, Monteris, Carthera, Samus, Sapience, DSP Pharma, Telix, Servier, Alpha Pharmaceuticals, Nervianos, and CapitalOne; is a data safety monitoring board member for Chimerix and VBI; and has consulted for MundiPharma, Insightec, Carthera, Kintara, Deciphera, Kazia, and Nervianos. IP reports research funding from Merck. TCB reports consulting roles for Predicine; has received financial support from AbbVie and Predicine, with consulting fees paid to Mayo Clinic; and has been a member of the advisory board for Neurametrix. MPr reports honoraria from the following for-profit companies: Bayer, Bristol Myers Squibb, Novartis, Gerson Lehrman Group, CMC Contrast, GSK, Mundipharma, Roche, BMJ Journals, MedMedia, AstraZeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dohme, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Boehringer Ingelheim, Telix, and Medscape. JCT reports research grants from Novocure and Munich Surgical Imaging; being on the advisory board of Advanced Accelerator Applications, Novartis; and Servier; and has received royalties from Springer Publishing. MPl reports being a founder of Tcelltech; has received research support from Bayer, Roche, Pfizer, and Merck; and is an advisory board member of Bayer and Servier. SD is speaker for the Congress of Neurological Surgeons (CNS) and the American Association of Neurological Surgeons; receives research funding from Alkermes; is a member of the Subcortical Surgery Group advisory board; has received royalties from Oxford University Press; and is provincial lead for CNS Oncology at Ontario Health. KT reports consulting fees from Oncohereos Biosciences; and advisory board roles for Advanced Accelerator Applications, Novartis; Sage Therapeutics; FYR Diagnostics; Cordance Medical; Telo Therapeutics; and Modifi Bio. MAV reports clinical trial funding to their institution from DeNovo Pharma, Infuseon, and Oncosynergy; and received honoraria fees from Biodexa and Servier Pharma. MW reports research grants from Novartis, Quercis, and Versameb; honoraria for advisory boards from Roche and Servier; and honoraria for consultation from Bayer, Curevac, Medac, Neurosense, Novartis, Novocure, Orbus, Philogen, and Servier. JRW reports research funding from AnHeart Therapeutics to their institution; received consulting fees from AnHeart Therapeutics and Servier; being on advisory boards for Roche and Merck; is a data safety monitoring member for Telix Pharmaceuticals; and is an employee of The Walter and Eliza Hall Institute and could be eligible for milestone and royalty payments related to Venetoclax. MK reports research grants from Bristol Myers Squibb, AbbVie, BioNTech, CNS Pharmaceuticals, Daiichi Sankyo, Immorna Therapeutics, Immvira Therapeutics, and Personalis; received consulting fees from The Jackson Lab for Genomic Research, AnHeart Therapeutics, Berg Pharma, George Clinical, Manarini Stemline, and Servier; received honoraria from GSK; and is on a data safety monitoring board for BPGbio. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The epidermal growth factor receptor (EGFR) plays a pivotal role in tumor progression and is an essential therapeutic target for treating malignant gliomas. Small interfering RNA (siRNA) has the potential to selectively degrade EGFR mRNA, yet its clinical utilization is impeded by various challenges, such as inefficient targeting and limited escape from lysosomes. Our research introduces polyethylene glycol (PEG) and endoplasmic reticulum membrane-coated siEGFR nanoplexes (PEhCv/siEGFR NPs) as an innovative approach to brain glioma therapy by overcoming several obstacles: 1) Tumor-derived endoplasmic reticulum membrane modifications provide a homing effect, facilitating targeted accumulation and cellular uptake; 2) Endoplasmic reticulum membrane proteins mediate a non-degradable "endosome-Golgi-endoplasmic reticulum" transport pathway, circumventing lysosomal degradation. These nanoplexes demonstrated significantly enhanced siEGFR gene silencing in both in vitro and in vivo U87 glioma models. The findings of this study pave the way for the advanced design and effective application of nucleic acid-based therapeutic nanocarriers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background and Objective: The identification of mutation hot spots in the isocitrate dehydrogenase (IDH) genes is one of the most important cancer genome-wide sequencing discoveries with relevant impact in the treatment of some orphan tumors. These genes were mostly found mutated in lower-grade gliomas (LGGs), acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) and in cholangiocarcinoma. This aberrant genomic condition represents a therapeutic target of great interest in cancer research, especially in AML, given the limitations of currently approved therapies in this field. In this review, we investigate the role of IDH mutation and the mutant IDH (mIDH)-targeted therapies for cholangiocarcinoma and glioma., Methods: Here, we provide an overview of the IDH mutation role and discuss its role in tumorigenesis and progression of some solid cancers, in which the therapeutic strategy can be completely changed thanks to these brand-new therapeutic options., Key Content and Findings: The encouraging early clinical data demonstrated to be a proof of concept for investigational mIDH1/2 inhibitors in tumors with a paucity of therapeutic possibilities., Conclusions: Moreover, we list the most important randomised clinical trials still active with their preliminary results.

Glioma is one of the most common central nervous system (CNS) cancers that can be found within the brain and the spinal cord. One of the pressing issues plaguing the development of therapeutics for glioma originates from the selective and semipermeable CNS membranes: the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). It is difficult to bypass these membranes and target the desired cancerous tissue because the purpose of the BBB and BSCB is to filter toxins and foreign material from invading CNS spaces. There are currently four varieties of Food and Drug Administration (FDA)-approved drug treatment for glioma; yet these therapies have limitations including, but not limited to, relatively low transmission through the BBB/BSCB, despite pharmacokinetic characteristics that allow them to cross the barriers. Steps must be taken to improve the development of novel and repurposed glioma treatments through the consideration of pharmacological profiles and innovative drug delivery techniques. This review addresses current FDA-approved glioma treatments' gaps, shortcomings, and challenges. We then outline how incorporating computational BBB/BSCB models and innovative drug delivery mechanisms will help motivate clinical advancements in glioma drug delivery. Ultimately, considering these attributes will improve the process of novel and repurposed drug development in glioma and the efficacy of glioma treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Glioma, a type of brain tumor, poses significant challenges due to its heterogeneous nature and limited treatment options. Interferon-related genes (IRGs) have emerged as potential players in glioma pathogenesis, yet their expression patterns and clinical implications remain to be fully elucidated. We conducted a comprehensive analysis to investigate the expression patterns and functional enrichment of IRGs in glioma. This involved constructing protein-protein interaction networks, heatmap analysis, survival curve plotting, diagnostic and prognostic assessments, differential expression analysis across glioma subgroups, GSVA, immune infiltration analysis, and drug sensitivity analysis. Our analysis revealed distinct expression patterns and functional enrichment of IRGs in glioma. Notably, IFNW1 and IFNA21 were markedly downregulated in glioma tissues compared to normal tissues, and higher expression levels were associated with improved overall survival and disease-specific survival. Furthermore, these genes showed diagnostic capabilities in distinguishing glioma tissues from normal tissues and were significantly downregulated in higher-grade and more aggressive gliomas. Differential expression analysis across glioma subgroups highlighted the association of IFNW1 and IFNA21 expression with key pathways and biological processes, including metabolic reprogramming and immune regulation. Immune infiltration analysis revealed their influence on immune cell composition in the tumor microenvironment. Additionally, elevated expression levels were associated with increased resistance to chemotherapeutic agents. Our findings underscore the potential of IFNW1 and IFNA21 as diagnostic biomarkers and prognostic indicators in glioma. Their roles in modulating glioma progression, immune response, and drug sensitivity highlight their significance as potential therapeutic targets. These results contribute to a deeper understanding of glioma biology and may inform the development of personalized treatment strategies for glioma patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pediatric low-grade gliomas (PLGG) are commonly treated with a combination of surgery, radiotherapy, and chemotherapy. Recent trends prioritize reducing long-term morbidities, particularly in younger patients. While historically chemotherapy was reserved for cases progressing after radiotherapy, evolving recommendations now advocate for its early use, particularly in younger age groups. The carboplatin and vincristine (CV) combination stands as a standard systemic therapy for PLGG, varying in dosage and administration between North America and Europe. Clinical trials have shown promising response rates, albeit with varying toxicity profiles. Vinblastine has emerged as another effective regimen with minimal toxicity. TPCV, a regimen combining thioguanine, procarbazine, lomustine, and vincristine, was compared to CV in a Children's Oncology Group trial, showing comparable outcomes, but more toxicity. Vinorelbine, temozolomide, and metronomic chemotherapy have also been explored, with varied success rates and toxicity profiles. Around 40-50% of PLGG patients require subsequent chemotherapy lines. Studies have shown varied efficacy in subsequent lines, with NF1 patients generally exhibiting better outcomes. The identification of molecular drivers like BRAF mutations has led to targeted therapies' development, showing promise in specific molecular subgroups. Trials comparing targeted therapy to conventional chemotherapy aim to delineate optimal treatment strategies based on molecular profiles. The landscape of chemotherapy in PLGG is evolving, with a growing focus on molecular subtyping and targeted therapies. Understanding the role of chemotherapy in conjunction with novel treatments is crucial for optimizing outcomes in pediatric patients with low-grade gliomas., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The aim of this study was to investigate the antiglioma effect of Cecropia pachystachya Trécul (CEC) leaves extract against C6 and U87 glioblastoma (GB) cells and in a rat preclinical GB model. The CEC extract reduced in vitro cell viability and biomass. In vivo, the extract decreased the tumor volume approximately 62%, without inducing systemic toxicity. The deficit in locomotion and memory and an anxiolytic-like behaviors induced in the GB model were minimized by CEC. The extract decreased the levels of reactive oxygen species, nitrites and thiobarbituric acid reactive substances and increased the activity of antioxidant enzymes in platelets, sera and brains of GB animals. The activity of NTPDases, 5'-nucleotidase and adenosine deaminase (ADA) was evaluated in lymphocytes, platelets and serum. In platelets, ATP and AMP hydrolysis was reduced and hydrolysis of ADP and the activity of ADA were increased in the control, while in CEC-treated animals no alteration in the hydrolysis of ADP was detected. In serum, the reduction in ATP hydrolysis was reversed by CEC. In lymphocytes, the increase in the hydrolysis of ATP, ADP and in the activity of ADA observed in GB model was altered by CEC administration. The observed increase in IL-6 and decrease in IL-10 levels in the serum of GB animals was reversed by CEC. These results demonstrate that CEC extract is a potential complementary treatment to GB, decreasing the tumor size, while modulating aspects of redox and purinergic systems., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: Scientists have been exploring anti-angiogenic strategies to inhibit angiogenesis and prevent tumor growth. Vasculogenic mimicry (VM) in glioblastoma multiforme (GBM) poses a challenge, complicating anti-angiogenesis therapy. A novel drug, GN25 (3-[{1,4-dihydro-5,8-dimethoxy-1,4-dioxo-2-naphthalenyl}thio]-propanoic acid), can inhibit tumor formation. This study aims to investigate the microenvironmental effects and molecular mechanisms of GN25 in anti-angiogenesis and anti-VM., Experimental Approach: MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay was used to evaluate the cell viability of different concentrations of GN25 in human umbilical vein endothelial cells (HUVEC) and Uppsala 87 malignant glioma (U87MG) cells. Functional assays were used to investigate the effects of GN25 on angiogenesis-related processes, whereas gelatin zymography, enzyme-linked immunosorbent assays, and Western blotting were utilized to assess the influence on matrix metalloproteinase (MMP)-2 and vascular endothelial growth factor (VEGF) secretion and related signaling pathways., Key Results: GN25 suppressed migration, wound healing, and tube formation in HUVECs and disrupted angiogenesis in a rat aorta ring and zebrafish embryo model. GN25 dose-dependently reduced phosphatidylinositol 3-kinase/AKT and inhibited MMP-2/VEGF secretion in HUVECs. In U87MG cells, GN25 inhibited migration, wound healing, and VM, accompanied by a decrease in MMP-2 and VEGF secretion. The results indicate that GN25 effectively inhibits angiogenesis and VM formation in HUVECs and U87MG cells without affecting preexisting vascular structures., Conclusion and Implications: This study elaborated GN25's potential as an anti-angiogenic agent by elucidating its inhibitory effects on classical angiogenesis. VM provides valuable insights for developing novel therapeutic strategies against tumor progression and angiogenesis-related diseases. These results indicate the potential of GN25 as a promising candidate for angiogenesis-related diseases., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The purpose of this study is to explore the shared molecular pathogenesis of traumatic brain injury (TBI) and high-grade glioma and investigate the mechanism of propofol (PF) as a potential protective agent. By analyzing the Chinese glioma genome atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases, we compared the transcriptomic data of high-grade glioma and TBI patients to identify common pathological mechanisms. Through bioinformatics analysis, in vitro experiments and in vivo TBI model, we investigated the regulatory effect of PF on extracellular matrix (ECM)-related genes through Prrx1 under oxidative stress. The impact of PF on BBB integrity under oxidative stress was investigated using a dual-layer BBB model, and we explored the protective effect of PF on tight junction proteins and ECM-related genes in mice after TBI. The study found that high-grade glioma and TBI share ECM instability as an important molecular pathological mechanism. PF stabilizes the ECM and protects the BBB by directly binding to Prrx1 or indirectly regulating Prrx1 through miRNAs. In addition, PF reduces intracellular calcium ions and ROS levels under oxidative stress, thereby preserving BBB integrity. In a TBI mouse model, PF protected BBB integrity through up-regulated tight junction proteins and stabilized the expression of ECM-related genes. Our study reveals the shared molecular pathogenesis between TBI and glioblastoma and demonstrate the potential of PF as a protective agent of BBB. This provides new targets and approaches for the development of novel neurotrauma therapeutic drugs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Malignant gliomas are an exceptionally lethal form of cancer with limited treatment options. Dihydroartemisinin (DHA), a sesquiterpene lactone antimalarial compound, has demonstrated therapeutic effects in various solid tumors. In our study, we aimed to investigate the mechanisms underlying the anticancer effects of DHA in gliomas. To explore the therapeutic and molecular mechanisms of DHA, we employed various assays, including cell viability, flow cytometry, mitochondrial membrane potential, glucose uptake and glioma xenograft models. Our data demonstrated that DHA significantly inhibited glioma cell proliferation in both temozolomide-resistant cells and glioma stem-like cells. We found that DHA-induced apoptosis occurred via the mitochondria-mediated pathway by initiating mitochondrial dysfunction before promoting apoptosis. Moreover, we discovered that DHA treatment substantially reduced the expression of the mitochondrial biogenesis-related gene, ERRα, in glioma cells. And the ERRα pathway is a critical target in treating glioma with DHA. Our results also demonstrated that the combination of DHA and temozolomide synergistically inhibited the proliferation of glioma cells. In vivo, DHA treatment remarkably extended survival time in mice bearing orthotopic glioblastoma xenografts. Thus, our findings suggest that DHA has a novel role in modulating cancer cell metabolism and suppressing glioma progression by activating the ERRα-regulated mitochondrial apoptosis pathway., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Re-irradiation (reRT) is an effective treatment modality for patients with recurrent glioma. Data on dose escalation, the use of simulated integrated boost and concomitant therapy to reRT are still scarce. In this monocentric cohort of n = 223 patients we investigated the influence of reRT dose escalation as well as the concomitant use of bevacizumab (BEV) with regard to post-recurrence survival (PRS) and risk of radionecrosis (RN)., Patients and Methods: Patients with recurrent glioma treated between July 2008 and August 2022 with reRT with BEV, reRT with temozolomide (TMZ) and reRT without concomitant systemic therapy were retrospectively analyzed. PRS and RN-free survival (RNFS) were calculated for all patients using the Kaplan-Meier estimator. Univariable and multivariable cox regression was performed for PRS and for RNFS. The reRT Risk Score (RRRS) was calculated for all patients., Results: Good, intermediate and poor risk of the RRRS translated into 11 months, 9 months and 7 months of median PRS (univariable: p = 0.008, multivariable: p = 0.013). ReRT was applied with a dose of ≤36 Gy (n = 140) or >36 Gy (n = 83). Concomitant bevacizumab (BEV) therapy was performed in n = 122 and concomitant temozolomide (TMZ) therapy in n = 32 patients. Median PRS was 10 months in patients treated with >36 Gy and 8 months in patients treated with ≤36 Gy (univariable: p = 0.032, multivariable: p = 0.576). Regarding concomitant TMZ therapy, median PRS was 14 months vs. 9 months for patients treated with or without TMZ (univariable: p = 0.041, multivariable: p = 0.019). No statistically significant influence on PRS was seen for concomitant BEV therapy in this series. RN was less frequent for reRT with concomitant BEV, (17/122; 13.9 %) than for reRT without BEV (30/101; 29.7 %). Regarding RNFS, the hazard ratio for reRT with BEV was 0.436 (univariable; p = 0.006) and 0.479 (multivariable; p = 0.023), respectively. ReRT dose did not show statistical significance in regards to RN (univariable: p = 0.073, multivariable: p = 0.404). RNFS was longer for patients receiving concomitant BEV to reRT than for patients treated with reRT only (mean 31.7 vs. 30.9 months, p = 0.004)., Conclusion: In this cohort, in patients treated with concomitant BEV therapy RN was less frequently detected and in patients treated with concomitant TMZ longer PRS was observed. Based on these results, the best concomitant therapy and the optimal dose should be decided on a patient-by-patient basis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Maximilian Niyazi has received speaker honoraria from Astra Zeneca und Brainlab. Raphael Bodensohn has received honoraria from NovoCure for participating in invited meetings of specialized centers. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Since the discovery of the association between BRAF mutations and fusions in the development of childhood low-grade gliomas and the subsequent recognition that most childhood low-grade glial and glioneuronal tumors have aberrant signaling through the RAS/RAF/MAP kinase pathway, there has been a dramatic change in how these tumors are conceptualized. Many of the fusions and mutations present in these tumors are associated with molecular targets, which have agents in development or already in clinical use. Various agents, including MEK inhibitors, BRAF inhibitors, MTOR inhibitors and, in small subsets of patients NTRK inhibitors, have been used successfully to treat children with recurrent disease, after failure of conventional approaches such as surgery or chemotherapy. The relative benefits of chemotherapy as compared to molecular-targeted therapy for children with newly diagnosed gliomas and neuroglial tumors are under study. Already the combination of an MEK inhibitor and a BRAF inhibitor has been shown superior to conventional chemotherapy (carboplatin and vincristine) in newly diagnosed children with BRAF-V600E mutated low-grade gliomas and neuroglial tumors. However, the long-term effects of such molecular-targeted treatment are unknown. The potential use of molecular-targeted therapy in early treatment has made it mandatory that the molecular make-up of the majority of low-grade glial and glioneuronal tumors is known before initiation of therapy. The primary exception to this rule is in children with neurofibromatosis type 1 who, by definition, have NF1 loss; however, even in this population, gliomas arising in late childhood and adolescence or those not responding to conventional treatment may be candidates for biopsy, especially before entry on molecular-targeted therapy trials., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Intraoperative photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) is a widely adopted technique to enhance the extent of resection during high-grade glioma (HGG) surgery. Recent updates to the package insert for 5-ALA in Japan now allow its use in combination with drugs that may induce photosensitivity, such as talaporfin sodium (TS). TS is employed in intraoperative photodynamic therapy (PDT) and has been shown to improve overall survival. The combination of 5-ALA with TS is expected to offer further benefits. However, the safety of this combination had not been established. This study reports on the safety of 5-ALA-PDD with TS-PDT in the treatment of recurrent HGG., Methods: 7 patients with recurrent HGG underwent tumor resection using a combination of 5-ALA-PDD and TS-PDT. The incidence of photosensitivity as an adverse effect associated with 5-ALA and TS was evaluated as described in the package insert. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0., Results: Tumor-specific fluorescence intensity was strong in 4 cases and weak in 3. Photosensitivity occurred in only 1 patient (14.3%). Three patients exhibited CTCAE grade 1 or 2 abnormal liver function, and 1 patient experienced CTCAE grade 1 γ-GTP elevation. All abnormalities improved during follow-up., Conclusions: The combined use of 5-ALA-PDD and TS-PDT for HGG surgery did not increase the risk of serious adverse events in our study. Further investigations with a larger number of cases are needed for a more accurate assessment of its safety and efficacy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Metabolites produced by the genus Streptomyces are the most important resource for discovering bioactive compounds. In this study, chemical investigation on the metabolites produced by the marine-derived Streptomyces sp. ZZ735 in rice solid medium led to the isolation of eighteen compounds (1-18). Chemical structures of the isolated compounds were determined based on their HRESIMS data and the extensive NMR spectral analyses. Streptonaphthothiazines A (1), B (2), 2-(2-hydroxy-2-methylpropanoylamino)-benzoic acid (7), and streptomycinoic acids A (17), B (18) are characterized as five previously undescribed compounds. The structural backbones of streptonaphthothiazines A (1), B (2) and streptomycinoic acids A (17), B (18) are found from a natural resource for the first time. It is also the first report of 2-(2-methylpropanoylamino)-benzoic acid (3), 2-(2-methylpropanoylamino)-benzamide (4), methyl 2-(3-hydroxypropanoylamino)-benzoate (5), 2-propionylaminobenzamide (6), and (2E)-3-(3-hydroxy-4,5-dimethoxyphenyl)-2-propenoic acid (15) as natural products. Streptonaphthothiazines A (1), B (2) and streptomycinoic acids A (17), B (18) have antiproliferative activity against human glioma U87MG or U251 cells with IC 50 values ranging from 31.8 to 37.9 μM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)