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Methods in Molecular Biology (Clifton,... 2024Mutation-containing immunogenic peptides from tumor cells, also named as neoantigens, have various amino acid descriptors and physical-chemical properties characterized...
Mutation-containing immunogenic peptides from tumor cells, also named as neoantigens, have various amino acid descriptors and physical-chemical properties characterized intrinsic features, which are useful in prioritizing the immunogenicity potentials of neoantigens and predicting patients' survival. Here, we describe a glioma neoantigen intrinsic feature database, GNIFdb, that hosts computationally predicted HLA-I restricted neoantigens of gliomas, their intrinsic features, and the tools for calculating intrinsic features and predicting overall survival of gliomas. We illustrate the application of GNIFdb in searching for possible neoantigen candidates from ATF6 that plays important roles in tumor growth and resistance to radiotherapy in glioblastoma. We also demonstrate the application of intrinsic feature associated tools in GNIFdb to predict the overall survival of primary IDH wild-type glioblastoma.
Topics: Humans; Histocompatibility Antigens Class I; Antigens, Neoplasm; Computer Simulation; Glioma; Computational Biology; Glioblastoma; Brain Neoplasms; Mutation
PubMed: 38907902
DOI: 10.1007/978-1-0716-3874-3_16 -
Cellular and Molecular Life Sciences :... Jun 2024While conventional cancer modalities, such as chemotherapy and radiotherapy, act through direct killing of tumor cells, cancer immunotherapy elicits potent anti-tumor... (Review)
Review
While conventional cancer modalities, such as chemotherapy and radiotherapy, act through direct killing of tumor cells, cancer immunotherapy elicits potent anti-tumor immune responses thereby eliminating tumors. Nevertheless, promising outcomes have not been reported in patients with glioblastoma (GBM) likely due to the immune privileged status of the central nervous system and immunosuppressive micro-environment within GBM. In the past years, several exciting findings, such as the re-discovery of meningeal lymphatic vessels (MLVs), three-dimensional anatomical reconstruction of MLV networks, and the demonstration of the promotion of GBM immunosurveillance by lymphatic drainage enhancement, have revealed an intricate communication between the nervous and immune systems, and brought hope for the development of new GBM treatment. Based on conceptual framework of the updated cancer-immunity (CI) cycle, here we focus on GBM antigen drainage and immune activation, the early events in driving the CI cycle. We also discuss the implications of these findings for developing new therapeutic approaches in tackling fatal GBM in the future.
Topics: Humans; Glioblastoma; Brain Neoplasms; Antigens, Neoplasm; Immunotherapy; Animals; Tumor Microenvironment; Lymphatic Vessels
PubMed: 38907858
DOI: 10.1007/s00018-024-05300-5 -
Cellular and Molecular Neurobiology Jun 2024The circadian system is a conserved time-keeping machinery that regulates a wide range of processes such as sleep/wake, feeding/fasting, and activity/rest cycles to...
The circadian system is a conserved time-keeping machinery that regulates a wide range of processes such as sleep/wake, feeding/fasting, and activity/rest cycles to coordinate behavior and physiology. Circadian disruption can be a contributing factor in the development of metabolic diseases, inflammatory disorders, and higher risk of cancer. Glioblastoma (GBM) is a highly aggressive grade 4 brain tumor that is resistant to conventional therapies and has a poor prognosis after diagnosis, with a median survival of only 12-15 months. GBM cells kept in culture were shown to contain a functional circadian oscillator. In seeking more efficient therapies with lower side effects, we evaluated the pharmacological modulation of the circadian clock by targeting the cytosolic kinases glycogen synthase kinase-3 (GSK-3) and casein kinase 1 ε/δ (CK1ε/δ) with specific inhibitors (CHIR99021 and PF670462, respectively), the cryptochrome protein stabilizer (KL001), or circadian disruption after Per2 knockdown expression in GBM-derived cells. CHIR99021-treated cells had a significant effect on cell viability, clock protein expression, migration, and cell cycle distribution. Moreover, cultures exhibited higher levels of reactive oxygen species and alterations in lipid droplet content after GSK-3 inhibition compared to control cells. The combined treatment of CHIR99021 with temozolomide was found to improve the effect on cell viability compared to temozolomide therapy alone. Per2 disruption affected both GBM migration and cell cycle progression. Overall, our results suggest that pharmacological modulation or molecular clock disruption severely affects GBM cell biology.
Topics: Glioblastoma; Humans; Cell Line, Tumor; Brain Neoplasms; Pyridines; Cell Survival; Cytosol; Glycogen Synthase Kinase 3; Pyrimidines; Cell Movement; Circadian Clocks; CLOCK Proteins; Period Circadian Proteins; Reactive Oxygen Species
PubMed: 38907776
DOI: 10.1007/s10571-024-01485-2 -
Neurosurgical Review Jun 2024To evaluate the utility of magnetic resonance imaging (MRI) histogram parameters in predicting O(6)-methylguanine-DNA methyltransferase promoter (pMGMT) methylation...
To evaluate the utility of magnetic resonance imaging (MRI) histogram parameters in predicting O(6)-methylguanine-DNA methyltransferase promoter (pMGMT) methylation status in IDH-wildtype glioblastoma (GBM). From November 2021 to July 2023, forty-six IDH-wildtype GBM patients with known pMGMT methylation status (25 unmethylated and 21 methylated) were enrolled in this retrospective study. Conventional MRI signs (including location, across the midline, margin, necrosis/cystic changes, hemorrhage, and enhancement pattern) were assessed and recorded. Histogram parameters were extracted and calculated by Firevoxel software based on contrast-enhanced T1-weighted images (CET1). Differences and diagnostic performance of conventional MRI signs and histogram parameters between the pMGMT-unmethylated and pMGMT-methylated groups were analyzed and compared. No differences were observed in the conventional MRI signs between pMGMT-unmethylated and pMGMT-methylated groups (all p > 0.05). Compared with the pMGMT-methylated group, pMGMT-unmethylated showed a higher minimum, mean, Perc.01, Perc.05, Perc.10, Perc.25, Perc.50, and coefficient of variation (CV) (all p < 0.05). Among all significant CET1 histogram parameters, minimum achieved the best distinguishing performance, with an area under the curve of 0.836. CET1 histogram parameters could provide additional value in predicting pMGMT methylation status in patients with IDH-wildtype GBM, with minimum being the most promising parameter.
Topics: Humans; Glioblastoma; Magnetic Resonance Imaging; Male; Female; Brain Neoplasms; Middle Aged; Promoter Regions, Genetic; Adult; DNA Methylation; Aged; Isocitrate Dehydrogenase; Retrospective Studies; O(6)-Methylguanine-DNA Methyltransferase
PubMed: 38907038
DOI: 10.1007/s10143-024-02522-w -
Scientific Reports Jun 2024Glioblastoma (GBM) is a highly aggressive and deadly brain cancer. Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM, but the majority of patients...
Glioblastoma (GBM) is a highly aggressive and deadly brain cancer. Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM, but the majority of patients experience recurrence and invasion of tumor cells. We investigated whether TMZ treatment of GBM cells regulates matrix metalloproteinases (MMPs), which have the main function to promote tumor cell invasion. TMZ effectively killed GL261, U343, and U87MG cells at a concentration of 500 µM, and surviving cells upregulated MMP9 expression and its activity but not those of MMP2. TMZ also elevated levels of MMP9 mRNA and MMP9 promoter activity. Subcutaneous graft tumors survived from TMZ treatment also exhibited increased expression of MMP9 and enhanced gelatinolytic activity. TMZ-mediated MMP9 upregulation was specifically mediated through the phosphorylation of p38 and JNK. This then stimulates AP-1 activity through the upregulation of c-Fos and c-Jun. Inhibition of the p38, JNK, or both pathways counteracted the TMZ-induced upregulation of MMP9 and AP-1. This study proposes a potential adverse effect of TMZ treatment for GBM: upregulation of MMP9 expression potentially associated with increased invasion and poor prognosis. This study also provides valuable insights into the molecular mechanisms by which TMZ treatment leads to increased MMP9 expression in GBM cells.
Topics: Temozolomide; Glioblastoma; Matrix Metalloproteinase 9; Humans; p38 Mitogen-Activated Protein Kinases; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; MAP Kinase Signaling System; Antineoplastic Agents, Alkylating; Animals; Brain Neoplasms; Transcription Factor AP-1; Up-Regulation; Mice
PubMed: 38906916
DOI: 10.1038/s41598-024-65398-2 -
Nature Communications Jun 2024Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for...
Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). Using this method, we show that patient-derived glioblastoma (GBM) samples with acquired temozolomide (TMZ) resistance display elevated HR and MMEJ activity, suggesting that these pathways contribute to treatment resistance. We screen clinically relevant small molecules for DSBR inhibition with the aim of identifying improved GBM combination therapy regimens. We identify the ATM kinase inhibitor, AZD1390, as a potent dual HR/MMEJ inhibitor that suppresses radiation-induced phosphorylation of DSBR proteins, blocks DSB end resection, and enhances the cytotoxic effects of TMZ in treatment-naïve and treatment-resistant GBMs with TP53 mutation. We further show that a combination of G2/M checkpoint deficiency and reliance upon ATM-dependent DSBR renders TP53 mutant GBMs hypersensitive to TMZ/AZD1390 and radiation/AZD1390 combinations. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes an approach for simultaneously measuring multiple DSBR pathways in treatment selection and oncology research.
Topics: Humans; Ataxia Telangiectasia Mutated Proteins; Glioblastoma; Tumor Suppressor Protein p53; DNA Breaks, Double-Stranded; Temozolomide; Cell Line, Tumor; Mutation; Drug Resistance, Neoplasm; DNA Repair; Brain Neoplasms; Animals; DNA End-Joining Repair; Mice; Phosphorylation
PubMed: 38906885
DOI: 10.1038/s41467-024-49316-8 -
JCO Precision Oncology Jun 2024This case illustrates the utility and impact of molecular testing and molecular tumor board discussion in the management of AYA patients with brain tumors.
This case illustrates the utility and impact of molecular testing and molecular tumor board discussion in the management of AYA patients with brain tumors.
Topics: Humans; Astrocytoma; Proto-Oncogene Proteins p21(ras); Mutation; Brain Neoplasms; Young Adult; Protein Kinase Inhibitors; Male; Female; Adult
PubMed: 38905571
DOI: 10.1200/PO.24.00174 -
Neuroradiology Jun 2024Pediatric spinal cord gliomas (PSGs) are rare in children and few reports detail their imaging features. We tested the association of tumoral grade with imaging features...
PURPOSE
Pediatric spinal cord gliomas (PSGs) are rare in children and few reports detail their imaging features. We tested the association of tumoral grade with imaging features and proposed a novel approach to categorize post-contrast enhancement patterns in PSGs.
METHODS
This single-center, retrospective study included patients <21 years of age with preoperative spinal MRI and confirmed pathological diagnosis of PSG from 2000-2022. Tumors were classified using the 5th edition of the WHO CNS Tumors Classification. Two radiologists reviewed multiple imaging features, and classified enhancement patterns using a novel approach. Fisher's exact test determined associations between imaging and histological features.
RESULTS
Forty-one PSGs were reviewed. Thirty-four were intramedullary, and seven were extramedullary. Pilocytic astrocytoma was the most common tumor (39.02%). Pain and weakness were the most prevalent symptoms. Seven patients (17.07%) died. Cyst, syringomyelia, and leptomeningeal enhancement were associated with tumor grade. Widening of the spinal canal was observed only in low-grade astrocytomas. There was a significant association between tumor grade and contrast enhancement pattern. Specifically, low-grade PSGs were more likely to exhibit type 1A enhancement (mass-like, with well-defined enhancing margins) and less likely to exhibit type 1B enhancement (mass-like, with ill-defined enhancing margins).
CONCLUSION
PSGs display overlapping imaging features, making grade differentiation challenging based solely on imaging. The correlation between tumor grade and contrast enhancement patterns suggests a potential diagnostic avenue, requiring further validation with larger, multicenter studies. Furthermore, Low-grade PSGs display cysts and syringomyelia more frequently, and leptomeningeal enhancement is less common.
PubMed: 38902483
DOI: 10.1007/s00234-024-03395-y -
Scientific Reports Jun 2024Natural products are an unsurpassed source of leading structures in drug discovery. The biosynthetic machinery of the producing organism offers an important source for...
Natural products are an unsurpassed source of leading structures in drug discovery. The biosynthetic machinery of the producing organism offers an important source for modifying complex natural products, leading to analogs that are unattainable by chemical semisynthesis or total synthesis. In this report, through the combination of natural products chemistry and diversity-oriented synthesis, a diversity-enhanced extracts approach is proposed using chemical reactions that remodel molecular scaffolds directly on extracts of natural resources. This method was applied to subextract enriched in sesquiterpene lactones from Ambrosia tenuifolia (Fam. Asteraceae) using acid media conditions (p-toluenesulfonic acid) to change molecular skeletons. The chemically modified extract was then fractionated by a bioguided approach to obtain the pure compounds responsible for the anti-glioblastoma (GBM) activity in T98G cell cultures. Indeed, with the best candidate, chronobiological experiments were performed to evaluate temporal susceptibility to the treatment on GBM cell cultures to define the best time to apply the therapy. Finally, bioinformatics tools were used to supply qualitative and quantitative information on the physicochemical properties, chemical space, and structural similarity of the compound library obtained. As a result, natural products derivatives containing new molecular skeletons were obtained, with possible applications as chemotherapeutic agents against human GBM T98G cell cultures.
Topics: Humans; Glioblastoma; Cell Line, Tumor; Plant Extracts; Antineoplastic Agents, Phytogenic; Biological Products; Asteraceae; Sesquiterpenes; Lactones; Antineoplastic Agents
PubMed: 38902325
DOI: 10.1038/s41598-024-63639-y -
Scientific Reports Jun 2024Central nervous system tumors have resisted effective chemotherapy because most therapeutics do not penetrate the blood-tumor-brain-barrier. Nanomedicines between...
Central nervous system tumors have resisted effective chemotherapy because most therapeutics do not penetrate the blood-tumor-brain-barrier. Nanomedicines between ~ 10 and 100 nm accumulate in many solid tumors by the enhanced permeability and retention effect, but it is controversial whether the effect can be exploited for treatment of brain tumors. PLX038A is a long-acting prodrug of the topoisomerase 1 inhibitor SN-38. It is composed of a 15 nm 4-arm 40 kDa PEG tethered to four SN-38 moieties by linkers that slowly cleave to release the SN-38. The prodrug was remarkably effective at suppressing growth of intracranial breast cancer and glioblastoma (GBM), significantly increasing the life span of mice harboring them. We addressed the important issue of whether the prodrug releases SN-38 systemically and then penetrates the brain to exert anti-tumor effects, or whether it directly penetrates the blood-tumor-brain-barrier and releases the SN-38 cargo within the tumor. We argue that the amount of SN-38 formed systemically is insufficient to inhibit the tumors, and show by PET imaging that a close surrogate of the 40 kDa PEG carrier in PLX038A accumulates and is retained in the GBM. We conclude that the prodrug penetrates the blood-tumor-brain-barrier, accumulates in the tumor microenvironment and releases its SN-38 cargo from within. Based on our results, we pose the provocative question as to whether the 40 kDa nanomolecule PEG carrier might serve as a "Trojan horse" to carry other drugs past the blood-tumor-brain-barrier and release them into brain tumors.
Topics: Animals; Brain Neoplasms; Irinotecan; Blood-Brain Barrier; Mice; Prodrugs; Humans; Cell Line, Tumor; Female; Xenograft Model Antitumor Assays; Glioblastoma; Camptothecin
PubMed: 38898077
DOI: 10.1038/s41598-024-64186-2