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Cell Death & Disease Jun 2024The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell...
The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell surface Fas expression desensitizes cancer cells to Fas-induced apoptosis. Here, we show that the increase in Fas microaggregate formation on the plasma membrane in response to the inhibition of endocytosis sensitizes cancer cells to Fas-induced apoptosis. We used a clinically accessible Rho-kinase inhibitor, fasudil, that reduces endocytosis dynamics by increasing plasma membrane tension. In combination with exogenous soluble FasL (sFasL), fasudil promoted cancer cell apoptosis, but this collaborative effect was substantially weaker in nonmalignant cells. The combination of sFasL and fasudil prevented glioblastoma cell growth in embryonic stem cell-derived brain organoids and induced tumor regression in a xenograft mouse model. Our results demonstrate that sFasL has strong potential for apoptosis-directed cancer therapy when Fas microaggregate formation is augmented by mechano-inhibition of endocytosis.
Topics: Humans; Endocytosis; Apoptosis; Animals; Fas Ligand Protein; fas Receptor; Mice; Cell Line, Tumor; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Xenograft Model Antitumor Assays; Glioblastoma
PubMed: 38909035
DOI: 10.1038/s41419-024-06822-3 -
Radiologia 2024The 2021 World Health Organization classification of CNS tumours was greeted with enthusiasm as well as an initial potential overwhelm. However, with time and...
The 2021 World Health Organization classification of CNS tumours was greeted with enthusiasm as well as an initial potential overwhelm. However, with time and experience, our understanding of its key aspects has notably improved. Using our collective expertise gained in neuro-oncology units in hospitals in different countries, we have compiled a practical guide for radiologists that clarifies the classification criteria for diffuse gliomas in adults. Its format is clear and concise to facilitate its incorporation into everyday clinical practice. The document includes a historical overview of the classifications and highlights the most important recent additions. It describes the main types in detail with an emphasis on their appearance on imaging. The authors also address the most debated issues in recent years. It will better prepare radiologists to conduct accurate presurgical diagnoses and collaborate effectively in clinical decision making, thus impacting decisions on treatment, prognosis, and overall patient care.
Topics: Humans; Glioma; Brain Neoplasms; Adult; World Health Organization; Preoperative Care
PubMed: 38908887
DOI: 10.1016/j.rxeng.2024.03.002 -
Medicina 2024The frontal aslant tract (FAT) connects the supplementary motor area (SMA) with the pars opercularis. Its role in language and its implications in glioma surgery remain...
The frontal aslant tract (FAT) connects the supplementary motor area (SMA) with the pars opercularis. Its role in language and its implications in glioma surgery remain under discussion. We present an anatomosurgical study of three cases with surgical resolution. Three patients with gliomas in the left frontal lobe were operated on using an awake patient protocol with cortical and subcortical mapping techniques, conducting motor and language evaluations. Tractography was performed using DSI Studio software. All three patients showed intraoperative language inhibition through subcortical stimulation of the FAT. Resection involving the FAT correlated with language deficits in all cases and movement initiation deficits in two cases. All patients recovered from their deficits at six months postoperatively. In conclusion, the tract has been successfully reconstructed, showing both anatomical and functional complexity, supporting the idea of its mapping and preservation in glioma surgery. Future interdisciplinary studies are necessary to determine the transient or permanent nature of the deficits.
Topics: Humans; Brain Neoplasms; Glioma; Male; Frontal Lobe; Middle Aged; Female; Adult; Neurosurgical Procedures; Brain Mapping; Motor Cortex; Diffusion Tensor Imaging
PubMed: 38907981
DOI: No ID Found -
Medicina 2024Ewing sarcoma (ES) and primitive neuroectodermal tumor (PNET) belong to the group of neoplasms called small round cell tumors. PNETs have been divided into central and...
Ewing sarcoma (ES) and primitive neuroectodermal tumor (PNET) belong to the group of neoplasms called small round cell tumors. PNETs have been divided into central and peripheral. ES and peripheral PNETs arise from bones, soft tissues, or peripheral nerves. We present a case of hepatic ES/PNET in a healthy man that began four months before consultation with abdominal symptoms and weight loss. Upper gastrointestinal endoscopy and laboratory tests revealed no notable findings. The abdominal tomography revealed an enlarged liver due to a solid lesion that involved all its segments with intravenous contrast enhancement and large areas of necrosis. It compressed and displaced neighboring structures. Core needle biopsy of the liver lesion was performed: small round cell neoplasm. Immunohistochemistry revealed negativity for CD45, CKA1/A3, chromogranin, synaptophysin, and cytokeratins CK7 and CK20. Dim CD56 expression and CD99, FLI-1, and NKX2 positivity. He underwent chemotherapy treatment with carboplatin and etoposide for 6 cycles with clinical improvement and tolerance. Control images showed reduction of the mass with involvement of the right hepatic lobe, involvement of the inferior vena cava, infiltration of the right adrenal gland and upper pole of the right kidney. He was referred to hepatobiliary surgery for surgical resection of the residual lesion. The patient rejected the proposed surgical procedure. Our objective is to highlight the clinical and histological diagnostic challenge of this entity that requires ruling out other clinical entities.
Topics: Humans; Male; Liver Neoplasms; Sarcoma, Ewing; Tomography, X-Ray Computed; Immunohistochemistry; Adult; Neuroectodermal Tumors, Primitive, Peripheral
PubMed: 38907976
DOI: No ID Found -
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 -
BMC Cancer Jun 2024Diffuse midline glioma (DMG), H3 K27M-mutant is a type of diffuse high-grade glioma that occurs in the brain midline carrying an extremely poor prognosis under the best...
PURPOSE
Diffuse midline glioma (DMG), H3 K27M-mutant is a type of diffuse high-grade glioma that occurs in the brain midline carrying an extremely poor prognosis under the best efforts of surgery, radiation, and other therapies. For better therapy, we explored the efficacy and toxicity of a novel therapy that combines apatinib and temozolomide in DMG.
METHODS
A retrospective analysis of 32 patients with DMG who underwent apatinib plus temozolomide treatment was performed. Apatinib was given 500 mg in adults, 250 mg in pediatric patients once daily. Temozolomide was administered at 200 mg/m/d according to the standard 5/28 days regimen. The main clinical data included basic information of patients, radiological and pathological characteristics of tumors, treatment, adverse reactions, prognosis.
RESULTS
The objective response rate was 24.1%, and the disease control rate was 79.3%. The median PFS of all patients was 5.8 months, and median OS was 10.3 months. A total of 236 cycles of treatment were available for safety assessment and the toxicity of the combination therapy was relatively well tolerated. The most common grade 3 toxicities were myelosuppression including leukopenia (5.08%), neutropenia (4.24%), lymphopenia (2.12%), thrombocytopenia (1.69%) and anemia (1.27%). Grade 4 toxicities included neutropenia (2.12%), thrombocytopenia (2.12%) and proteinuria (1.69%). All the adverse events were relieved after symptomatic treatment or dose reduction.
CONCLUSIONS
Apatinib plus temozolomide could be an effective regimen with manageable toxicities and favorable efficacy and may outperform temozolomide monotherapy, particularly in newly diagnosed adults with tumors located outside the pons. The novel therapy deserves further investigation in adult DMG patients.
Topics: Humans; Temozolomide; Female; Male; Adult; Pyridines; Glioma; Adolescent; Retrospective Studies; Child; Brain Neoplasms; Young Adult; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Middle Aged; Treatment Outcome
PubMed: 38907215
DOI: 10.1186/s12885-024-12373-9 -
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