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International Journal of Molecular... Apr 2024Glioblastoma (GBM) is the most aggressive malignant primary central nervous system (CNS) tumor and, despite decades of research, it remains a lethal disease with a...
Glioblastoma (GBM) is the most aggressive malignant primary central nervous system (CNS) tumor and, despite decades of research, it remains a lethal disease with a median overall survival of less than two years [...].
Topics: Humans; Glioblastoma; Aggression
PubMed: 38612900
DOI: 10.3390/ijms25074090 -
Biomaterials Nov 2023Glioblastoma multiforme (GBM) is the most common and lethal primary brain cancer. Current pharmacological interventions marginally increase the 12-month overall survival...
Glioblastoma multiforme (GBM) is the most common and lethal primary brain cancer. Current pharmacological interventions marginally increase the 12-month overall survival of patients with GBM. Among the novel therapeutic strategies being pursued, micro-RNAs, a class of non-coding RNAs, are receiving considerable attention for their regulation of several pathways implicated in tumorigenesis and survival. Notably, microRNA-181a-5p (miR-181a) has consistently been reported to be downregulated in GBM clinical samples, and its overexpression negatively affects tumor growth both in vitro and in vivo. To improve the delivery of miR-181a to GBM cells, we sought to develop a modified lipid-based nanocarrier capable of encapsulating and delivering miR-181a to GBM cells in vitro and in vivo. Optimized ionizable-lipid containing lipid nanoparticles (LNP) were constructed by covering the miR-181a-loaded LNP with alternating layers of miR-181a, poly-l-arginine and hyaluronic acid through the layer-by-layer technique. The resulting hyaluronan-decorated lipid nanoparticles (HA-LNP) targeted GBM cells more efficiently than non-modified LNP and mediated siRNA and miRNA transfection in vitro. Finally, delivery of miR-181a by HA-LNP induced significant cellular death of U87 GBM cells in vitro and delayed tumor growth in an in vivo subcutaneous tumor model.
Topics: Humans; Glioblastoma; Hyaluronic Acid; Cell Line, Tumor; MicroRNAs; Lipids; Cell Proliferation
PubMed: 37778056
DOI: 10.1016/j.biomaterials.2023.122341 -
Journal of Neurosurgery Sep 2023Management of patients with glioblastoma (GBM) is complex and involves implementing standard therapies including resection, radiation therapy, and chemotherapy, as well... (Review)
Review
Management of patients with glioblastoma (GBM) is complex and involves implementing standard therapies including resection, radiation therapy, and chemotherapy, as well as novel immunotherapies and targeted small-molecule inhibitors through clinical trials and precision medicine approaches. As treatments have advanced, the radiological and clinical assessment of patients with GBM has become even more challenging and nuanced. Advances in spatial resolution and both anatomical and physiological information that can be derived from MRI have greatly improved the noninvasive assessment of GBM before, during, and after therapy. Identification of pseudoprogression (PsP), defined as changes concerning for tumor progression that are, in fact, transient and related to treatment response, is critical for successful patient management. These temporary changes can produce new clinical symptoms due to mass effect and edema. Differentiating this entity from true tumor progression is a major decision point in the patient's management and prognosis. Providers may choose to start an alternative therapy, transition to a clinical trial, consider repeat resection, or continue with the current therapy in hopes of resolution. In this review, the authors describe the invasive and noninvasive techniques neurosurgeons need to be aware of to identify PsP and facilitate surgical decision-making.
Topics: Humans; Glioblastoma; Neurosurgeons; Brain Neoplasms; Disease Progression; Magnetic Resonance Imaging
PubMed: 36790010
DOI: 10.3171/2022.12.JNS222173 -
Signal Transduction and Targeted Therapy Oct 2023Glioblastoma, a rare, and highly lethal form of brain cancer, poses significant challenges in terms of therapeutic resistance, and poor survival rates for both adult and... (Review)
Review
Glioblastoma, a rare, and highly lethal form of brain cancer, poses significant challenges in terms of therapeutic resistance, and poor survival rates for both adult and paediatric patients alike. Despite advancements in brain cancer research driven by a technological revolution, translating our understanding of glioblastoma pathogenesis into improved clinical outcomes remains a critical unmet need. This review emphasises the intricate role of receptor tyrosine kinase signalling pathways, epigenetic mechanisms, and metabolic functions in glioblastoma tumourigenesis and therapeutic resistance. We also discuss the extensive efforts over the past two decades that have explored targeted therapies against these pathways. Emerging therapeutic approaches, such as antibody-toxin conjugates or CAR T cell therapies, offer potential by specifically targeting proteins on the glioblastoma cell surface. Combination strategies incorporating protein-targeted therapy and immune-based therapies demonstrate great promise for future clinical research. Moreover, gaining insights into the role of cell-of-origin in glioblastoma treatment response holds the potential to advance precision medicine approaches. Addressing these challenges is crucial to improving outcomes for glioblastoma patients and moving towards more effective precision therapies.
Topics: Adult; Humans; Child; Glioblastoma; Signal Transduction; Brain Neoplasms; Brain; Precision Medicine
PubMed: 37857607
DOI: 10.1038/s41392-023-01637-8 -
Frontiers in Immunology 2023Despite tremendous efforts to exploit effective therapeutic strategies, most glioblastoma (GBM) inevitably relapse and become resistant to therapies, including... (Review)
Review
Despite tremendous efforts to exploit effective therapeutic strategies, most glioblastoma (GBM) inevitably relapse and become resistant to therapies, including radiotherapy and immunotherapy. The tumor microenvironment (TME) of recurrent GBM (rGBM) is highly immunosuppressive, dominated by tumor-associated macrophages (TAMs). TAMs consist of tissue-resident microglia and monocyte-derived macrophages (MDMs), which are essential for favoring tumor growth, invasion, angiogenesis, immune suppression, and therapeutic resistance; however, restricted by the absence of potent methods, the heterogeneity and plasticity of TAMs in rGBM remain incompletely investigated. Recent application of single-cell technologies, such as single-cell RNA-sequencing has enabled us to decipher the unforeseen diversity and dynamics of TAMs and to identify new subsets of TAMs which regulate anti-tumor immunity. Here, we first review hallmarks of the TME, progress and challenges of immunotherapy, and the biology of TAMs in the context of rGBM, including their origins, categories, and functions. Next, from a single-cell perspective, we highlight recent findings regarding the distinctions between tissue-resident microglia and MDMs, the identification and characterization of specific TAM subsets, and the dynamic alterations of TAMs during tumor progression and treatment. Last, we briefly discuss the potential of TAM-targeted strategies for combination immunotherapy in rGBM. We anticipate the comprehensive understanding of the diversity and dynamics of TAMs in rGBM will shed light on further improvement of immunotherapeutic efficacy in rGBM.
Topics: Humans; Tumor-Associated Macrophages; Glioblastoma; Macrophages; Chronic Disease; Recurrence; Tumor Microenvironment
PubMed: 37731483
DOI: 10.3389/fimmu.2023.1238233 -
Cancer Reports (Hoboken, N.J.) Oct 2023A form of cancer called astrocytoma can develop in the brain or spinal cord and sometimes causes death. A detailed overview of the precise signaling cascade underlying... (Review)
Review
BACKGROUND
A form of cancer called astrocytoma can develop in the brain or spinal cord and sometimes causes death. A detailed overview of the precise signaling cascade underlying astrocytoma formation has not yet been revealed, although various factors have been investigated. Therefore, our objective was to unravel and summarize our current understanding of molecular genetics and associated signaling pathways with some possible therapeutic strategies for astrocytoma.
RECENT FINDINGS
In general, four different forms of astrocytoma have been identified in individuals, including circumscribed, diffuse, anaplastic, and multiforme glioblastoma, according to a recent literature review. All types of astrocytoma have a direct connection with some oncogenic signaling cascade. Common signaling is MAPK cascade, including Ras-Raf-ERK, up-regulated with activating EGFR/AKT/PTEN/mTOR and PDGFR. Recent breakthrough studies found that BRAF mutations, including KIAA1549: BRAF and BRAF V600E are responsible for astrocytoma progression. Additionally, cancer progression is influenced by mutations in some tumor suppressor genes, such as the Tp53/ATRX and MGMT mutant. As synthetic medications must cross the blood-brain barrier (BBB), modulating signal systems such as miRNA is the primary option for treating patients with astrocytoma. However, available surgery, radiation therapy, and experimental therapies such as adjuvant therapy, anti-angiogenic therapy, and EGFR-targeting antibody drug are the usual treatment for most types of astrocytoma. Similar to conventional anticancer medications, some phytochemicals slow tumor growth by simultaneously controlling several cellular proteins, including those involved in cell cycle regulation, apoptosis, metastatic spread, tyrosine kinase, growth factor receptor, and antioxidant-related proteins.
CONCLUSION
In conclusion, cellular and molecular signaling is directly associated with the development of astrocytoma, and a combination of conventional and alternative therapies can improve the malignancy of cancer patients.
Topics: Humans; Proto-Oncogene Proteins B-raf; Brain Neoplasms; Astrocytoma; Glioblastoma; ErbB Receptors
PubMed: 37675821
DOI: 10.1002/cnr2.1889 -
Neuro-oncology Nov 2023
Topics: Humans; Glioblastoma; Sterol Regulatory Element Binding Protein 1; Lipid Metabolism; Cholesterol
PubMed: 37623320
DOI: 10.1093/neuonc/noad145 -
Neuro-oncology Aug 2023People with NF1 have an increased prevalence of central nervous system malignancy. However, little is known about the clinical course or pathologic features of...
BACKGROUND
People with NF1 have an increased prevalence of central nervous system malignancy. However, little is known about the clinical course or pathologic features of NF1-associated gliomas in adults, limiting clinical care and research.
METHODS
Adults (≥18 years) with NF1 and histologically confirmed non-optic pathway gliomas (non-OPGs) at Johns Hopkins Hospital, Memorial Sloan Kettering Cancer Center, and Washington University presenting between 1990 and 2020 were identified. Retrospective data were collated, and pathology was reviewed centrally.
RESULTS
Forty-five patients, comprising 23 females (51%), met eligibility criteria, with a median of age 37 (18-68 years) and performance status of 80% (30%-100%). Tissue was available for 35 patients. Diagnoses included infiltrating (low-grade) astrocytoma (9), glioblastoma (7), high-grade astrocytoma with piloid features (4), pilocytic astrocytoma (4), high-grade astrocytoma (3), WHO diagnosis not reached (4) and one each of gliosarcoma, ganglioglioma, embryonal tumor, and diffuse midline glioma. Seventy-one percent of tumors were midline and underwent biopsy only. All 27 tumors evaluated were IDH1-wild-type, independent of histology. In the 10 cases with molecular testing, the most common genetic variants were NF1, EGFR, ATRX, CDKN2A/B, TP53, TERT, and MSH2/3 mutation. While the treatments provided varied, the median overall survival was 24 months [2-267 months] across all ages, and 38.5 [18-109] months in individuals with grade 1-2 gliomas.
CONCLUSIONS
Non-OPGs in adults with NF1, including low-grade tumors, often have an aggressive clinical course, indicating a need to better understand the pathobiology of these NF1-associated gliomas.
Topics: Female; Humans; Adult; Neurofibromatosis 1; Retrospective Studies; Glioma; Astrocytoma; Brain Neoplasms; Disease Progression
PubMed: 36840626
DOI: 10.1093/neuonc/noad033 -
Clinical Cancer Research : An Official... Dec 2023Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often...
PURPOSE
Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan.
EXPERIMENTAL DESIGN
Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy.
RESULTS
Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice.
CONCLUSIONS
This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.
Topics: Humans; Animals; Mice; Aged; Glioblastoma; Senotherapeutics; Brain Neoplasms; Mutation; DNA Methylation
PubMed: 37725593
DOI: 10.1158/1078-0432.CCR-23-0834 -
Graefe's Archive For Clinical and... Dec 2023Acute acquired comitant esotropia (AACE) is an uncommon subtype of esotropia characterized by sudden and usually late onset of a relatively large angle of comitant... (Review)
Review
BACKGROUND
Acute acquired comitant esotropia (AACE) is an uncommon subtype of esotropia characterized by sudden and usually late onset of a relatively large angle of comitant esotropia with diplopia in older children and adults.
METHODS
A literature survey regarding neurological pathologies in AACE was conducted using databases (PubMed, MEDLINE, EMBASE, BioMed Central, the Cochrane Library, and Web of Science) in order to collect data for a narrative review of published reports and available literature.
RESULTS
The results of the literature survey were analyzed to provide an overview of the current knowledge of neurological pathologies in AACE. The results revealed that AACE with unclear etiologies can occur in many cases in both children and adults. Functional etiological factors for AACE were found to be due to many reasons, such as functional accommodative spasm, the excessive near work use of mobile phones/smartphones, and other digital screens. In addition, AACE was found to be associated with neurological disorders, such as astrocytoma of the corpus callosum, medulloblastoma, tumors of the brain stem or cerebellum, Arnold-Chiari malformation, cerebellar astrocytoma, Chiari 1 malformation, idiopathic intracranial hypertension, pontine glioma, cerebellar ataxia, thalamic lesions, myasthenia gravis, certain types of seizures, and hydrocephalus.
CONCLUSIONS
Previously reported cases of AACE with unknown etiologies have been reported in both children and adults. However, AACE can be associated with neurological disorders that require neuroimaging probes. The author recommends that clinicians should perform comprehensive neurological assessments to rule out neurological pathologies in AACE, especially in the presence of nystagmus or abnormal ocular and neurological indications (e.g., headache, cerebellar imbalance, weakness, nystagmus, papilloedema, clumsiness, and poor motor coordination).
Topics: Child; Adult; Humans; Esotropia; Arnold-Chiari Malformation; Astrocytoma; Headache; Eye; Acute Disease; Retrospective Studies
PubMed: 37145335
DOI: 10.1007/s00417-023-06092-3