In Vivo Mouse Models for Adult Brain Tumors: Exploring Tumorigenesis and Advancing Immunotherapy Development.

Brain tumors, particularly glioblastoma (GBM), are devastating and challenging to treat, with a low 5-year survival rate of only 6.6%. Mouse models are established to understand tumorigenesis and develop new therapeutic strategies. Large-scale genomic studies have facilitated the identification of genetic alterations driving human brain tumor development and progression. Genetically engineered mouse models (GEMMs) with clinically relevant genetic alterations are widely used to investigate tumor origin. Additionally, syngeneic implantation models, utilizing cell lines derived from GEMMs or other sources, are popular for their consistent and relatively short latency period, addressing various brain cancer research questions. In recent years, the success of immunotherapy in specific cancer types has led to a surge in cancer immunology-related research which specifically necessitates the utilization of immunocompetent mouse models. In this review, we provide a comprehensive summary of GEMMs and syngeneic mouse models for adult brain tumors, emphasizing key features such as model origin, genetic alteration background, oncogenic mechanisms, and immune-related characteristics. Our review serves as a valuable resource for the brain tumor research community, aiding in the selection of appropriate models to study cancer immunology.

Direct Observation of a Single Peroneal Myotendinous Unit Anatomic Variant: A Case Report and Systematic Review.

CASE: A 29-year-old woman with acute peroneal tendon subluxation underwent superior retinacular repair. On exposure, a single peroneal myotendinous unit was encountered, as opposed to the usual presence of independent peroneal tendons arising from separate muscle bellies. At 3-year follow-up, she has had no recurrence with full return to activity and no limitations. CONCLUSION: Multiple peroneal myotendinous variants have been described; however, this report is the first to describe direct intraoperative observation of a single peroneal myotendinous unit. Whether this anatomic variant contributed to the patient's problem or has other potential clinical sequelae remains to be elucidated.

Update for astrocytomas: medical and surgical management considerations.

Astrocytomas include a wide range of tumors with unique mutations and varying grades of malignancy. These tumors all originate from the astrocyte, a star-shaped glial cell that plays a major role in supporting functions of the central nervous system (CNS), including blood-brain barrier (BBB) development and maintenance, water and ion regulation, influencing neuronal synaptogenesis, and stimulating the immunological response. In terms of epidemiology, glioblastoma (GB), the most common and malignant astrocytoma, generally occur with higher rates in Australia, Western Europe, and Canada, with the lowest rates in Southeast Asia. Additionally, significantly higher rates of GB are observed in males and non-Hispanic whites. It has been suggested that higher levels of testosterone observed in biological males may account for the increased rates of GB. Hereditary syndromes such as Cowden, Lynch, Turcot, Li-Fraumeni, and neurofibromatosis type 1 have been linked to increased rates of astrocytoma development. While there are a number of specific gene mutations that may influence malignancy or be targeted in astrocytoma treatment, O 6-methylguanine-DNA methyltransferase (MGMT) gene function is an important predictor of astrocytoma response to chemotherapeutic agent temozolomide (TMZ). TMZ for primary and bevacizumab in the setting of recurrent tumor formation are two of the main chemotherapeutic agents currently approved in the treatment of astrocytomas. While stereotactic radiosurgery (SRS) has debatable implications for increased survival in comparison to whole-brain radiotherapy (WBRT), SRS demonstrates increased precision with reduced radiation toxicity. When considering surgical resection of astrocytoma, the extent of resection (EoR) is taken into consideration. Subtotal resection (STR) spares the margins of the T1 enhanced magnetic resonance imaging (MRI) region, gross total resection (GTR) includes the margins, and supramaximal resection (SMR) extends beyond the margin of the T1 and into the T2 region. Surgical resection, radiation, and chemotherapy are integral components of astrocytoma treatment.

Immunotherapy reverses glioma-driven dysfunction of immune system homeostasis.

BACKGROUND: Glioma-induced immune dysregulation of the hematopoietic system has been described in a limited number of studies. In this study, our group further demonstrates that gliomas interrupt the cellular differentiation programming and outcomes of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. HSPCs from glioma-bearing mice are reprogrammed and driven towards expansion of myeloid lineage precursors and myeloid-derived suppressor cells (MDSCs) in secondary lymphoid organs. However, we found this expansion is reversed by immunotherapy. Adoptive cellular therapy (ACT) has been demonstrably efficacious in multiple preclinical models of central nervous system (CNS) malignancies, and here we describe how glioma-induced dysfunction is reversed by this immunotherapeutic platform. METHODS: The impact of orthotopic KR158B-luc glioma on HSPCs was evaluated in an unbiased fashion using single cell RNAseq (scRNAseq) of lineage- cells and phenotypically using flow cytometry. Mature myeloid cell frequencies and function were also evaluated using flow cytometry. Finally, ACT containing total body irradiation, tumor RNA-pulsed dendritic cells, tumor-reactive T cells and HSPCs isolated from glioma-bearing or non-tumor-bearing mice were used to evaluate cell fate differentiation and survival. RESULTS: Using scRNAseq, we observed an altered HSPC landscape in glioma-bearing versus non-tumor-bearing mice . In addition, an expansion of myeloid lineage subsets, including granulocyte macrophage precursors (GMPs) and MDSCs, were observed in glioma-bearing mice relative to non-tumor-bearing controls. Furthermore, MDSCs from glioma-bearing mice demonstrated increased suppressive capacity toward tumor-specific T cells as compared with MDSCs from non-tumor-bearing hosts. Interestingly, treatment with ACT overcame these suppressive properties. When HSPCs from glioma-bearing mice were transferred in the context of ACT, we observed significant survival benefit and long-term cures in orthotopic glioma models compared with mice treated with ACT using non-glioma-bearing HSPCs.

Arteriovenous Malformations: An Update on Models and Therapeutic Targets.

Arteriovenous malformations (AVMs) are an anomaly of the vascular system where feeding arteries are directly connected to the venous drainage network. While AVMs can arise anywhere in the body and have been described in most tissues, brain AVMs are of significant concern because of the risk of hemorrhage which carries significant morbidity and mortality. The prevalence of AVM's and the mechanisms underlying their formation are not well understood. For this reason, patients who undergo treatment for symptomatic AVM's remain at increased risk of subsequent bleeds and adverse outcomes. The cerebrovascular network is delicate and novel animal models continue to provide insight into its dynamics in the context of AVM's. As the molecular players in the formation of familial and sporadic AVM's are better understood, novel therapeutic approaches have been developed to mitigate their associated risks. Here we discuss the current literature surrounding AVM's including the development of models and therapeutic targets which are currently being investigated.

Proteinopathies and Neurotrauma: Update on Degenerative Cascades.

Neurotrauma, especially repetitive neurotrauma, is associated with the development of progressive neurodegeneration leading to chronic traumatic encephalopathy (CTE). Exposure to neurotrauma regularly occurs during sports and military service, often not requiring medical care. However, exposure to severe and/or repeated sub-clinical neurotrauma has been shown cause physical and psychological disability, leading to reduce life expectancy. Misfolding of proteins, or proteinopathy, is a pathological hallmark of CTE, in which chronic injury leads to local and diffuse protein aggregates. These aggregates are an overlapping feature of many neurodegenerative diseases such as CTE, Alzheimer's Disease, Parkinsons disease. Neurotrauma is also a significant risk factor for the development of these diseases, however the mechanism's underlying this association are not well understood. While phosphorylated tau aggregates are the primary feature of CTE, amyloid-beta, Transactive response DNA-binding protein 43 (TDP-43), and alpha-synuclein (αSyn) are also well documented. Aberrant misfolding of these proteins has been shown to disrupt brain homeostasis leading to neurodegeneration in a disease dependent manor. In CTE, the interaction between proteinopathies and their associated neurodegeneration is a current area of study. Here we provide an update on current literature surrounding the prevalence, characteristics, and pathogenesis of proteinopathies in CTE.

The current landscape of immunotherapy for pediatric brain tumors.

Pediatric central nervous system tumors are the most common solid malignancies in childhood, and aggressive therapy often leads to long-term sequelae in survivors, making these tumors challenging to treat. Immunotherapy has revolutionized prospects for many cancer types in adults, but the intrinsic complexity of treating pediatric patients and the scarcity of clinical studies of children to inform effective approaches have hampered the development of effective immunotherapies in pediatric settings. Here, we review recent advances and ongoing challenges in pediatric brain cancer immunotherapy, as well as considerations for efficient clinical translation of efficacious immunotherapies into pediatric settings.

Therapeutic approaches targeting splicing factor mutations in myelodysplastic syndromes and acute myeloid leukemia.

PURPOSE OF REVIEW: Mutations in components of the spliceosome are the most common acquired lesions in myelodysplastic syndromes (MDS) and are frequently identified in other myeloid malignancies with a high rate of progression to acute myeloid leukemia (AML) including chronic myelomonocytic leukemia and primary myelofibrosis. The only curative option for these disorders remains allogeneic stem-cell transplantation, which is associated with high morbidity and mortality in these patients. The purpose of this review is to highlight the recent therapeutic developments and strategies being pursued for clinical benefit in splicing factor mutant myeloid malignancies. RECENT FINDINGS: Cells harboring splicing factor mutations have increased aberrant splicing leading to R-loop formation and cell cycle stalling that create dependencies on Checkpoint kinase 1 (CHK1) activation and canonical splicing maintained by protein arginine methyltransferase activity. Both targeting of the spliceosome and targeting of the downstream consequences of splicing factor mutation expression show promise as selective strategies for the treatment of splicing factor-mutant myeloid malignancies. SUMMARY: An improved understanding of the therapeutic vulnerabilities in splicing factor-mutant MDS and AML has led to the development of clinical trials of small molecule inhibitors that target the spliceosome, ataxia telangectasia and Rad3 related (ATR)-CHK1 pathway, and methylation of splicing components.

Chronic sleep restriction increases soluble hippocampal Aß-42 and impairs cognitive performance.

Currently, over 44 million people worldwide suffer from Alzheimer's disease (AD). A common feature of AD is disrupted sleep. Sleep is essential for many psychological and physiological functions, though 35.3% of adults report getting less than 7 hours per night. The present research examined whether chronic sleep restriction would elevate hippocampal amyloid-beta1-42 expression or alter cognitive ability in adult C57BL/6 mice. Chronic sleep restriction was associated with cognitive impairment and increased hippocampal amyloid-beta. Thus, chronic sleep loss may have a detrimental effect upon cognitive function, in part, via increasing amyloid-beta levels in the hippocampus, even in non-genetically modified mice.