Search

Simple Summary: We discuss the role of risk-stratification and personalized treatment for various pediatric cancer patients, with the goal being to improve tumor control and decrease late effects of radiation in long-term survivors. We discuss settings in which radiation can be safely omitted or de-escalated, such as Hodgkin lymphoma, Wilms tumor with lung metastases and WNT pathway Medulloblastoma, and settings that warrant treatment escalation such as larger tumors with rhabdomyosarcoma or Ewing sarcoma, poor responders to chemotherapy and oligometastatic disease settings. We also summarize currently enrolling COG and other cooperative group trials. While the cure rate of cancer in children has markedly improved in the last few decades, late effects continue to be a problem in survivors. Radiotherapy, which is a major component of treatment in many cancers, is one of the major agents responsible for late toxicity. In the past decade, radiotherapy has been omitted in patients achieving excellent response to chemotherapy, such as in Hodgkin lymphoma and some Wilms tumors with lung metastases. Likewise, response to chemotherapy has been used to determine whether lower doses of radiation can be delivered in intracranial germinoma and pediatric nasopharyngeal carcinoma. Molecular subtyping in medulloblastoma is currently being employed, and in WNT-pathway M0 tumors, the reduction in radiotherapy dose to the craniospinal axis and tumor bed is currently being investigated. Finally, dose escalation was recently evaluated in patients with rhabdomyosarcoma > 5 cm who do not achieve a complete response to initial 9 weeks of chemotherapy as well as for unresectable Ewing sarcoma patients to improve local control. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explored the current practices in the real world for grade 2 glioma, an uncommon primary brain cancer. Leveraging the prospective BRAIN registry, this study demonstrates that whilst sequential radiotherapy and chemotherapy improve progression-free survival in high-risk grade 2 glioma, the majority of patients are observed following surgery. In high-risk patients who are observed, 61% remain progression-free at 12 months, with 10% being progression-free at 5 years. This clinically meaningful progression-free survival suggests that validated biomarkers beyond the usual definition of high-risk are required to better inform patient management. Factors contributing to decision-making are underway. Background: Grade-2 gliomas (G2-glioma) are uncommon. In 2016, RTOG9802 established the addition of chemotherapy after radiation (CRT) as a new standard of care for patients with high-risk G2-glioma, defined as subtotal resection or age ≥40 yrs. Here, we report current practices using real-world data. Methods: Patients diagnosed with G2-glioma from 1 January 2016 to 31 December 2022 were identified in BRAIN, a prospective clinical registry collecting data on patients with brain tumours. High- and low-risk were defined as per RTOG9802. Two time periods, January 2016–December 2019 (TP1) and January 2020–December 2022 (TP2), were defined. Survival was estimated using the Kaplan–Meier method. Results: 224 patients were identified. Overall, 38 (17%) were low-risk, with 35 (91%) observed without further treatment. A total of 186 (83%) were high-risk, with 96 (52%) observed, 63 (34%) receiving CRT, and 19 (10%) receiving radiation. Over time, CRT use increased (TP1 vs. TP2: 22% vs. 36%, p = 0.004), and the rate of biopsy (TP1 vs. TP2: 35% vs. 20%, p = 0.02) and radiotherapy alone (TP1 vs. TP2: 14% vs. 4%, p = 0.01) decreased. Median progression-free survival (PFS) was significantly longer in high-risk patients who received CRT (NR) over observation (39 months) (HR 0.49, p = 0.007). In high-risk patients who were observed, 59 (61%) were progression-free at 12 months and 10 (10%) at 5 years. OS data remains immature. Conclusion: Congruent with RTOG9802, real-world BRAIN data shows CRT is associated with improved PFS compared to observation in high-risk G2-glioma. Whilst CRT use has increased over time, observation after surgery remains the most common strategy, with some high-risk patients achieving clinically meaningful PFS. Validated biomarkers are urgently required to better inform patient management. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) uses the Leloir pathway to catabolize D-Galactose (Gal) for tumor growth. Selective targeting of the Leloir pathway with Gal-based antimetabolites has potential for the treatment of GBM. Here, we tested the effect of a Gal-based antimetabolite, 4-deoxy-4-fluorogalactose (4DFG) on the viability and metabolism of GBM cells in culture. 4DFG is a good Glut3/Glut14 substrate and acts as a potent glioma chemotherapeutic. GBM cell cultures were used to examine toxicity and alterations in glycan composition. 4DFG is moderately potent against GBM cells in vitro (IC50: 125–300 µM). Glycosylation in GBM was disrupted by 4DFG. The effect of 4DFG on D-glucose (Glc) metabolism in GBM cells was assessed by using 13C NMR-based tracer studies. 13C-NMR-based metabolic flux analysis revealed that both glycolytic and mitochondrial metabolic fluxes of [U-13C]Glc were significantly decreased in the presence of 4DFG in GBM cells. Survival analysis in an intracranial mouse model during treatment with 4DFG (6 × 25 mg/kg of 4DFG, intravenously) showed improved outcomes by three-fold (p < 0.01). 4DFG is metabolized by GBM in vitro and in vivo, and is lethal to GBM tumors, but well tolerated in mice. A functional Gal-scavenging pathway in GBM allows Gal-based antimetabolites to act as chemotherapeutics. Background: Glioblastoma (GBM) uses Glut3 and/or Glut14 and the Leloir pathway to catabolize D-Galactose (Gal). UDP-4-deoxy-4-fluorogalactose (UDP-4DFG) is a potent inhibitor of the two key enzymes, UDP-galactose-4-epimerase (GALE) and UDP-Glucose 6-dehydrogenase (UGDH), involved in Gal metabolism and in glycan synthesis. The Gal antimetabolite 4-deoxy-4-fluorogalactose (4DFG) is a good substrate for Glut3/Glut14 and acts as a potent glioma chemotherapeutic. Methods: Primary GBM cell cultures were used to examine toxicity and alterations in glycan composition via lectin binding in fixed cells and by Western blots. Toxicity/efficacy in vivo data was performed in mouse flank and intracranial models. The effect of 4DFG on D-glucose (Glc) metabolism in GBM cells was assessed by using 13C NMR-based tracer studies. Results: 4DFG is moderately potent against GBM cells (IC50: 125–300 µM). GBM glycosylation is disrupted by 4DFG. Survival analysis in an intracranial mouse model showed that treatment with 4DFG (6 × 25 mg/kg of 4DFG, intravenously) improved outcomes by three-fold (p < 0.01). Metabolic flux analysis revealed that both glycolytic and mitochondrial metabolic fluxes of [U-13C]Glc were significantly decreased in the presence of 4DFG in GBM cells. Conclusion: A functional Gal-scavenging pathway in GBM allows Gal-based antimetabolites to act as chemotherapeutics. 4DFG is metabolized by GBM in vitro and in vivo, is lethal to GBM tumors, and is well tolerated in mice. [ABSTRACT FROM AUTHOR]

Using microRNAs (miRNAs) as potential circulating biomarkers in diagnosing and treating glioblastoma (GBM) has garnered a lot of scientific and clinical impetus in the past decade. As an aggressive primary brain tumor, GBM poses challenges in early detection and effective treatment with significant current diagnostic constraints and limited therapeutic strategies. MiRNA dysregulation is present in GBM. The intricate involvement of miRNAs in altering cell proliferation, invasion, and immune escape makes them prospective candidates for identifying and monitoring GBM diagnosis and response to treatment. These miRNAs could play a dual role, acting as both potential diagnostic markers and targets for therapy. By modulating the activity of various oncogenic and tumor-suppressive proteins, miRNAs create opportunities for precision medicine and targeted therapies in GBM. This review centers on the critical role and function of circulating miRNA biomarkers in GBM diagnosis and treatment. It highlights their significance in providing insights into disease progression, aiding in early diagnosis, and potential use as targets for novel therapeutic interventions. Ultimately, the study of miRNA would contribute to improving patient outcomes in the challenging landscape of GBM management. [ABSTRACT FROM AUTHOR]

The study explored proteomics to better understand the relationship between type 2 diabetes (T2DM) and hypertension (HT) in Thai adults, using shotgun proteomics and bioinformatics analysis. Plasma samples were taken from 61 subjects: 14 healthy subjects (mean age = 40.85 ± 7.12), 13 with T2DM (mean age = 57.38 ± 6.03), 16 with HT (mean age = 66.87 ± 10.09), and 18 with coexisting T2DM/HT (mean age = 58.22 ± 10.65). Proteins were identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Protein–protein interactions were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) version 11.5. We identified six unique proteins in T2DM patients, including translationally controlled 1 (TPT1) and nibrin (NBN), which are associated with the DNA damage response. In HT patients, seven unique proteins were identified, among them long-chain fatty acid-CoA ligase (ASCL), which functions in the stimulation of triacylglycerol and cholesterol synthesis, and NADPH oxidase activator 1 (NOXA1), which is involved in high blood pressure via angiotensin II-induced reactive oxygen species (ROS)-generating systems. In coexisting T2DM/HT patients, six unique proteins were identified, of which two—microtubule-associated protein 1A (MAP1A)—might be involved in dementia via RhoB-p53 and diacylglycerol kinase beta (DGKB), associated with lipid metabolism. This study identified new candidate proteins that are possibly involved in the pathology of these diseases. [ABSTRACT FROM AUTHOR]

Lattice structures show advantages in mechanical properties and energy absorption efficiency owing to their lightweight, high strength and adjustable geometry. This article reviews lattice structure classification, design and applications, especially those based on additive manufacturing (AM) technology. This article first introduces the basic concepts and classification of lattice structures, including the classification based on topological shapes, such as strut, surface, shell, hollow-strut, and so on, and the classification based on the deformation mechanism. Then, the design methods of lattice structure are analyzed in detail, including the design based on basic unit, mathematical algorithm and gradient structure. Next, the effects of different lattice elements, relative density, material system, load direction and fabrication methods on the mechanical performance of AM-produced lattice structures are discussed. Finally, the advantages of lattice structures in energy absorption performance are summarized, aiming at providing theoretical guidance for further optimizing and expanding the engineering application potential of lattices. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is an incurable primary brain cancer characterized by increased reactive oxygen species (ROS) production. The redox-sensitive tumor suppressor gene TP53, wild-type (wt) for 70% of patients, regulates redox homeostasis. Glioblastoma stem cells (GSCs) increase thioredoxin (Trx) and glutathione (GSH) antioxidant systems as survival redox-adaptive mechanisms to maintain ROS below the cytotoxic threshold. Auranofin, an FDA-approved anti-rheumatoid drug, inhibits thioredoxin reductase 1 (TrxR1). L-buthionine sulfoximine (L-BSO) and the natural product piperlongumine (PPL) inhibit the GSH system. We evaluated the cytotoxic effects of Auranofin alone and in combination with L-BSO or PPL in GBM cell lines and GSCs with a known TP53 status. The Cancer Genome Atlas/GBM analysis revealed a significant positive correlation between wtp53 and TrxR1 expression in GBM. Auranofin induced ROS-dependent cytotoxicity within a micromolar range in GSCs. Auranofin decreased TrxR1 expression, AKT (Ser-473) phosphorylation, and increased p53, p21, and PARP-1 apoptotic cleavage in wtp53-GSCs, while mutant-p53 was decreased in a mutant-p53 GSC line. Additionally, p53-knockdown in a wtp53-GSC line decreased TrxR1 expression and significantly increased sensitivity to Auranofin, suggesting the role of wtp53 as a negative redox-sensitive mechanism in response to Auranofin in GSCs. The combination of Auranofin and L-BSO synergistically increased ROS, decreased IC50s, and induced long-term cytotoxicity irrespective of p53 in GBM cell lines and GSCs. Intriguingly, Auranofin increased the expression of glutathione S-transferase pi-1 (GSTP-1), a target of PPL. Combining Auranofin with PPL synergistically decreased IC50s to a nanomolar range in GSCs, supporting the potential to repurpose Auranofin and PPL in GBM. [ABSTRACT FROM AUTHOR]

Simple Summary: Central Nervous System (CNS) pediatric tumors represent the most common solid tumors in children with a wide variability in terms of survival and therapeutic response. Unlike their adult counterparts, the mutational landscape of pediatric CNS tumors is mostly characterized by oncogenic fusions rather than multiple mutated genes. We report four pediatric cases associated with rare oncogenic fusions, providing an overview of oncogenic fusion pathogenesis, histological phenotype, diagnostic and theranostic impact. Our work underlines that most of these rare oncogenic fusions are not specific to a single morpho-molecular entity among the pediatric CNS tumors. Even within tumors harboring the same oncogenic fusions, a wide range of morphological, molecular and epigenetic entities can be observed. These findings highlight the need for caution when applying the fifth CNS WHO classification, as the vast majority of these fusions are not yet incorporated in the diagnosis, including grade evaluation and DNA methylation classification. Background and Objectives: Central Nervous System (CNS) pediatric tumors represent the most common solid tumors in children with a wide variability in terms of survival and therapeutic response. By contrast to their adult counterpart, the mutational landscape of pediatric CNS tumors is characterized by oncogenic fusions rather than multiple mutated genes. CNS pediatric tumors associated with oncogenic fusions represent a complex landscape of tumors with wide radiological, morphological and clinical heterogeneity. In the fifth CNS WHO classification, there are few pediatric CNS tumors for which diagnosis is based on a single oncogenic fusion. This work aims to provide an overview of the impact of rare oncogenic fusions (NTRK, ROS, ALK, MET, FGFR, RAF, MN1, BCOR and CIC genes) on pathogenesis, histological phenotype, diagnostics and theranostics in pediatric CNS tumors. We report four cases of pediatric CNS tumors associated with NTRK (n = 2), ROS (n = 1) and FGFR3 (n = 1) oncogenic fusion genes as a proof of concept. Cases presentation and literature review: The literature review and the cohort that we described here underline that most of these rare oncogenic fusions are not specific to a single morpho-molecular entity. Even within tumors harboring the same oncogenic fusions, a wide range of morphological, molecular and epigenetic entities can be observed. Conclusions: These findings highlight the need for caution when applying the fifth CNS WHO classification, as the vast majority of these fusions are not yet incorporated in the diagnosis, including grade evaluation and DNA methylation classification. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM), a serious brain cancer, has poor treatment outcomes despite surgery, radiation, and chemotherapy. The blood–brain barrier (BBB) makes GBM-targeted drug delivery difficult. Recent studies have shown that nanomedicine delivery systems (NDDSs) can target GBM safely and effectively. In this review, we look at ways to overcome the BBB with NDDSs in preclinical studies, summarize the clinical progress, and discuss strategies to improve NDDSs and speed up their use in GBM treatment through clinical trials. Glioblastoma (GBM) is a prevalent type of malignancy within the central nervous system (CNS) that is associated with a poor prognosis. The standard treatment for GBM includes the surgical resection of the tumor, followed by radiotherapy and chemotherapy; yet, despite these interventions, overall treatment outcomes remain suboptimal. The blood–brain barrier (BBB), which plays a crucial role in maintaining the stability of brain tissue under normal physiological conditions of the CNS, also poses a significant obstacle to the effective delivery of therapeutic agents to GBMs. Recent preclinical studies have demonstrated that nanomedicine delivery systems (NDDSs) offer promising results, demonstrating both effective GBM targeting and safety, thereby presenting a potential solution for targeted drug delivery. In this review, we first explore the various strategies employed in preclinical studies to overcome the BBB for drug delivery. Subsequently, the results of the clinical translation of NDDSs are summarized, highlighting the progress made. Finally, we discuss potential strategies for advancing the development of NDDSs and accelerating their translational research through well-designed clinical trials in GBM therapy. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite an established standard of care including surgical resection, radiation therapy, and chemotherapy, GBM unfortunately is associated with a dismal prognosis. Therefore, researchers are extensively evaluating avenues to expand GBM therapy and improve outcomes in patients with GBM. In this review, we provide a broad overview of novel GBM therapies that have recently completed or are actively undergoing study in clinical trials. These therapies expand across medical, surgical, and radiation clinical trials. We additionally review methods for improving clinical trial design in GBM. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is an aggressive and highly malignant primary brain tumor characterized by rapid growth and a poor prognosis for patients. Despite advancements in treatment, the median survival time for GBM patients remains low. One of the crucial challenges in understanding and treating GBMs involves its remarkable cellular heterogeneity and adaptability. Central to the survival and proliferation of GBM cells is their ability to undergo metabolic reprogramming. Metabolic reprogramming is a process that allows cancer cells to alter their metabolism to meet the increased demands of rapid growth and to survive in the often oxygen- and nutrient-deficient tumor microenvironment. These changes in metabolism include the Warburg effect, alterations in several key metabolic pathways including glutamine metabolism, fatty acid synthesis, and the tricarboxylic acid (TCA) cycle, increased uptake and utilization of glutamine, and more. Despite the complexity and adaptability of GBM metabolism, a deeper understanding of its metabolic reprogramming offers hope for developing more effective therapeutic interventions against GBMs. [ABSTRACT FROM AUTHOR]

Meningiomas are predominantly benign tumors, but there are also malignant forms that are associated with a poor prognosis. Like almost all tumors, meningiomas metabolize glucose as part of aerobic glycolysis (Warburg effect) for energy supply, so there are attempts to influence the prognosis of tumor diseases using a glucose-reduced diet. This altered metabolism leads to so called hallmarks of cancer, such as glycation and glycosylation. In this study, we investigated the influence of low (3 mM), normal (5.5 mM) and high glucose (15 mM) on a malignant meningioma cell line (IOMM-Lee, WHO grade 3). In addition, the influence of methylglyoxal, a by-product of glycolysis and a precursor for glycation, was investigated. Impedance-based methods (ECIS and RTCA) were used to study migration and invasion, and immunoblotting was used to analyze the expression of proteins relevant to these processes, such as focal adhesion kinase (FAK), merlin or integrin ß1. We were able to show that low glucose reduced the invasive potential of the cells, which was associated with a reduced amount of sialic acid. Under high glucose, barrier function was impaired and adhesion decreased, which correlated with a decreased expression of FAK. [ABSTRACT FROM AUTHOR]

Simple Summary: Currently, there are no effective therapies for glioblastoma. Infiltrating myeloid cells contributes significantly to the immune suppressive tumor microenvironment that is characteristic of GBM. Monocytic myeloid-derived suppressor cells are chief immune suppressive cells found in the glioma microenvironment. Understanding the mechanisms of M-MDSC differentiation and T-cell suppression is imperative for generating therapies that target this tumor-supportive cell population. In this study, we found that glioma-secreted CSF1R ligands, M-CSF and IL-34, promote M-MDSCs to suppress CD8 T cells. These M-MDSCs partially utilize nitric oxide synthase to illicit their suppressive activity. However, spatial RNAseq points to glioma microenvironment niches driving M-MDSC heterogeneity. Our findings identify key regulators of differentiation and suppressive mechanisms of M-MDSCs and confirm the importance of targeting this cell population in glioma. Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2+/CX3CR1+ M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2+/CX3CR1+ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma-secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in the M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that is driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Seizures are one of the most common and severe symptoms of meningioma, leading to increased morbidity and mortality in the affected patients. Therefore, seizure prevention represents an important goal in the treatment of meningioma patients. For this purpose, our study aims to identify predictors for the occurrence of preoperative and postoperative seizures in meningioma. Neurosurgical tumor resection was demonstrated as an effective treatment of seizures in meningioma patients but is also associated with a moderate risk of new-onset seizures after surgery. The present study identified several independent predictors for seizures in meningioma that could contribute to improved seizure treatment and a deeper understanding of the occurrence of seizures in meningioma patients. Seizure is a common symptom of meningioma that has a major impact on patients' quality of life. The purpose of this study was to identify predictive factors for the occurrence of preoperative and postoperative seizures. The data of patients with resection of histologically confirmed meningioma at University Hospital Leipzig from 2009 to 2018 were retrospectively examined. Univariate and multivariate logistic regression analyses of different factors influencing seizure outcome were performed. The male gender was identified as an independent positive predictor for preoperative seizures (odds ratio [OR] 1.917 [95% confidence interval {CI} 1.044–3.521], p = 0.036), whereas headache (OR 0.230 [95% CI 0.091–0.582], p = 0.002) and neurological deficits (OR 0.223; [95% CI 0.121–0.410], p < 0.001) were demonstrated to be negative predictive factors. Sensorimotor deficit after surgery (OR 4.490 [95% CI 2.231–9.037], p < 0.001) was found to be a positive predictor for the occurrence of postoperative seizures. The identified predictors for the occurrence of seizures in meningioma can contribute to improving seizure treatment and patients' quality of life. [ABSTRACT FROM AUTHOR]

Simple Summary: It is known that there are sex differences in adverse events experienced following cancer treatment. However, little is known about sex differences in adverse events experienced in individuals with metastatic cancer. Here, using SEER-Medicare data, we investigate sex differences in adverse events in lung cancer individuals with brain metastasis who are 66 years old and older. Sex differences in adverse events were observed and were dependent on lung cancer histology, age at diagnosis, year of diagnosis and treatment as well as potential interplay between these variables. Sex differences are evident in adverse events (AEs) related to brain tumors, yet sex differences in AEs specific to brain metastases (BrMs) are underexplored. Lung cancer BrMs dominate among BrM, comprising over half of cases. This study examined sex differences in AEs associated with lung cancer BrMs in individuals aged 66 or older using the SEER-Medicare dataset. Multivariable logistic regression, adjusted for demographic factors and comorbidities, stratified by histological subtype, treatment, age, and year of diagnosis were used to analyze AEs among those with BrMs from primary lung tumors. Year of diagnosis was grouped into prior/post-2013, to account for shifts in treatment paradigms. The results showed nuanced sex-specific AEs. Females diagnosed post-2013 with small-cell, squamous-cell, or other non-small-cell carcinoma BrMs had a higher headache likelihood than males. Males with adenocarcinoma post-2013 were more likely to experience brain herniation. Females aged 76 and older with small-cell BrM exhibited increased vision difficulty risk compared to males of the same age, with no significant difference in other age groups. Males treated for adenocarcinoma faced heightened hemorrhagic stroke risk. This study reveals sex-specific disparities in AEs among older individuals with lung cancer BrMs, varying by histological subtype, age, diagnosis year, and treatment. [ABSTRACT FROM AUTHOR]

Meningiomas are the most common primary intracranial tumors in adults and typically have a slow-growing and benign nature. However, there is also a substantial subset of meningiomas that shows aggressive clinical behavior and is refractory to standard treatment modalities, which are still limited to surgery and/or radiotherapy. Despite intensive research, no systemic treatment options are yet available in the clinic for these challenging tumors, resulting in poor patient outcome. Intensive research on the molecular pathogenesis of meningiomas has led to improved diagnostic tools, but so far there is no standardized implementation for the molecular profiling of these tumors for clinical practice. Recent research advances have also focused on the immunophenotyping of meningiomas, leading to several clinical trials examining the use of immune checkpoint blockade therapy in patients with clinically aggressive subtypes. In this review, we aim to summarize the current knowledge on the molecular and immunological landscape of meningiomas in detail and provide current and progressive ideas for future directions. [ABSTRACT FROM AUTHOR]

Radiation therapy continues to be the cornerstone treatment for malignant brain tumors, the majority of which express wild-type p53. Therefore, the identification of drugs that promote the ionizing radiation (IR)-induced activation of p53 is expected to increase the efficacy of radiation therapy for these tumors. The growth inhibitory effects of CEP-1347, a known inhibitor of MDM4 expression, on malignant brain tumor cell lines expressing wild-type p53 were examined, alone or in combination with IR, by dye exclusion and/or colony formation assays. The effects of CEP-1347 on the p53 pathway, alone or in combination with IR, were examined by RT-PCR and Western blot analyses. The combination of CEP-1347 and IR activated p53 in malignant brain tumor cells and inhibited their growth more effectively than either alone. Mechanistically, CEP-1347 and IR each reduced MDM4 expression, while their combination did not result in further decreases. CEP-1347 promoted IR-induced Chk2 phosphorylation and increased p53 expression in concert with IR in a Chk2-dependent manner. The present results show, for the first time, that CEP-1347 is capable of promoting Chk2-mediated p53 activation by IR in addition to inhibiting the expression of MDM4 and, thus, CEP-1347 has potential as a radiosensitizer for malignant brain tumors expressing wild-type p53. [ABSTRACT FROM AUTHOR]

As the most common and aggressive primary malignant brain tumor, glioblastoma is still lacking a satisfactory curative approach. The standard management consisting of gross total resection followed by radiotherapy and chemotherapy with temozolomide only prolongs patients' life moderately. In recent years, many therapeutics have failed to give a breakthrough in GBM treatment. In the search for new treatment solutions, we became interested in the repurposing of existing medicines, which have established safety profiles. We focused on the possible implementation of well-known drugs, metformin, and arginine. Metformin is widely used in diabetes treatment, but arginine is mainly a cardiovascular protective drug. We evaluated the effects of metformin and arginine on total DNA methylation, as well as the oxidative stress evoked by treatment with those agents. In glioblastoma cell lines, a decrease in 5-methylcytosine contents was observed with increasing drug concentration. When combined with temozolomide, both guanidines parallelly increased DNA methylation and decreased 8-oxo-deoxyguanosine contents. These effects can be explained by specific interactions of the guanidine group with m5CpG dinucleotide. We showed that metformin and arginine act on the epigenetic level, influencing the foreground and potent DNA regulatory mechanisms. Therefore, they can be used separately or in combination with temozolomide, in various stages of disease, depending on desired treatment effects. [ABSTRACT FROM AUTHOR]

There is increased recognition for solutions that address the social determinants of health (SDOHs)—the context in which families are raising children. Unfortunately, implementing solutions that address inequities in the SDOHs has proven to be difficult. Many child and family serving systems and communities do not know where to start or do not have the capacity to identify and implement upstream SDOH strategies. As such, we conducted a scoping review to assess the status of evidence connecting strategies that address the SDOHs and child well-being. A total of 29,079 records were identified using natural language processing with 341 records meeting inclusion criteria (e.g., outcomes focused on child well-being, interventions happening at a population level, and evaluations of prevention strategies in the United States). Records were coded, and the findings are presented by the SDOH domain, such as strategies that addressed economic stability (n = 94), education access and quality (n = 17), food security (n = 106), healthcare access and quality (n = 96), neighborhood and built environment (n = 7), and social and community context (n = 12). This review provides an overview of the associations between population-level SDOH strategies and the impact—good and bad—on child well-being and may be a useful resource for communities and practitioners when considering equitable solutions that promote thriving childhoods. [ABSTRACT FROM AUTHOR]

Background: Gliomas, including the most severe form known as glioblastomas, are primary brain tumors arising from glial cells, with significant impact on adults, particularly men aged 45 to 70. Recent advancements in the WHO (World Health Organization) classification now correlate genetic markers with glioma phenotypes, enhancing diagnostic precision and therapeutic strategies. Aims and Methods: This scoping review aims to evaluate the current state of deep learning (DL) applications in the genetic characterization of adult gliomas, addressing the potential of these technologies for a reliable virtual biopsy. Results: We reviewed 17 studies, analyzing the evolution of DL algorithms from fully convolutional networks to more advanced architectures (ResNet and DenseNet). The methods involved various validation techniques, including k-fold cross-validation and external dataset validation. Conclusions: Our findings highlight significant variability in reported performance, largely due to small, homogeneous datasets and inconsistent validation methods. Despite promising results, particularly in predicting individual genetic traits, the lack of robust external validation limits the generalizability of these models. Future efforts should focus on developing larger, more diverse datasets and integrating multidisciplinary collaboration to enhance model reliability. This review underscores the potential of DL in advancing glioma characterization, paving the way for more precise, non-invasive diagnostic tools. The development of a robust algorithm capable of predicting the somatic genetics of gliomas or glioblastomas could accelerate the diagnostic process and inform therapeutic decisions more quickly, while maintaining the same level of accuracy as the traditional diagnostic pathway, which involves invasive tumor biopsies. [ABSTRACT FROM AUTHOR]

The uptake of four liposomal formulations was tested with the murine endothelial cell line bEnd.3 and the human glioblastoma cell line U-87 MG. All formulations were composed of DPPC, cholesterol, 5 mol% of mPEG (2000 Da, conjugated to DSPE), and the dye DiD. Three of the formulations had an additional PEG chain (nominally 5000 Da, conjugated to DSPE) with either succinimide (NHS), glucose (PEG-bound at C-6), or 4-aminophenyl β-D-glucopyranoside (bound at C-1) as ligands at the distal end. Measuring the uptake kinetics at 1 h and 3 h for liposomal incubation concentrations of 100 µM, 500 µM, and 1000 µM, we calculated the liposomal uptake saturation S and the saturation half-time t1/2. We show that only succinimide has an elevated uptake in bEnd.3 cells, which makes it a very promising and so far largely unexplored candidate for BBB transfer and brain cancer therapies. Half-times are uniform at low concentrations but diversify for high concentrations for bEnd.3 cells. Contrary, U-87 MG cells show almost identical saturations for all three ligands, making a uniform uptake mechanism likely. Only mPEG liposomes stay at 60% of the saturation for ligand-coated liposomes. Half-times are diverse at low concentrations but unify at high concentrations for U-87 MG cells. [ABSTRACT FROM AUTHOR]

As effective treatment of glioblastoma is still an unmet need, targeted delivery systems for efficient treatment are of utmost interest. Therefore, in this paper, surface modifications with a small peptide c(RGD) or physiological protein (ApoE3) were investigated. Cellular uptake in murine endothelial cells (bEnd.3) and different glioma cells (human U-87 MG, rat F98) was tested to elucidate possible differences and to correlate the uptake to the receptor expression. Different liposomal formulations were measured at 1 and 3 h for three lipid incubation concentrations. We calculated the liposomal uptake saturation S and the saturation half-time t1/2. An up to 9.6-fold increased uptake for ApoE3-modified liposomes, primarily in tumor cells, was found. Contrarily, c(RGD) liposomes showed a stronger increase in uptake in endothelial cells (up to 40.5-fold). The uptake of modified liposomes revealed enormous differences in S and t1/2 when comparing different tumor cell lines. However, for ApoE3-modified liposomes, we proved comparable saturation values (~25,000) for F98 cells and U-87 MG cells despite a 6-fold lower expression of LRP1 in F98 cells and a 5-fold slower uptake rate. Our findings suggest that cellular uptake of surface-modified liposomes depends more on the target structure than the ligand type, with significant differences between cell types of different origins. [ABSTRACT FROM AUTHOR]

In this paper, I present a comprehensive pipeline integrating a Fine-Tuned Convolutional Neural Network (FT-CNN) and a Residual-UNet (RUNet) architecture for the automated analysis of MRI brain scans. The proposed system addresses the dual challenges of brain tumor classification and segmentation, which are crucial tasks in medical image analysis for precise diagnosis and treatment planning. Initially, the pipeline preprocesses the FigShare brain MRI image dataset, comprising 3064 images, by normalizing and resizing them to achieve uniformity and compatibility with the model. The FT-CNN model then classifies the preprocessed images into distinct tumor types: glioma, meningioma, and pituitary tumor. Following classification, the RUNet model performs pixel-level segmentation to delineate tumor regions within the MRI scans. The FT-CNN leverages the VGG19 architecture, pre-trained on large datasets and fine-tuned for specific tumor classification tasks. Features extracted from MRI images are used to train the FT-CNN, demonstrating robust performance in discriminating between tumor types. Subsequently, the RUNet model, inspired by the U-Net design and enhanced with residual blocks, effectively segments tumors by combining high-resolution spatial information from the encoding path with context-rich features from the bottleneck. My experimental results indicate that the integrated pipeline achieves high accuracy in both classification (96%) and segmentation tasks (98%), showcasing its potential for clinical applications in brain tumor diagnosis. For the classification task, the metrics involved are loss, accuracy, confusion matrix, and classification report, while for the segmentation task, the metrics used are loss, accuracy, Dice coefficient, intersection over union, and Jaccard distance. To further validate the generalizability and robustness of the integrated pipeline, I evaluated the model on two additional datasets. The first dataset consists of 7023 images for classification tasks, expanding to a four-class dataset. The second dataset contains approximately 3929 images for both classification and segmentation tasks, including a binary classification scenario. The model demonstrated robust performance, achieving 95% accuracy on the four-class task and high accuracy (96%) in the binary classification and segmentation tasks, with a Dice coefficient of 95%. [ABSTRACT FROM AUTHOR]

Meningiomas represent approximately 40% of all primary tumors of the central nervous system (CNS) and, based on the latest World Health Organization (WHO) guidelines, are classified into three grades and fifteen subtypes. The optimal treatment comprises gross total tumor resection. The WHO grade and the extent of tumor resection assessed by the Simpson grading system are the most important predictors of recurrence. Atypical meningiomas, a grade 2 meningioma, which represent almost a fifth of all meningiomas, have a recurrence rate of around 50%. Currently, different histopathologic, cytogenetic, and molecular genetic alterations have been associated with different meningioma phenotypes; however, the data are insufficient to enable the development of specific treatment plans. The optimal treatment, in terms of adjuvant radiotherapy and postoperative systemic therapy in atypical meningiomas, remains controversial, with inconclusive evidence in the literature and existing studies. We review the recent literature to identify studies investigating relevant atypical meningioma biomarkers and their clinical application and effects on treatment options. [ABSTRACT FROM AUTHOR]

Simple Summary: Intramedullary primary spinal cord tumors represent a heterogeneous group of very rare tumors. In cases of recurrence or high-grade tumors, radiotherapy, chemotherapy, or targeted therapies can be indicated. The purpose of this review is to clarify the actual knowledge about intramedullary primary spinal cord tumors in light of the latest progress made in their classification. Intramedullary primary spinal cord tumors are rare in adults and their classification has recently evolved. Their treatment most frequently relies on maximal safe surgical resection. Herein, we review, in light of the WHO 2021 classification of central nervous system tumors, the knowledge regarding the role of radiotherapy and systemic treatments in spinal ependymomas, spinal astrocytomas (pilocytic astrocytoma, diffuse astrocytoma, spinal glioblastoma IDH wildtype, diffuse midline glioma H3-K27M altered, and high-grade astrocytoma with piloid features), neuro-glial tumors (ganglioglioma and diffuse leptomeningeal glioneuronal tumor), and hemangioblastomas. In spinal ependymomas, radiotherapy is recommended for incompletely resected grade 2 tumors, grade 3 tumors, and recurrent tumors not amenable to re-surgery. Chemotherapy is used in recurrent cases. In spinal astrocytomas, radiotherapy is recommended for incompletely resected grade 2 astrocytomas and grade 3 or 4 tumors as well as recurrent tumors. Chemotherapy is indicated for newly diagnosed high-grade astrocytomas and recurrent cases. In hemangioblastomas not amenable to surgery, radiotherapy is an effective alternative option. Targeted therapies are playing an increasingly important role in the management of some intramedullary primary spinal cord tumor subtypes. BRAF and/or MEK inhibitors have demonstrated efficacy in pilocytic astrocytomas and glioneuronal tumors, belzutifan in von Hippel–Lindau-related hemangioblastomas, and promising results have been reported with ONC201 in diffuse midline glioma H3-K27M altered. [ABSTRACT FROM AUTHOR]

Poor diet is the top modifiable mortality risk factor globally, accounting for 11 million deaths annually with half being from diet-linked atherosclerotic cardiovascular disease (ASCVD). Yet, most of the world cannot afford a healthy diet—as the hidden costs of the inadequate global food system total over USD 13 trillion annually—let alone the much more clinically, financially, and ecologically costly and resource-intensive medical interventions required to address the disease progression and acute complications of ASCVD. Yet, AI is increasingly understood as a force multiplying revolutionary technology which may catalyze multi-sector efforts in medicine and public health to better address these significant health challenges. This novel narrative review seeks to provide the first known overview of the state-of-the-art in clinical interventions and public health policies in healthy diets for ASCVD, accelerated by health equity-focused AI. It is written from the first-hand practitioner perspective to provide greater relevance and applicability for health professionals and data scientists. The review summarizes the emerging trends and leading use cases in population health risk stratification and precision public health, AI democratizing clinical diagnosis, digital twins in precision nutrition, and AI-enabled culinary medicine as medical education and treatment. This review may, therefore, help inform and advance the evidence-based foundation for more clinically effective, financially efficient, and societally equitable dietary and nutrition interventions for ASCVD. [ABSTRACT FROM AUTHOR]

The implementation of Industry 4.0 has integrated manufacturing, electronics, and engineering materials, leading to the creation of smart parts (SPs) that provide information on production system conditions. However, SP development faces challenges due to limitations in manufacturing processes and integrating electronic components. This systematic review synthesizes scientific articles on SP fabrication using additive manufacturing (AM), identifying the advantages and disadvantages of AM techniques in SP production and distinguishing between SPs and smart spare parts (SSPs). The methodology involves establishing a reference framework, formulating SP-related questions, and applying inclusion criteria and keywords, initially resulting in 1603 articles. After applying exclusion criteria, 70 articles remained. The results show that while SP development is advancing, widespread application of AM-manufactured SP is recent. SPs can anticipate production system failures, minimize design artifacts, and reduce manufacturing costs. Furthermore, the review highlights that SSPs, a subcategory of SPs, primarily differs by replacing conventional critical parts in the industry, offering enhanced functionality and reliability in industrial applications. The study concludes that continued research and development in this field is essential for further advancements and broader adoption of these technologies. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most common and aggressive brain tumor in adults. Despite surgery, radiation, and chemotherapy, survival rates remain low, which emphasizes the urgent need for improved therapies. Current preclinical models use untreated tumors, which do not reflect the clinical scenario where patients already receive initial treatments. This review examines the effects of current treatments on the properties of recurrent tumors and evaluates preclinical models that incorporate these standard treatments to better mimic real patient conditions. Improving these models could help to identify more effective treatments, potentially leading to better outcomes for glioblastoma patients. Glioblastoma (GBM) presents a significant public health challenge as the deadliest and most common malignant brain tumor in adults. Despite standard-of-care treatment, which includes surgery, radiation, and chemotherapy, mortality rates are high, underscoring the critical need for advancing GBM therapy. Over the past two decades, numerous clinical trials have been performed, yet only a small fraction demonstrated a benefit, raising concerns about the predictability of current preclinical models. Traditionally, preclinical studies utilize treatment-naïve tumors, failing to model the clinical scenario where patients undergo standard-of-care treatment prior to recurrence. Recurrent GBM generally exhibits distinct molecular alterations influenced by treatment selection pressures. In this review, we discuss the impact of treatment—surgery, radiation, and chemotherapy—on GBM. We also provide a summary of treatments used in preclinical models, advocating for their integration to enhance the translation of novel strategies to improve therapeutic outcomes in GBM. [ABSTRACT FROM AUTHOR]

Damage to the central nervous system (CNS) often leads to irreversible neurological deficits, and there are currently few effective treatments available. However, recent advancements in regenerative medicine have identified CNS organoids as promising therapeutic options for addressing CNS injuries. These organoids, composed of various neurons and supporting cells, have shown potential for direct repair at injury sites. CNS organoids resemble the structure and function of actual brain tissue, which allows them to adapt and function well within the physiological environment when transplanted into injury sites. Research findings suggest that CNS organoids can replace damaged neurons, form new neural connections, and promote neural recovery. This review highlights the emerging benefits, evaluates preclinical transplantation outcomes, and explores future strategies for optimizing neuroregeneration using CNS organoids. With continued research and technological advancements, these organoids could provide new hope for patients suffering from neurological deficits. [ABSTRACT FROM AUTHOR]

Paediatric high-grade gliomas are among the most common malignancies found in children. Despite morphological similarities to their adult counterparts, there are profound biological and molecular differences. Furthermore, and thanks to molecular biology, the diagnostic pathology of paediatric high-grade gliomas has experimented a dramatic shift towards molecular classification, with important prognostic implications, as is appropriately reflected in both the current WHO Classification of Tumours of the Central Nervous System and the WHO Classification of Paediatric Tumours. Emphasis is placed on histone 3, IDH1, and IDH2 alterations, and on Receptor of Tyrosine Kinase fusions. In this review we present the current diagnostic categories from the diagnostic pathology perspective including molecular features. [ABSTRACT FROM AUTHOR]

Glioblastoma cell lines derived from different patients are widely used in tumor biology research and drug screening. A key feature of glioblastoma is the high level of inter- and intratumor heterogeneity that accounts for treatment resistance. Our aim was to investigate whether intratumor heterogeneity is maintained in cell models. Single-cell RNA sequencing was used to investigate the cellular composition of a tumor sample and six patient-derived glioblastoma cell lines. Three cell lines preserved the mutational profile of the original tumor, whereas three others differed from their precursors. Copy-number variation analysis showed significantly rearranged genomes in all the cell lines and in the tumor sample. The tumor had the most complex cell composition, including cancer cells and microenvironmental cells. Cell lines with a conserved genome had less diverse cellularity, and during cultivation, a relative increase in the stem-cell-derived progenitors was noticed. Cell lines with genomes different from those of the primary tumors mainly contained neural progenitor cells and microenvironmental cells. The establishment of cell lines without the driver mutations that are intrinsic to the original tumors may be related to the selection of clones or cell populations during cultivation. Thus, patient-derived glioblastoma cell lines differ substantially in their cellular profile, which should be taken into account in translational studies. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a severe form of brain tumor that has a high fatality rate. It grows aggressively and most of the time results in resistance to traditional treatments like chemo- and radiotherapy and surgery. Biodiversity, beyond representing a big resource for human well-being, provides several natural compounds that have shown great potential as anticancer drugs. Many of them are being extensively researched and significantly slow GBM progression by reducing the proliferation rate, migration, and inflammation and also by modulating oxidative stress. Here, the use of some natural compounds, such as Allium lusitanicum, Succisa pratensis, and Dianthus superbus, was explored to tackle GBM; they showed their impact on cell number reduction, which was partially given by cell cycle quiescence. Furthermore, a reduced cell migration ability was reported, accomplished by morphological cytoskeleton changes, which even highlighted a mesenchymal–epithelial transition. Furthermore, metabolic studies showed an induced cell oxidative stress modulation and a massive metabolic rearrangement. Therefore, a new therapeutic option was suggested to overcome the limitations of conventional treatments and thereby improve patient outcomes. [ABSTRACT FROM AUTHOR]

Pediatric high-grade glioma (pHGG) encompasses a wide range of gliomas with different genomic, epigenomic, and transcriptomic features. Almost 50% of pHGGs present a mutation in genes coding for histone 3, including the subtype harboring the H3.3-G34 mutation. In this context, histone mutations are frequently associated with mutations in TP53 and ATRX, along with PDGFRA and NOTCH2NL amplifications. Moreover, the H3.3-G34 histone mutation induces epigenetic changes in immune-related genes and exerts modulatory functions on the microenvironment. Also, the functionality of the blood–brain barrier (BBB) has an impact on treatment response. The prognosis remains poor with conventional treatments, thus eliciting the investigation of additional and alternative therapies. Promising molecular targets include PDGFRA amplification, BRAF mutation, EGFR amplification, NF1 loss, and IDH mutation. Considering that pHGGs harboring the H3.3-G34R mutation appear to be more susceptible to immunotherapies (ITs), different options have been recently explored, including immune checkpoint inhibitors, antibody mediated IT, and Car-T cells. This review aims to summarize the knowledge concerning cancer biology and cancer-immune cell interaction in this set of pediatric gliomas, with a focus on possible therapeutic options. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a malignant Grade VI cancer type with a median survival duration of only 8–16 months. Earlier detection of GBM could enable more effective treatment. Hyperpolarized magnetic resonance spectroscopy (HPMRS) could detect GBM earlier than conventional anatomical MRI in glioblastoma murine models. We further investigated whether artificial intelligence (A.I.) could detect GBM earlier than HPMRS. We developed a deep learning model that combines multiple modalities of cancer data to predict tumor progression, assess treatment effects, and to reconstruct in vivo metabolomic information from ex vivo data. Our model can detect GBM progression two weeks earlier than conventional MRIs and a week earlier than HPMRS alone. Our model accurately predicted in vivo biomarkers from HPMRS, and the results inferred biological relevance. Additionally, the model showed potential for examining treatment effects. Our model successfully detected tumor progression two weeks earlier than conventional MRIs and accurately predicted in vivo biomarkers using ex vivo information such as conventional MRIs, HPMRS, and tumor size data. The accuracy of these predictions is consistent with biological relevance. [ABSTRACT FROM AUTHOR]

High-grade glioma is the most frequent and lethal primary tumor of the central nervous system. Despite advances in surgical, pharmacological, and cell-directed therapies, there have been no updates to the standard of care in over a decade. This cross-sectional study analyzes patient and trial data from 201 interventional trials completed between 2010 and 2023, encompassing 18,563 participants. Although we found that all trials reported participant age and sex, only 52% of trials reported participant demographics, resulting in 51% of total participant demographics being unreported. The majority of studies did not report ethnicity, with approximately 60% of participants unreported. Additionally, males were significantly underrepresented in trials, comprising 60% of participants despite representing 75% of glioblastoma patients. Improved demographic reporting has been observed since 2011; however, it is inconsistent. Furthermore, we cataloged the geographic diversity of trials across the United States and found significant coverage deserts in relatively rural, but highly affected, areas such as Montana and Maine. We found a wider distribution of trials in both urban and wealthier regions, which indicates extensive coverage gaps and decreased access to participation for patients of a lower socioeconomic status. [ABSTRACT FROM AUTHOR]

Pediatric low-grade gliomas (PLGGs) comprise a heterogeneous set of low-grade glial and glioneuronal tumors, collectively representing the most frequent CNS tumors of childhood and adolescence. Despite excellent overall survival rates, the chronic nature of the disease bears a high risk of long-term disease- and therapy-related morbidity in affected patients. Recent in-depth molecular profiling and studies of the genetic landscape of PLGGs led to the discovery of the paramount role of frequent upregulation of RAS/MAPK and mTOR signaling in tumorigenesis and progression of these tumors. Beyond, the subsequent unveiling of RAS/MAPK-driven oncogene-induced senescence in these tumors may shape the understanding of the molecular mechanisms determining the versatile progression patterns of PLGGs, potentially providing a promising target for novel therapies. Recent in vitro and in vivo studies moreover indicate a strong dependence of PLGG formation and growth on the tumor microenvironment. In this work, we provide an overview of the current understanding of the multilayered cellular mechanisms and clinical factors determining the natural progression patterns and the characteristic biological behavior of these tumors, aiming to provide a foundation for advanced stratification for the management of these tumors within a multimodal treatment approach. [ABSTRACT FROM AUTHOR]

Glioma cells overexpress different peptide receptors that are useful for research, diagnosis, management, and treatment of the disease. Oncogenic peptides favor the proliferation, migration, and invasion of glioma cells, as well as angiogenesis, whereas anticancer peptides exert antiproliferative, antimigration, and anti-angiogenic effects against gliomas. Other peptides exert a dual effect on gliomas, that is, both proliferative and antiproliferative actions. Peptidergic systems are therapeutic targets, as peptide receptor antagonists/peptides or peptide receptor agonists can be administered to treat gliomas. Other anticancer strategies exerting beneficial effects against gliomas are discussed herein, and future research lines to be developed for gliomas are also suggested. Despite the large amount of data supporting the involvement of peptides in glioma progression, no anticancer drugs targeting peptidergic systems are currently available in clinical practice to treat gliomas. [ABSTRACT FROM AUTHOR]

Gliomas, particularly glioblastoma (GBM), represent the most prevalent and aggressive tumors of the central nervous system (CNS). Despite recent treatment advancements, patient survival rates remain low. The diagnosis of GBM traditionally relies on neuroimaging methods such as magnetic resonance imaging (MRI) or computed tomography (CT) scans and postoperative confirmation via histopathological and molecular analysis. Imaging techniques struggle to differentiate between tumor progression and treatment-related changes, leading to potential misinterpretation and treatment delays. Similarly, tissue biopsies, while informative, are invasive and not suitable for monitoring ongoing treatments. These challenges have led to the emergence of liquid biopsy, particularly through blood samples, as a promising alternative for GBM diagnosis and monitoring. Presently, blood and cerebrospinal fluid (CSF) sampling offers a minimally invasive means of obtaining tumor-related information to guide therapy. The idea that blood or any biofluid tests can be used to screen many cancer types has huge potential. Tumors release various components into the bloodstream or other biofluids, including cell-free nucleic acids such as microRNAs (miRNAs), circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), proteins, extracellular vesicles (EVs) or exosomes, metabolites, and other factors. These factors have been shown to cross the blood-brain barrier (BBB), presenting an opportunity for the minimally invasive monitoring of GBM as well as for the real-time assessment of distinct genetic, epigenetic, transcriptomic, proteomic, and metabolomic changes associated with brain tumors. Despite their potential, the clinical utility of liquid biopsy-based circulating biomarkers is somewhat constrained by limitations such as the absence of standardized methodologies for blood or CSF collection, analyte extraction, analysis methods, and small cohort sizes. Additionally, tissue biopsies offer more precise insights into tumor morphology and the microenvironment. Therefore, the objective of a liquid biopsy should be to complement and enhance the diagnostic accuracy and monitoring of GBM patients by providing additional information alongside traditional tissue biopsies. Moreover, utilizing a combination of diverse biomarker types may enhance clinical effectiveness compared to solely relying on one biomarker category, potentially improving diagnostic sensitivity and specificity and addressing some of the existing limitations associated with liquid biomarkers for GBM. This review presents an overview of the latest research on circulating biomarkers found in GBM blood or CSF samples, discusses their potential as diagnostic, predictive, and prognostic indicators, and discusses associated challenges and future perspectives. [ABSTRACT FROM AUTHOR]

Obesity, a global pandemic, poses a major threat to healthcare systems worldwide. Adipose tissue, the energy-storing organ during excessive energy intake, functions as a thermoregulator, interacting with other tissues to regulate systemic metabolism. Specifically, brown adipose tissue (BAT) is positively associated with an increased resistance to obesity, due to its thermogenic function in the presence of uncoupled protein 1 (UCP1). Recently, studies on climate change and the influence of environmental pollutants on energy homeostasis and obesity have drawn increasing attention. The reciprocal relationship between increasing adiposity and increasing temperatures results in reduced adaptive thermogenesis, decreased physical activity, and increased carbon footprint production. In addition, the impact of climate change makes obese individuals more prone to developing type 2 diabetes mellitus (T2DM). An impaired response to heat stress, compromised vasodilation, and sweating increase the risk of diabetes-related comorbidities. This comprehensive review provides information about the effects of climate change on obesity and adipose tissue, the risk of T2DM development, and insights into the environmental pollutants causing adipose tissue dysfunction and obesity. The effects of altered dietary patterns on adiposity and adaptation strategies to mitigate the detrimental effects of climate change are also discussed. [ABSTRACT FROM AUTHOR]

Pediatric high-grade gliomas are a devastating subset of brain tumors, characterized by their aggressive pathophysiology and limited treatment options. Among them, H3 K27-altered diffuse midline gliomas (DMG) of the brainstem stand out due to their distinct molecular features and dismal prognosis. Recent advances in molecular profiling techniques have unveiled the critical role of H3 K27 alterations, particularly a lysine-to-methionine mutation on position 27 (K27M) of the histone H3 tail, in the pathogenesis of DMG. These mutations result in epigenetic dysregulation, which leads to altered chromatin structure and gene expression patterns in DMG tumor cells, ultimately contributing to the aggressive phenotype of DMG. The exploration of targeted therapeutic avenues for DMG has gained momentum in recent years. Therapies, including epigenetic modifiers, kinase inhibitors, and immunotherapies, are under active investigation; these approaches aim to disrupt aberrant signaling cascades and overcome the various mechanisms of therapeutic resistance in DMG. Challenges, including blood–brain barrier penetration and DMG tumor heterogeneity, require innovative approaches to improve drug delivery and personalized treatment strategies. This review aims to provide a comprehensive overview of the evolving understanding of DMG, focusing on the intricate molecular mechanisms driving tumorigenesis/tumor progression and the current landscape of emerging targeted interventions. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a gradually worsening neurodegenerative disorder affecting the nervous system, marked by a slow progression and varied symptoms. It is the second most common neurodegenerative disease, affecting over six million people in the world. Its multifactorial etiology includes environmental, genomic, and epigenetic factors. Clinical symptoms consist of non-motor and motor symptoms, with motor symptoms being the classic presentation. Therapeutic approaches encompass pharmacological, non-pharmacological, and surgical interventions. Traditional pharmacological treatment consists of administering drugs (MAOIs, DA, and levodopa), while emerging evidence explores the potential of antidiabetic agents for neuroprotection and gene therapy for attenuating parkinsonian symptoms. Non-pharmacological treatments, such as exercise, a calcium-rich diet, and adequate vitamin D supplementation, aim to slow disease progression and prevent complications. For those patients who have medically induced side effects and/or refractory symptoms, surgery is a therapeutic option. Deep brain stimulation is the primary surgical option, associated with motor symptom improvement. Levodopa/carbidopa intestinal gel infusion through percutaneous endoscopic gastrojejunostomy and a portable infusion pump succeeded in reducing "off" time, where non-motor and motor symptoms occur, and increasing "on" time. This article aims to address the general aspects of PD and to provide a comparative comprehensive review of the conventional and the latest therapeutic advancements and emerging treatments for PD. Nevertheless, further studies are required to optimize treatment and provide suitable alternatives. [ABSTRACT FROM AUTHOR]

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm. [ABSTRACT FROM AUTHOR]

This work introduces an unsupervised framework for video anomaly detection, leveraging a hybrid deep learning model that combines a vision transformer (ViT) with a convolutional spatiotemporal relationship (STR) attention block. The proposed model addresses the challenges of anomaly detection in video surveillance by capturing both local and global relationships within video frames, a task that traditional convolutional neural networks (CNNs) often struggle with due to their localized field of view. We have utilized a pre-trained ViT as an encoder for feature extraction, which is then processed by the STR attention block to enhance the detection of spatiotemporal relationships among objects in videos. The novelty of this work is utilizing the ViT with the STR attention to detect video anomalies effectively in large and heterogeneous datasets, an important thing given the diverse environments and scenarios encountered in real-world surveillance. The framework was evaluated on three benchmark datasets, i.e., the UCSD-Ped2, CHUCK Avenue, and ShanghaiTech. This demonstrates the model's superior performance in detecting anomalies compared to state-of-the-art methods, showcasing its potential to significantly enhance automated video surveillance systems by achieving area under the receiver operating characteristic curve (AUC ROC) values of 95.6, 86.8, and 82.1. To show the effectiveness of the proposed framework in detecting anomalies in extra-large datasets, we trained the model on a subset of the huge contemporary CHAD dataset that contains over 1 million frames, achieving AUC ROC values of 71.8 and 64.2 for CHAD-Cam 1 and CHAD-Cam 2, respectively, which outperforms the state-of-the-art techniques. [ABSTRACT FROM AUTHOR]

The world of cancer treatment is evolving rapidly and has improved the prospects of many cancer patients. Yet, there are still many cancers where treatment prospects have not (or hardly) improved. Glioblastoma is the most common malignant primary brain tumor, and even though it is sensitive to many chemotherapeutics when tested under laboratory conditions, its clinical prospects are still very poor. The blood–brain barrier (BBB) is considered at least partly responsible for the high failure rate of many promising treatment strategies. We describe the workings of the BBB during healthy conditions and within the glioblastoma environment. How the BBB acts as a barrier for therapeutic options is described as well as various approaches developed and tested for passing or opening the BBB, with the ultimate aim to allow access to brain tumors and improve patient perspectives. [ABSTRACT FROM AUTHOR]

Simple Summary: Medulloblastoma is the most common type of malignant brain tumor that occurs in the pediatric population. It is associated with significant morbidity and mortality due to the long-lasting side effects associated with its treatment and its high potential for relapse despite the implementation of aggressive therapeutic modalities, including surgery, chemotherapy, and craniospinal irradiation. Hence, enhancing medulloblastomas' response to therapy and attenuating their ability to resist treatment is an important clinical goal. Herein, we explore the various mechanisms that drive this resistance, which can be shared with other types of brain tumors, specific to medulloblastoma, or specific to a molecular subtype of medulloblastoma. Subsequently, we discuss potential targeted agents and innovative therapeutic strategies that can help in undermining the discussed mechanisms and enhancing this tumor type's response to treatment. Medulloblastoma is the most frequently encountered malignant brain tumor in the pediatric population. The standard of care currently consists of surgical resection, craniospinal irradiation, and multi-agent chemotherapy. However, despite this combination of multiple aggressive modalities, recurrence of the disease remains a substantial concern, and treatment resistance is a rising issue. The development of this resistance results from the interplay of a myriad of anatomical properties, cellular processes, molecular pathways, and genetic and epigenetic alterations. In fact, several efforts have been directed towards this domain and characterizing the major contributors to this resistance. Herein, this review highlights the different mechanisms that drive relapse and are implicated in the occurrence of treatment resistance and discusses them in the context of the latest molecular-based classification of medulloblastoma. These mechanisms include the impermeability of the blood-brain barrier to drugs, the overactivation of specific molecular pathways, the resistant and multipotent nature of cancer stem cells, intratumoral and intertumoral heterogeneity, and metabolic plasticity. Subsequently, we build on that to explore potential strategies and targeted agents that can abrogate these mechanisms, undermine the development of treatment resistance, and augment medulloblastoma's response to therapeutic modalities. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most aggressive tumor in the central nervous system, with a survival rate of less than 15 months despite multimodal therapy. Tumor recurrence frequently occurs after removal. Tumoral angiogenesis, the formation of neovessels, has a positive impact on tumor progression and invasion, although there are controversial results in the specialized literature regarding its impact on survival. This study aims to correlate the immunoexpression of angiogenesis markers (CD34, CD105) with the proliferation index Ki67 and p53 in primary and secondary glioblastomas. This retrospective study included 54 patients diagnosed with glioblastoma at the Pathology Department of County Emergency Clinical Hospital Târgu Mureș. Microvascular density was determined using CD34 and CD105 antibodies, and the results were correlated with the immunoexpression of p53, IDH1, ATRX and Ki67. The number of neoformed blood vessels varied among cases, characterized by different shapes and calibers, with endothelial cells showing modified morphology and moderate to marked pleomorphism. Neovessels with a glomeruloid aspect, associated with intense positivity for CD34 or CD105 in endothelial cells, were observed, characteristic of glioblastomas. Mean microvascular density values were higher for the CD34 marker in all cases, though there were no statistically significant differences compared to CD105. Mutant IDH1 and ATRX glioblastomas, wild-type p53 glioblastomas, and those with a Ki67 index above 20% showed a more abundant microvascular density, with statistical correlations not reaching significance. This study highlighted a variety of percentage intervals of microvascular density in primary and secondary glioblastomas using immunohistochemical markers CD34 and CD105, respectively, with no statistically significant correlation between evaluated microvascular density and p53 or Ki67. [ABSTRACT FROM AUTHOR]

Glioblastoma Multiforme (GBM) is an aggressive brain tumor with a high mortality rate. Direct reprogramming of glial cells to different cell lineages, such as induced neural stem cells (iNSCs) and induced neurons (iNeurons), provides genetic tools to manipulate a cell's fate as a potential therapy for neurological diseases. NeuroD1 (ND1) is a master transcriptional factor for neurogenesis and it promotes neuronal differentiation. In the present study, we tested the hypothesis that the expression of ND1 in GBM cells can force them to differentiate toward post-mitotic neurons and halt GBM tumor progression. In cultured human GBM cell lines, including LN229, U87, and U373 as temozolomide (TMZ)-sensitive and T98G as TMZ-resistant cells, the neuronal lineage conversion was induced by an adeno-associated virus (AAV) package carrying ND1. Twenty-one days after AAV-ND1 transduction, ND1-expressing cells displayed neuronal markers MAP2, TUJ1, and NeuN. The ND1-induced transdifferentiation was regulated by Wnt signaling and markedly enhanced under a hypoxic condition (2% O2 vs. 21% O2). ND1-expressing GBM cultures had fewer BrdU-positive proliferating cells compared to vector control cultures. Increased cell death was visualized by TUNEL staining, and reduced migrative activity was demonstrated in the wound-healing test after ND1 reprogramming in both TMZ-sensitive and -resistant GBM cells. In a striking contrast to cancer cells, converted cells expressed the anti-tumor gene p53. In an orthotopical GBM mouse model, AAV-ND1-reprogrammed U373 cells were transplanted into the fornix of the cyclosporine-immunocompromised C57BL/6 mouse brain. Compared to control GBM cell-formed tumors, cells from ND1-reprogrammed cultures formed smaller tumors and expressed neuronal markers such as TUJ1 in the brain. Thus, reprogramming using a single-factor ND1 overcame drug resistance, converting malignant cells of heterogeneous GBM cells to normal neuron-like cells in vitro and in vivo. These novel observations warrant further research using patient-derived GBM cells and patient-derived xenograft (PDX) models as a potentially effective treatment for a deadly brain cancer and likely other astrocytoma tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Inconsistent engraftment of luciferase-expressing tumors, especially GL261 Red-FLuc, has been reported in the recent literature. However, techniques to improve tumor take have not been described. Our study aimed to optimize two luciferase-expressing mouse glioblastoma models, GL261 Red-FLuc and TRP-mCherry-FLuc, which revealed differences in tumor development and characteristics. While the features of each tumor were distinct, with GL261 Red-FLuc tumors showing high mitotic activity and vascularization and TRP-mCherry-FLuc tumors displaying necrosis and invasiveness, each exhibited features reminiscent of patients with glioblastoma. Furthermore, we developed a method for high-throughput sample analysis by quantifying the luciferase-positive tumor volume using artificial intelligence. Our findings provide valuable insights for researchers using similar models, emphasizing the need to consider tumor engraftment for robust preclinical research. Glioblastoma (GBM) is the most aggressive brain cancer. To model GBM in research, orthotopic brain tumor models, including syngeneic models like GL261 and genetically engineered mouse models like TRP, are used. In longitudinal studies, tumor growth and the treatment response are typically tracked with in vivo imaging, including bioluminescence imaging (BLI), which is quick, cost-effective, and easily quantifiable. However, BLI requires luciferase-tagged cells, and recent studies indicate that the luciferase gene can elicit an immune response, leading to tumor rejection and experimental variation. We sought to optimize the engraftment of two luciferase-expressing GBM models, GL261 Red-FLuc and TRP-mCherry-FLuc, showing differences in tumor take, with GL261 Red-FLuc cells requiring immunocompromised mice for 100% engraftment. Immunohistochemistry and MRI revealed distinct tumor characteristics: GL261 Red-FLuc tumors were well-demarcated with densely packed cells, high mitotic activity, and vascularization. In contrast, TRP-mCherry-FLuc tumors were large, invasive, and necrotic, with perivascular invasion. Quantifying the tumor volume using the HALO® AI analysis platform yielded results comparable to manual measurements, providing a standardized and efficient approach for the reliable, high-throughput analysis of luciferase-expressing tumors. Our study highlights the importance of considering tumor engraftment when using luciferase-expressing GBM models, providing insights for preclinical research design. [ABSTRACT FROM AUTHOR]

An important goal of smart cities is to ensure city safety and reduce city risks. However, because the chemical industry park is often located interior and surroundings of a city, it is easy to induce explosions in case of natural disasters, causing serious losses. To investigate the possibility of explosion damage to other storage tanks in chemical industrial parks caused by tank explosions, the evolution process of tank explosion damage was studied, and an analysis method to determine the most unfavorable process was provided. This method is based on regional grid division and shock wave overpressure calculation to obtain the probability of damage at the grid location. Based on the system fault evolution process, the space fault network model was used to calculate the explosion damage evolution process of each storage tank, and the most unfavorable situation was finally determined. The paper assumes a positive linear relationship between the damage probability of the affected storage tank and the likelihood of explosion. The paper provides a calculation method for regional grid division, tank explosion overpressure, and damage probability. A mathematical model for the evolution process of tank explosion damage was constructed, and it is believed that the damage effects of tanks are a logical superposition. The results can provide a reference for controlling the explosion process in chemical industrial parks under the most unfavorable conditions and realize intelligent analysis and prediction of regional risks. [ABSTRACT FROM AUTHOR]

As the deployment of CCTV cameras for safety continues to increase, the monitoring workload has significantly exceeded the capacity of the current workforce. To overcome this problem, intelligent CCTV technologies and server-efficient deep learning analysis models are being developed. However, real-world applications exhibit performance degradation due to environmental changes and limited server processing capacity for multiple CCTVs. This study proposes a real-time pedestrian anomaly detection system with an edge–server structure that ensures efficiency and scalability. In the proposed system, the pedestrian abnormal behavior detection model analyzed by the edge uses a rule-based mechanism that can detect anomalies frequently, albeit less accurately, with high recall. The server uses a deep learning-based model with high precision because it analyzes only the sections detected by the edge. The proposed system was applied to an experimental environment using 20 video streams, 18 edge devices, and 3 servers equipped with 2 GPUs as a substitute for real CCTV. Pedestrian abnormal behavior was included in each video stream to conduct experiments in real-time processing and compare the abnormal behavior detection performance between the case with the edge and server alone and that with the edge and server in combination. Through these experiments, we verified that 20 video streams can be processed with 18 edges and 3 GPU servers, which confirms the scalability of the proposed system according to the number of events per hour and the event duration. We also demonstrate that the pedestrian anomaly detection model with the edge and server is more efficient and scalable than the models with these components alone. The linkage of the edge and server can reduce the false detection rate and provide a more accurate analysis. This research contributes to the development of control systems in urban safety and public security by proposing an efficient and scalable analysis system for large-scale CCTV environments. [ABSTRACT FROM AUTHOR]