Brain Tumor Glioblastoma Research Articles

STEM-17. THE UROKINASE RECEPTOR AS A NOVEL IMMUNOTHERAPEUTIC TARGET IN BRAIN CANCERS

Abstract Glioblastoma (GBM) is the common malignant brain tumor in adults, accounting for approximately 15% of all CNS tumors, and 48.6% of malignant brain tumors, with a median survival of approximately 15 months. GBM is characterized by extensive inter- and intra-tumoral heterogeneity and an extremely immunosuppressive tumor microenvironment. Following Standard-of-Care surgical resection and chemoradiotherapy, patients inevitably relapse, at which point few therapeutic avenues exist, owing in part due to a lack of clinically relevant targets. Data from our target identification pipeline shows the urokinase plasminogen activator receptor (uPAR) is significantly upregulated at recurrence on putative GBM brain tumor initiating cells (BTICs), which are believed to drive de novo tumor formation, recurrence, and therapeutic resistance. uPAR plays an important role in the plasminogen activation system, and in the context of cancer, has been implicated in numerous pro-tumorigenic processes such as invasion, proliferation, and therapy resistance. We used CRISPR-Cas9 to genetically delete uPAR from our in-house patient-derived GBM cell lines, and found that knockout of uPAR in recurrent GBM cells significantly reduces various functional characteristics of BTICs in vitro. In our patient-derived mouse model of GBM, we found that knockout of uPAR significantly increases survival, and decreases tumor burden. Further, we generated novel anti-uPAR single domain antibodies (sdAbs) which specifically and efficiently bind uPAR at low nanomolar concentrations in vitro. We developed anti-uPAR CAR Ts using the binder sequence of the sdAbs, which showed potent cytotoxicity in vitro, and drastically reduced tumor burden and extended survival in vivo. Further, we identified uPAR as being highly expressed on brain metastases from multiple origins (lung-to-brain, melanoma-to-brain, etc.), and demonstrate that anti-uPAR CAR Ts effectively kill brain metastases in vitro, and significantly extend survival using in vivo brain metastasis models. From this work we believe uPAR to be a clinically relevant target in both recurrent GBM and brain metastases, and investigation into therapeutic strategies targeting uPAR-positive brain cancers should be explored further.

Therapeutic Contribution of Tau-Binding Thiazoloflavonoid Hybrid Derivatives Against Glioblastoma Using Pharmacological Approach in 3D Spheroids.

Growing evidence has unveiled the pathological significance of Tau in many cancers, including the most aggressive and lethal brain tumor glioblastoma multiform (GBM). In this regard, we have recently examined the structure-activity relationship of a new series of seventeen 2-aminothiazole-fused to flavonoid hybrid compounds (TZF) on Tau-overexpressing GBM cells. Here, we evaluated the anticancer activities of the two lead compounds 2 and 9 using multi-cellular spheroids (MCSs) which represent an easy 3D human cell model to mimic GBM organization, physical constraints and drug penetration. The two compounds reduced cell evasion from spheroids up to three times, especially for Tau-expressing cells. As a first step towards a therapeutic approach, we quantified the effects of these compounds on MCS growth using two complementary protocols: single and repeated treatments. A single injection with compound 9 slowed down the growth of MCSs formed with U87 shCTRL cells by 40% at 10 µM. More interestingly, multiple treatment with compound 9 slowed the growth of U87 shCTRL spheroids by 40% at a concentration of 5 µM, supporting the increased bioavailability of compound 9 within MCSs. In conclusion, compound 9 deserves particular attention as promising candidate for specifically targeting Tau-expressing cancers such as GBM.

Glioblastoma Arising in Lynch-like Syndrome after Repeated Development of Colorectal Cancers: A Case Report.

We herein report a patient with Lynch-like syndrome in whom a brain tumor (glioblastoma) developed after repeated resection of colorectal cancer. The patient had a significant family history of cancer. Immunohistochemical expression of mismatch repair proteins was decreased in both brain and colon tumors, but no pathogenic variant of the related genes was detected. Although brain tumors occasionally develop in Lynch syndrome, they have not been reported in cases of Lynch-like syndrome. This first report of Lynch-like syndrome with the development of glioblastoma suggests the need for further investigation on the surveillance of brain tumors in patients with this syndrome.

Fungal endophytes isolated from Withania somnifera Markedly exhibit antitumor activity against human glioblastoma

In the current study, five fungal endophytes (WR-1, WR-2, WR-3, WR-4, WS-6) were isolated from the roots and stem of Withania somnifera (L.) Dunal, and tested fungal culture filtrates (FCF) against the brain tumour (glioblastoma) cell line (U-87). All FCFs showed anti-tumour activity with an IC50 value of 3.5, 6.0, 3.2, 6.0, and 0.95 µg/mL, respectively. HPLC fractionation of WS-6 showed the presence of 11 compounds (A1–A11), all with good anti-tumour activities (IC 50 3.5, 5.0, 5.0, 3.6, 2.5, 1.7, 2.3, 2.7, 0.9, 1.8 and 0.4 µg/mL, respectively). We report for the first time, the anti-tumour activity of 1-Docosene, Phenol, 2,4-bis(1,1-dimethylethyl), 1,2-Benzenedicarboxylic acid, diisooctyl ester, Hexadecane, 1,1-bis(dodecyloxy)-, Benzene, 1,1'-(2-methyl-2-(phenylthio)cyclopropylidene) bis-, Naphthalene, 1,2-dihydro-1-phenyl- (A1–A6), identified by GC-MS. The rest (A7–A11) had earlier reports of anticancer activities on cell lines other than U-87. We conclude that endophytic WS-6 (Aspergillus fumigatus) produces antitumor compounds that might be helpful in future drug development against brain tumours, especially glioblastoma.

Positronium image of the human brain in vivo.

Positronium is abundantly produced within the molecular voids of a patient's body during positron emission tomography (PET). Its properties dynamically respond to the submolecular architecture of the tissue and the partial pressure of oxygen. Current PET systems record only two annihilation photons and cannot provide information about the positronium lifetime. This study presents the in vivo images of positronium lifetime in a human, for a patient with a glioblastoma brain tumor, by using the dedicated Jagiellonian PET system enabling simultaneous detection of annihilation photons and prompt gamma emitted by a radionuclide. The prompt gamma provides information on the time of positronium formation. The photons from positronium annihilation are used to reconstruct the place and time of its decay. In the presented case study, the determined positron and positronium lifetimes in glioblastoma cells are shorter than those in salivary glands and those in healthy brain tissues, indicating that positronium imaging could be used to diagnose disease in vivo.

CAR-T Cells Therapy in Glioblastoma: A Systematic Review on Molecular Targets and Treatment Strategies.

The most common primary brain tumor is glioblastoma (GBM), yet the current therapeutic options for this disease are not promising. Although immunotherapeutic techniques have shown poor success in GBM thus far despite efforts, new developments provide optimism. One of these developments is chimeric antigen receptor (CAR)-T cell treatment, which includes removing and genetically modifying autologous T cells to produce a receptor that targets a GBM antigen before reintroducing the cells into the patient's body. A number of preclinical studies have produced encouraging results, which have led to the start of clinical trials assessing these CAR-T cell treatments for GBM and other brain tumors. Although results in tumors such as diffuse intrinsic pontine gliomas and lymphomas have been promising, preliminary findings in GBM have not produced any clinical benefits. The paucity of particular antigens in GBM, their inconsistent expression patterns, and the possible immunoediting-induced loss of these antigens after antigen-targeted therapy are some possible causes for this discrepancy. The goal of this systematic literature review is to assess potential approaches for creating CAR-T cells that are more effective for this indication, as well as the clinical experiences that are already being had with CAR-T cell therapy in GBM. Up until 9 May 2024, a thorough search was carried out across the three main medical databases: PubMed, Web of Science, and Scopus. Relevant Medical Subject Heading (MeSH) terms and keywords associated with "glioblastoma", "CAR-T", "T cell therapy", "overall survival", and "progression free survival" were employed in the search approach. Preclinical and clinical research on the application of CAR-T cells as a therapeutic approach for GBM are included in the review. A total of 838 papers were identified. Of these, 379 articles were assessed for eligibility, resulting in 8 articles meeting the inclusion criteria. The included studies were conducted between 2015 and 2023, with a total of 151 patients enrolled. The studies varied in CAR-T cell types. EGFRvIII CAR-T cells were the most frequently investigated, used in three studies (37.5%). Intravenous delivery was the most common method of delivery (62.5%). Median OS ranged from 5.5 to 11.1 months across the studies. PFS was reported in only two studies, with values of 7.5 months and 1.3 months. This systematic review highlights the evolving research on CAR-T cell therapy for GBM, emphasizing its potential despite challenges. Targeting antigens like EGFRvIII and IL13Rα2 shows promise in treating recurrent GBM. However, issues such as antigen escape, tumor heterogeneity, and immunosuppression require further optimization. Innovative delivery methods, combination therapies, and personalized approaches are crucial for enhancing CAR-T cell efficacy. Ongoing research is essential to refine these therapies and improve outcomes for GBM patients.

KCa channel targeting impairs DNA repair and invasiveness of patient-derived glioblastoma stem cells in culture and orthotopic mouse xenografts which only in part is predictable by KCa expression levels.

Prognosis of glioblastoma patients is still poor despite multimodal therapy. The highly brain-infiltrating growth in concert with a pronounced therapy resistance particularly of mesenchymal glioblastoma stem-like cells (GSCs) has been proposed to contribute to therapy failure. Recently, we have shown that a mesenchymal-to-proneural mRNA signature of patient derived GSC-enriched (pGSC) cultures associates with in vitro radioresistance and gel invasion. Importantly, this pGSC mRNA signature is prognostic for patients' tumor recurrence pattern and overall survival. Two mesenchymal markers of the mRNA signature encode for IKCa and BKCa Ca2+-activated K+ channels. Therefore, we analyzed here the effect of IKCa- and BKCa-targeting concomitant to (fractionated) irradiation on radioresistance and glioblastoma spreading in pGSC cultures and in pGSC-derived orthotopic xenograft glioma mouse models. To this end, in vitro gel invasion, clonogenic survival, in vitro and in vivo residual DNA double strand breaks (DSBs), tumor growth, and brain invasion were assessed in the dependence on tumor irradiation and K+ channel targeting. As a result, the IKCa- and BKCa-blocker TRAM-34 and paxilline, respectively, increased number of residual DSBs and (numerically) decreased clonogenic survival in some but not in all IKCa- and BKCa-expressing pGSC cultures, respectively. In addition, BKCa- but not IKCa-blockade slowed-down gel invasion in vitro. Moreover, systemic administration of TRAM-34 or paxilline concomitant to fractionated tumor irradiation increased in the xenograft model(s) residual number of DSBs and attenuated glioblastoma brain invasion and (numerically) tumor growth. We conclude, that KCa-blockade concomitant to fractionated radiotherapy might be a promising new strategy in glioblastoma therapy.

Studying the Pathogenic Effect of New Nucleotide Changes in the Promoter Region of the TERT Gene in Patients with Glioblastoma Brain Tumor

Introduction: Brain tumors are considered to be one of the most dangerous types of cancer, despite decades of research and treatment efforts. The activation of the telomerase enzyme is a critical factor in the immortality of these cells. Mutations in the promoter region of the TERT gene, particularly in the promoter hot spots, can influence the binding of activating transcription factors and inhibit the binding of negative regulatory factors of the TERT gene, ultimately regulating the gene's expression. This study aimed to identify and investigate the mutations of the TERT gene promoter region in glioblastoma, a malignant brain tumor, using bioinformatics. Methods: A study was conducted using the case-control method where 35 patients with glioblastoma multiform brain tumor were examined along with 40 people who were examined as control samples. In this research, the Touchdown PCR technique and direct DNA sequencing were used to detect mutations in the promoter region of the TERT gene in patients with glioblastoma. Furthermore, bioinformatic analyses were conducted to investigate the pathogenic effect of nucleotide changes in this gene region. Results: In the core region of the TERT gene promoter, three-point mutations were identified (c.*146C>T، c.*144C>G and c.*143G>C). Two of these mutations were novel and have been observed for the first time in glioblastoma multiform. The remaining mutation was located in the promoter core's hot spot of the gene. This mutation was known as c.*146C>T. Conclusion: In this research, the harmful impact of TERT promoter region mutations as a biomarker for glioblastoma was examined. These findings suggest that mutations in regulatory regions, as well as coding sequences, could be significant contributory factors in the process of carcinogenesis.

So what I'm stressed? A qualitative study examining caregivers' reactions to emerging biomarkers of stress

BackgroundCaregivers of adults with cancer often report significant distress yet remain difficult to engage in supportive services. While the field of Psychosomatic Medicine has continued to identify important markers of physiologic stress, and demonstrated disruption in these markers in caregiver populations, no research has investigated whether biomarker information on caregivers’ reaction to stress could impact their willingness to address their ongoing distress. MethodsHere, we report on a qualitative study (N = 17) in which we conducted individual interviews with cancer caregivers to explore their key attitudes towards, and subjective experience of, mock stress biomarker data. A total of 17 caregivers of patients (M age = 56.1 years; SD = 12.3) with primarily metastatic brain tumors (glioblastoma) were interviewed regarding four commercially available biomarkers (telomere length; hair cortisol, activity levels and heart rate variability). Once presented with information about stress biomarkers, caregivers were asked to discuss their subjective reaction as if it was their own data as well as their motivation and willingness to seek support after receiving such information. We identified and extracted relevant themes. ResultsAnalysis utilizing the framework method revealed four emerging themes. The first theme described caregivers' ability to manage stress and willingness to engage with supportive services. Second, caregivers generally accepted the biomarker data but preferred it to be presented in a specific way. The third theme demonstrated that for some, biomarker data may actually increase their subjective distress (e.g., whether or not something could be done to improve their mental state). The last theme described how biomarkers were generally received as meaningful motivators that could increase caregivers’ willingness to engage with supportive services. ConclusionsIn addition to the more general identified theme of CG's willingness to engage with additional support, we gained insights into caregivers' reaction to the stress biomarkers presented. Findings will set the stage for the utility of stress biomarker information and whether it influences cancer caregivers' willingness to address their distress and motivation to engage in supportive services.

The gut-brain-axis: A positive relationship between gut microbial dysbiosis and glioblastoma brain tumour

The glioblastoma brain tumour (GBM) stands out as the most aggressive and resistant-to-treatment malignancy. Nevertheless, the gut-brain connection plays a pivotal role in influencing the growth and activation of the central nervous system. In this particular investigation, we aimed to assess and characterize the gut microbial ecosystem in GBM patients, both quantitatively and qualitatively. We collected faecal samples from 15 healthy volunteers and 25 GBM patients. To delve into the microbial content, we employed PCR-DGGE, targeting the V3 region of the 16S rRNA gene, and conducted qPCR to measure the levels of crucial intestinal bacteria. For a more in-depth analysis, high-throughput sequencing was performed on a selection of 20 random faecal samples (10 from healthy individuals and 10 from GBM patients), targeting the V3+V4 region of the 16S rRNA gene. Our findings from examining the richness and diversity of the gut microbiota unveiled that GBM patients exhibited significantly higher microbial diversity compared to healthy individuals. At the phylum level, Proteobacteria saw a significant increase, while Firmicutes experienced a noteworthy decrease in the GBM group. Moving down to the family level, we observed significantly elevated levels of Enterobacteriaceae, Bacteroidaceae, and Lachnospiraceae in GBM patients, while levels of Veillonellaceae, Rikenellaceae, and Prevotellaceae were notably lower. Delving into genera statistics, we noted a substantial increase in the abundance of Parasutterella, Escherichia-Shigella, and Bacteroides, alongside significantly lower levels of Ruminococcus 2, Faecalibacterium, and Prevotella_9 in the GBM group compared to the control group. Furthermore, when examining specific species, we found a significant increase in Bacteroides vulgatus and Escherichia coli in the GBM group. These observations collectively indicate a marked dysbiosis in the gut microbial composition of GBM patients. Additionally, the GBM group exhibited notably higher levels of alpha diversity when compared to the control group. This increase in diversity suggests a significant bacterial overgrowth in the gut of GBM patients in contrast to the controls. As a result, this research opens up potential avenues to gain a better understanding of the underlying mechanisms, pathways, and potential treatments for GBM, stemming from the significant implications of gut microbial dysbiosis in these patients.

RAPID resistance to BET inhibitors is mediated by FGFR1 in glioblastoma

Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that intrinsic resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Additionally, small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.

Exploring fetal brain tumor glioblastoma symptom verification with self organizing maps and vulnerability data analysis

Brain tumor glioblastoma is a disease that is caused for a child who has abnormal cells in the brain, which is found using MRI “Magnetic Resonance Imaging” brain image using a powerful magnetic field, radio waves, and a computer to produce detailed images of the body's internal structures it is a standard diagnostic tool for a wide range of medical conditions, from detecting brain and spinal cord injuries to identifying tumors and also in evaluating joint problems. This is treatable, and by enabling the factor for happening, the factor for dissolving the dead tissues. If the brain tumor glioblastoma is untreated, the child will go to death; to avoid this, the child has to treat the brain problem using the scan of MRI images. Using the neural network, brain-related difficulties have to be resolved. It is identified to make the diagnosis of glioblastoma. This research deals with the techniques of max rationalizing and min rationalizing images, and the method of boosted division time attribute extraction has been involved in diagnosing glioblastoma. The process of maximum and min rationalization is used to recognize the Brain tumor glioblastoma in the brain images for treatment efficiency. The image segment is created for image recognition. The method of boosted division time attribute extraction is used in image recognition with the help of MRI for image extraction. The proposed boosted division time attribute extraction method helps to recognize the fetal images and find Brain tumor glioblastoma with feasible accuracy using image rationalization against the brain tumor glioblastoma diagnosis. In addition, 45% of adults are affected by the tumor, 40% of children and 5% are in death situations. To reduce this ratio, in this study, the Brain tumor glioblastoma is identified and segmented to recognize the fetal images and find the Brain tumor glioblastoma diagnosis. Then the tumor grades were analyzed using the efficient method for the imaging MRI with the diagnosis result of partially high. The accuracy of the proposed TAE-PIS system is 98.12% which is higher when compared to other methods like Genetic algorithm, Convolution neural network, fuzzy-based minimum and maximum neural network and kernel-based support vector machine respectively. Experimental results show that the proposed method archives rate of 98.12% accuracy with low response time and compared with the Genetic algorithm (GA), Convolutional Neural Network (CNN), fuzzy-based minimum and maximum neural network (Fuzzy min–max NN), and kernel-based support vector machine. Specifically, the proposed method achieves a substantial improvement of 80.82%, 82.13%, 85.61%, and 87.03% compared to GA, CNN, Fuzzy min–max NN, and kernel-based support vector machine, respectively.

Comparison of Ultrasonographic Images of Glioblastoma Tumor with Magnetic Resonance Images: Rat Animal Model

Purpose: Magnetic Resonance Imaging (MRI) can guide the surgical strategy to identify brain tumors and monitor treatment response. It is possible to use transcranial Ultrasound (US) for periodical follow-ups. Ultrasound waves pass through the delicate areas of the skull called acoustic windows. In this study, the efficiency of ultrasound imaging was performed to diagnose glioblastoma brain tumors and the results were compared with MR images.
 Materials and Methods: Male Wistar rats were anesthetized by intraperitoneal injection of Ketamine and Xylazine. A stereotaxic device was used to determine the injection coordinates. C6 GBM cell lines were injected into the brains of rats. After two weeks, the formation of a glioblastoma tumor was confirmed histopathologically. The brain of animals was imaged by B-mode ultrasound and MRI. The section with the largest tumor dimensions was selected and the dimensions of the skull and tumor were measured based on the pixel size of each of the imaging methods. Pearson coefficient of correlation and Limits Of Agreement (LOA) were calculated for comparisons of the skull and tumor dimensions.
 Results: The skull and the tumor dimensions showed a significant correlation between the B-mode ultrasound and the MRI measurements (R = 0.99 and p < 0.05). According to the Bland-Altman analysis, the mean difference was 0.31 mm (SD = 0.20) for skull and tumor dimensions. The exact shape of the tumor is not completely clear in the ultrasound images, but it can be useful to detect the presence of the tumor and its approximate dimensions.
 Conclusion: In conclusion, a glioblastoma tumor was produced in the male Wistar rat. The tumor dimensions were properly assessed by B-mode ultrasound image processing and compared with MR imaging.

Single-cell mechanical assay unveils viscoelastic similarities in normal and neoplastic brain cells

Understanding cancer cell mechanics allows for the identification of novel disease mechanisms, diagnostic biomarkers, and targeted therapies. In this study, we utilized our previously established fluid shear stress assay to investigate and compare the viscoelastic properties of normal immortalized human astrocytes and invasive human glioblastoma (GBM) cells when subjected to physiological levels of shear stress that are present in the brain microenvironment. We used a parallel-flow microfluidic shear system and a camera-coupled optical microscope to expose single cells to fluid shear stress and monitor the resulting deformation in real time, respectively. From the video-rate imaging, we fed cell deformation information from digital image correlation into a three-parameter generalized Maxwell model to quantify the nuclear and cytoplasmic viscoelastic properties of single cells. We further quantified actin cytoskeleton density and alignment in immortalized human astrocytes and GBM cells via fluorescence microscopy and image analysis techniques. Results from our study show that contrary to the behavior of many extracranial cells, normal and cancerous brain cells do not exhibit significant differences in their viscoelastic properties. Moreover, we also found that the viscoelastic properties of the nucleus and cytoplasm as well as the actin cytoskeletal densities of both brain cell types are similar. Our work suggests that malignant GBM cells exhibit unique mechanical behaviors not seen in other cancer cell types. These results warrant future studies to elucidate the distinct biophysical characteristics of the brain and reveal novel mechanical attributes of GBM and other primary brain tumors.

Signature reversion of three disease-associated gene signatures prioritizes cancer drug repurposing candidates.

Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease-associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease-associated gene signatures (i.e., limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low-survival human cancers. Our results were enriched for candidates that had been used in clinical trials or performed well in the PRISM drug screen. Additionally, we found that pamidronate and nimodipine, drugs predicted to be efficacious against the brain tumor glioblastoma (GBM), inhibited the growth of a GBM cell line and cells isolated from a patient-derived xenograft (PDX). Our results demonstrate that by applying multiple disease-associated gene signature methods, we prioritized several drug repurposing candidates for low-survival cancers.

DNA hypomethylator phenotype reprograms glutamatergic network in receptor tyrosine kinase gene-mutated glioblastoma

DNA methylation is crucial for chromatin structure and gene expression and its aberrancies, including the global “hypomethylator phenotype”, are associated with cancer. Here we show that an underlying mechanism for this phenotype in the large proportion of the highly lethal brain tumor glioblastoma (GBM) carrying receptor tyrosine kinase gene mutations, involves the mechanistic target of rapamycin complex 2 (mTORC2), that is critical for growth factor signaling. In this scenario, mTORC2 suppresses the expression of the de novo DNA methyltransferase (DNMT3A) thereby inducing genome-wide DNA hypomethylation. Mechanistically, mTORC2 facilitates a redistribution of EZH2 histone methyltransferase into the promoter region of DNMT3A, and epigenetically represses the expression of DNA methyltransferase. Integrated analyses in both orthotopic mouse models and clinical GBM samples indicate that the DNA hypomethylator phenotype consistently reprograms a glutamate metabolism network, eventually driving GBM cell invasion and survival. These results nominate mTORC2 as a novel regulator of DNA hypomethylation in cancer and an exploitable target against cancer-promoting epigenetics.

Single-cell nanobiopsy enables multigenerational longitudinal transcriptomics of cancer cells.

Single-cell RNA sequencing has revolutionized our understanding of cellular heterogeneity, but routine methods require cell lysis and fail to probe the dynamic trajectories responsible for cellular state transitions, which can only be inferred. Here, we present a nanobiopsy platform that enables the injection of exogenous molecules and multigenerational longitudinal cytoplasmic sampling from a single cell and its progeny. The technique is based on scanning ion conductance microscopy (SICM) and, as a proof of concept, was applied to longitudinally profile the transcriptome of single glioblastoma (GBM) brain tumor cells in vitro over 72 hours. The GBM cells were biopsied before and after exposure to chemotherapy and radiotherapy, and our results suggest that treatment either induces or selects for more transcriptionally stable cells. We envision the nanobiopsy will contribute to transforming standard single-cell transcriptomics from a static analysis into a dynamic assay.

A deep convolutional neural network for the automatic segmentation of glioblastoma brain tumor: Joint spatial pyramid module and attention mechanism network

This study proposes a deep convolutional neural network for the automatic segmentation of glioblastoma brain tumors, aiming sat replacing the manual segmentation method that is both time-consuming and labor-intensive. There are many challenges for automatic segmentation to finely segment sub-regions from multi-sequence magnetic resonance images because of the complexity and variability of glioblastomas, such as the loss of boundary information, misclassified regions, and subregion size. To overcome these challenges, this study introduces a spatial pyramid module and attention mechanism to the automatic segmentation algorithm, which focuses on multi-scale spatial details and context information. The proposed method has been tested in the public benchmarks BraTS 2018, BraTS 2019, BraTS 2020 and BraTS 2021 datasets. The Dice score on the enhanced tumor, whole tumor, and tumor core were respectively 79.90 %, 89.63 %, and 85.89 % on the BraTS 2018 dataset, respectively 77.14 %, 89.58 %, and 83.33 % on the BraTS 2019 dataset, and respectively 77.80 %, 90.04 %, and 83.18 % on the BraTS 2020 dataset, and respectively 83.48 %, 90.70 %, and 88.94 % on the BraTS 2021 dataset offering performance on par with that of state-of-the-art methods with only 1.90 M parameters. In addition, our approach significantly reduced the requirements for experimental equipment, and the average time taken to segment one case was only 1.48 s; these two benefits rendered the proposed network intensely competitive for clinical practice.

Alkylating agents are possible inducers of glioblastoma and other brain tumors.

Epidemiological evidence of an association between exposure to chemical carcinogens and an increased risk for development of glioblastoma (GBM) is limited to weak statistical associations in cohorts of firefighters, farmers, residents exposed to air pollution, and soldiers exposed to toxic chemicals (e.g., military burn pits, oil-well fire smoke). A history of ionizing radiation therapy to the head or neck is associated with an increased risk of GBM. Ionizing radiation induces point mutations, frameshift mutations, double-strand breaks, and chromosomal insertions or deletions. Mutational profiles associated with chemical exposures overlap with the broad mutational patterns seen with ionizing radiation. Data on 16 agents (15 chemicals and radio frequency radiation) that induced tumors in the rodent brain were extracted from 602 Technical Reports on 2-years cancer bioassays found in the National Toxicology Program database. Ten of the 15 chemical agents that induce brain tumors are alkylating agents. Three of the 15 chemical agents have idiosyncratic structures and might be alkylating agents. Only two of the 15 chemical agents are definitively not alkylating agents. The rat model is thought to be of possible relevance to humans suggesting that exposure to alkylating chemicals should be considered in epidemiology studies on GBM and other brain tumors.

Behavior of glioblastoma brain tumor stem cells following a suborbital rocket flight: reaching the “edge” of outer space

The emerging arena of space exploration has created opportunities to study cancer cell biology in the environments of microgravity and hypergravity. Studying cellular behavior in altered gravity conditions has allowed researchers to make observations of cell function that would otherwise remain unnoticed. The patient-derived QNS108 brain tumor initiating cell line (BTIC), isolated from glioblastoma (GBM) tissue, was launched on a suborbital, parabolic rocket flight conducted by EXOS Aerospace Systems & Technologies. All biologicals and appropriate ground controls were secured post-launch and transported back to our research facility. Cells from the rocket-flight and ground-based controls were isolated from the culture containers and expanded on adherent flasks for two weeks. In vitro migration, proliferation, and stemness assays were performed. Following cell expansion, male nude mice were intracranially injected with either ground-control (GC) or rocket-flight (RF) exposed cells to assess tumorigenic capacity (n = 5 per group). Patient-derived QNS108 BTICs exposed to RF displayed more aggressive tumor growth than the GC cells in vitro and in vivo. RF cells showed significantly higher migration (p < 0.0000) and stemness profiles (p < 0.01) when compared to GC cells. Further, RF cells, when implanted in vivo in the brain of rodents had larger tumor-associated cystic growth areas (p = 0.00029) and decreased survival (p = 0.0172) as compared to those animals that had GC cells implanted.