GSH and GABA decreases in IDH1-mutated low-grade gliomas detected by HERMES spectral editing at 3 T in vivo

Abstract Telomerase reverse transcriptase (TERT) expression is essential for tumor proliferation and is an attractive therapeutic target for gliomas. TERT expression has previously been shown to enhance glucose flux via the pentose phosphate pathway (PPP) in low grade gliomas expressing TERT. Hyperpolarized δ-[1-13C]gluconolactone has been used to detect flux via the PPP by monitoring its conversion to 6-phospho-[1-13C]gluconate (6PG) in isolated perfused liver. The goal of our study was to evaluate whether hyperpolarized δ-[1-13C]gluconolactone can be used to monitor elevated PPP flux induced by TERT expression in low grade gliomas, thereby providing a non-invasive method of assessing TERT expression in vivo. Immortalized normal human astrocytes without (NHApre) and with TERT expression (NHApost) were used in cell bioreactor experiments. In vivo experiment with rats bearing orthotopic NHApost or patient-derived low-grade oligodendroglioma (SF10417) tumors were contacted. Dynamic 13C MR spectra were acquired at 14T (cells) or 3T (rats) following injection of hyperpolarized δ-[1-13C]gluconolactone. NHApost cells showed significantly higher flux through the PPP compared to NHApre. This finding was in agreement with previous results indicating that TERT expression elevates PPP flux. In all rats δ-[1-13C]gluconolactone and 6PG were observed indicating that δ-[1-13C]gluconolactone crosses the blood-brain barrier and is rapidly metabolized. Furthermore, both models presented homogeneous distribution of δ-[1-13C]gluconolactone in the brain and higher ratio of 6PG-to-δ-[1-13C]gluconolactone in the tumor area. In summary we show in vivo that hyperpolarized δ-[1-13C]gluconolactone metabolism to 6-phospho-[1-13C]gluconate is significantly higher in tumor compared to contralateral normal brain in TERT-expressing genetically-engineered and patient-derived low-grade oligodendrogliomas. Due to its fundamental role in tumor proliferation, TERT is both a tumor biomarker and a therapeutic target. Monitoring HP δ-[1-13C]gluconolactone metabolism, therefore, has the potential to inform on tumor burden and response to therapy in the clinic.

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Development of a Novel Dual-Order Protein-Based Nanodelivery Carrier That Rapidly Targets Low-Grade Gliomas with Microscopic Metastasis in Vivo

ACS Omega ◽

10.1021/acsomega.0c03073 ◽

2020 ◽

Vol 5 (32) ◽

pp. 20653-20663

Author(s):

Zihao Wang ◽

Xinbo Zhou ◽

Yuru Xu ◽

Shiyong Fan ◽

Ning Tian ◽

...

Keyword(s):

Low Grade ◽

Low Grade Gliomas

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TMOD-23. A NOVEL BRAF V600E LOW-GRADE GLIOMA MOUSE MODEL HIGHLIGHTS EXOMIC AND TUMOR IMMUNE ALTERATIONS AND DIFFERING THERAPEUTIC RESPONSES IN LOW- AND HIGH-GRADE GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.973 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii232-ii233

Author(s):

Anne Marie Barrette ◽

Lasse Meyer ◽

Yoko Hirata ◽

Stefan Grossauer ◽

Edbert Lu ◽

...

Keyword(s):

Mapk Pathway ◽

Low Grade Glioma ◽

Braf V600e ◽

Common Mutation ◽

Low Grade ◽

High Grade ◽

Checkpoint Inhibition ◽

Immune Infiltrate ◽

Low Grade Gliomas

Abstract Pediatric low-grade glioma (pLGG), the most common brain cancer in children, is difficult to treat especially at recurrence. The BRAF V600E mutation is the second most common mutation in pLGG, and in a high-risk group for progression is associated with deletion of the tumor suppressor CDKN2A. A better understanding of the factors contributing to progression, in particular the role of the immune infiltrate is needed, but studies have been hindered by the lack of low-grade glioma mouse models. We utilized transgenic mice with a cre-activatable (CA) allele of BRAF V600E to generate endogenous models for low-grade gliomas. We found that BRAF V600E expression cooperates with hemizygous CDKN2A deletion to induce low-grade gliomas, with tumors forming at a greater latency than by homozygous deletion. Cell line derivatives from low-grade lesions continue to grow slower upon orthotopic injection than those we previously derived from high-grade tumors. Murine LGG can progress to higher grade tumors within the mouse lifespan and we observe exomic changes and alterations in the tumor immune infiltrate associated with progression, the details of which will be discussed at the meeting. High-grade cells’ phenotypic changes within in vivo passage are accompanied by exomic changes. The high-grade glioma immune infiltrate is altered by dual MAPK pathway inhibition with dabrafenib and trametinib. Adding dual immune checkpoint inhibition by anti-PD-L1 and anti-CTLA-4 antibodies significantly extends survival of dabrafenib-trametinib dual treatment. Human BRAF V600E mutant tumors reportedly have a higher tumor immune infiltrate than that of BRAF wildtype gliomas, consistent with our murine RESULTS: Here we present a novel model for BRAF V600E mutant gliomas in mice that has a frequent rate of progression, similar to human BRAF V600E mutant gliomas, and an active immune infiltrate in high grade tumors which makes them susceptible to the immunostimulatory effects of dual checkpoint inhibition.

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Comparison of Immunological and Functional Assays for Measurement of Soluble Fibrin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649796 ◽

1995 ◽

Vol 74 (02) ◽

pp. 673-679 ◽

Cited By ~ 21

Author(s):

C E Dempfle ◽

S A Pfitzner ◽

M Dollman ◽

K Huck ◽

G Stehle ◽

...

Keyword(s):

Venous Thrombosis ◽

Low Grade ◽

Plasma Samples ◽

Normal Range ◽

Soluble Fibrin ◽

Discriminating Power ◽

Fibrin Monomer ◽

Cerebral Ischemic

SummaryVarious assays have been developed for quantitation of soluble fibrin or fibrin monomer in clinical plasma samples, since this parameter directly reflects in vivo thrombin action on fibrinogen. Using plasma samples from healthy blood donors, patients with cerebral ischemic insult, patients with septicemia, and patients with venous thrombosis, we compared two immunologic tests using monoclonal antibodies against fibrin-specific neo-epitopes, and two functional tests based on the cofactor activity of soluble fibrin complexes in tPA-induced plasminogen activation. Test A (Enzymun®-Test FM) showed the best discriminating power among normal range and pathological samples. Test B (Fibrinostika® soluble fibrin) clearly separated normal range from pathological samples, but failed to discriminate among samples from patients with low grade coagulation activation in septicemia, and massive activation in venous thrombosis. Functional test C (Fibrin monomer test Behring) displayed good discriminating power between normal and pathological range samples, and correlated with test A (r = 0.61), whereas assay D (Coa-Set® Fibrin monomer) showed little discriminating power at values below 10 μg/ml and little correlation with other assays. Standardization of assays will require further characterization of analytes detected.

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Faculty Opinions recommendation of Low-grade gliomas in adults.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13679956.15104064 ◽

2012 ◽

Author(s):

Zvi Ram ◽

Rachel Grossman

Keyword(s):

Low Grade ◽

Low Grade Gliomas

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Faculty Opinions recommendation of Decreased quality of life and depression as predictors for shorter survival among patients with low-grade gliomas: a follow-up from 1990 to 2003.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718482634.793496837 ◽

2014 ◽

Author(s):

Rakesh Jalali

Keyword(s):

Quality Of Life ◽

Low Grade ◽

Low Grade Gliomas

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Domain Mapping and Deep Learning from Multiple MRI Clinical Datasets for Prediction of Molecular Subtypes in Low Grade Gliomas

Brain Sciences ◽

10.3390/brainsci10070463 ◽

2020 ◽

Vol 10 (7) ◽

pp. 463 ◽

Cited By ~ 1

Author(s):

Muhaddisa Barat Ali ◽

Irene Yu-Hua Gu ◽

Mitchel S. Berger ◽

Johan Pallud ◽

Derek Southwell ◽

...

Keyword(s):

Molecular Subtypes ◽

Negative Impact ◽

Molecular Classification ◽

Tumor Segmentation ◽

Test Accuracy ◽

Low Grade ◽

Idh Mutation ◽

Molecular Type ◽

Low Grade Gliomas ◽

Domain Mapping

Brain tumors, such as low grade gliomas (LGG), are molecularly classified which require the surgical collection of tissue samples. The pre-surgical or non-operative identification of LGG molecular type could improve patient counseling and treatment decisions. However, radiographic approaches to LGG molecular classification are currently lacking, as clinicians are unable to reliably predict LGG molecular type using magnetic resonance imaging (MRI) studies. Machine learning approaches may improve the prediction of LGG molecular classification through MRI, however, the development of these techniques requires large annotated data sets. Merging clinical data from different hospitals to increase case numbers is needed, but the use of different scanners and settings can affect the results and simply combining them into a large dataset often have a significant negative impact on performance. This calls for efficient domain adaption methods. Despite some previous studies on domain adaptations, mapping MR images from different datasets to a common domain without affecting subtitle molecular-biomarker information has not been reported yet. In this paper, we propose an effective domain adaptation method based on Cycle Generative Adversarial Network (CycleGAN). The dataset is further enlarged by augmenting more MRIs using another GAN approach. Further, to tackle the issue of brain tumor segmentation that requires time and anatomical expertise to put exact boundary around the tumor, we have used a tight bounding box as a strategy. Finally, an efficient deep feature learning method, multi-stream convolutional autoencoder (CAE) and feature fusion, is proposed for the prediction of molecular subtypes (1p/19q-codeletion and IDH mutation). The experiments were conducted on a total of 161 patients consisting of FLAIR and T1 weighted with contrast enhanced (T1ce) MRIs from two different institutions in the USA and France. The proposed scheme is shown to achieve the test accuracy of 74 . 81 % on 1p/19q codeletion and 81 . 19 % on IDH mutation, with marked improvement over the results obtained without domain mapping. This approach is also shown to have comparable performance to several state-of-the-art methods.

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Neurodevelopmental outcomes of children with low-grade gliomas

Developmental Disabilities Research Reviews ◽

10.1002/ddrr.27 ◽

2008 ◽

Vol 14 (3) ◽

pp. 196-202 ◽

Cited By ~ 23

Author(s):

M. Douglas Ris ◽

Dean W. Beebe

Keyword(s):

Low Grade ◽

Neurodevelopmental Outcomes ◽

Low Grade Gliomas

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Poor Mitochondrial Health and Systemic Inflammation? Testing of a Classical Hypothesis

Innovation in Aging ◽

10.1093/geroni/igaa057.416 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 126-127

Author(s):

Marta Zampino ◽

Luigi Ferrucci ◽

Richard Spencer ◽

Kenneth Fishbein ◽

Eleanor Simonsick ◽

...

Keyword(s):

Mitochondrial Function ◽

Fat Body ◽

Reference Group ◽

Linear Regression Analysis ◽

Oxidative Capacity ◽

Conclusive Evidence ◽

Resonance Spectroscopy ◽

Low Grade ◽

Severe Impairment

Abstract Chronic low-grade inflammation often occurs with aging and has been associated with negative health outcomes. Despite extensive research on the origins of “inflammaging”, the causative mechanisms remain unclear. However, a connection between poor mitochondrial health and chronic inflammation has been hypothesized, with decreasing mitochondrial function occurring with age and precipitating an increase in reactive oxygen species and other pro-inflammatory macromolecules such as mitochondrial DNA. We tested this hypothesis on a population of 619 subjects from the Baltimore Longitudinal Study of Aging, measuring muscle mitochondrial oxidative capacity in vivo by phosphorus magnetic resonance spectroscopy (P-MRS), and plasma interleukin (IL)-6, the most widely used biomarker of inflammaging. The P-MRS-derived post-exercise phosphocreatine recovery time constant tau-PCr, a measure of oxidative capacity, was expressed as a categorical variable through assignment to quintiles. Participants in the first quintile of tau-PCr (best mitochondrial function) were taken as reference and compared to the others using linear regression analysis adjusted for sex, age, lean and fat body mass, and physical activity. Those participants with the lowest oxidative capacity had significantly higher log(IL-6) levels as compared to the reference group. However, data from the other quintiles was not significantly different from the reference values. In conclusion, severe impairment of oxidative capacity is associated with increased inflammation. This study design does not provide conclusive evidence of whether increased inflammation and impaired bioenergetic recovery are both caused by underlying poor health status, or whether mitochondrial deficits lead directly to the observed inflammation; we anticipate addressing this important question with longitudinal studies.

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