Ivy Glioblastoma Atlas Project

Ivy Glioblastoma Atlas Project

http://glioblastoma.alleninstitute.org/

The Ivy Glioblastoma Atlas Project is a foundational resource for exploring the anatomic and genetic basis of glioblastoma at the cellular and molecular levels.

Partnership

It is a collaborative partnership between the Ben and Catherine Ivy Foundation, the Allen Institute for Brain Science, and the Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment.

Funding Support

This project was supported by the Ben and Catherine Ivy Foundation (PIs: Ralph Puchalski, PhD, Allen Institute for Brain Science and Greg Foltz, MD, Swedish Neuroscience Institute).


Glioblastoma multiforme (GBM), an aggressive brain tumor, is characterized histologically by the presence of a necrotic center surrounded by so-calledpseudopalisading cells. Pseudopalisading necrosis has long been used as a prognostic feature. However, the underlying molecularmechanism regulating the progression of GBMs remains unclear.

Wang et al., hypothesized that the gene expression profilings of individual cancers, specifically necrosis-related genes, would provide objective information that would allow for the creation of a prognostic index. Gene expression profiles of necrotic and nonnecrotic areas were obtained from the Ivy Glioblastoma Atlas Project (IVY GAP) database to explore the differentially expressed genes.A robust signature of seven genes was identified as a predictor for glioblastoma and low-grade glioma (GBM/LGG) in patients from The Cancer Genome Atlas (TCGA) cohort. This set of genes was able to stratify GBM/LGG and GBM patients into high-risk and low-risk groups in the training set as well as the validation set. The TCGA, Repository for Molecular Brain Neoplasia Data (Rembrandt), and GSE16011 databases were then used to validate the expression level of these seven genes in GBMs and LGGs. Finally, the differentially expressed genes (DEGs) in the high-risk and low-risk groups were subjected to gene ontology enrichmentKyoto Encyclopedia of Genes and Genomes pathway, and gene set enrichment analyses, and they revealed that these DEGs were associated with immune and inflammatory responses. In conclusion, the study identified a novel seven-gene signature that may guide the prognostic prediction and development of therapeutic applications 1).


The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project data demonstrated that IL-8 transcript expression is negatively correlated with GBM patient survival (p = 0.001) and positively correlated with that of genes associated with the GIC phenotypes, such as KLF4, c-Myc, and HIF2α (p < 0.001). Immunohistochemical analysis of patient samples demonstrated elevated IL-8 expression in about 60% of recurrent GBM tumors relative to matched primary tumors and this expression also positively correlates with time to recurrence. Exposure to IL-8 significantly enhanced the self-renewing capacity of PDX GBM (average threefold, p < 0.0005), as well as increasing the expression of GIC markers in the CXCR2 population. Furthermore, IL-8 knockdown significantly delayed PDX GBM tumor growth in vivo (p < 0.0005). Finally, guided by in silico analysis of TCGA data, we examined the effect of therapy-induced IL-8 expression on the epigenomic landscape of GBM cells and observed increased trimethylation of H3K9 and H3K27. Our results show that autocrine IL-8 alters cellular plasticity and mediates alterations in histone status. These findings suggest that IL-8 signaling participates in regulating GBM adaptation to therapeutic stress and therefore represents a promising target for combination with conventional chemotherapy in order to limit GBM recurrence 2).


Immunohistochemical staining and the RNA-seq (sequencing) data from the IVY Glioblastoma Atlas Project showed FGF13 expression in glioma cells in the invasive edges of tumor specimens. Also, the intracellular distribution was mainly in the cytoplasm of tumor cells and colocalized with tubulin. Overexpression of FGF13 stabilized tubulin dynamics in vitro and knockdown of FGF13 decreased glioma invasion both in vitro and in vivo and prolonged overall survival of several xenograft models. FGF13 was negatively regulated by hypoxic condition. Silencing of FGF13 also decreased in vivo bevacizumab-induced glioma invasion. In conclusion, FGF13 regulated glioma cell invasion and bevacizumab-induced glioma invasion, and could be a novel target for glioma treatment 3).


In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance 4).

References

1)

Wang J, Ma J. Integrated Transcriptomic Analysis of Necrosis-related Gene in Diffuse Gliomas. J Neurol Surg A Cent Eur Neurosurg. 2019 Apr 1. doi: 10.1055/s-0039-1683448. [Epub ahead of print] PubMed PMID: 30934097.
2)

Hasan T, Caragher SP, Shireman JM, Park CH, Atashi F, Baisiwala S, Lee G, Guo D, Wang JY, Dey M, Wu M, Lesniak MS, Horbinski CM, James CD, Ahmed AU. Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma. Cell Death Dis. 2019 Mar 29;10(4):292. doi: 10.1038/s41419-019-1387-6. PubMed PMID: 30926789.
3)

Otani Y, Ichikawa T, Kurozumi K, Inoue S, Ishida J, Oka T, Shimizu T, Tomita Y, Hattori Y, Uneda A, Matsumoto Y, Michiue H, Date I. Fibroblast growth factor 13 regulates glioma cell invasion and is important for bevacizumab-induced glioma invasion. Oncogene. 2018 Feb 8;37(6):777-786. doi: 10.1038/onc.2017.373. Epub 2017 Oct 23. PubMed PMID: 29059154.
4)

Pollak J, Rai KG, Funk CC, Arora S, Lee E, Zhu J, Price ND, Paddison PJ, Ramirez JM, Rostomily RC. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy. PLoS One. 2017 Mar 6;12(3):e0172884. doi: 10.1371/journal.pone.0172884. eCollection 2017. PubMed PMID: 28264064; PubMed Central PMCID: PMC5338779.

Motocross accident

Motocross accident

Motocross is a form of off-road motorcycle racing held on enclosed off-road circuits. The sportevolved from motorcycle trials competitions held in the United Kingdom.

Motocross is a physically demanding sport held in all-weather conditions.

They have been gaining popularity among children and adolescents, raising concerns for increased risk of concussions in participating youth.


A 25-year-old man sustained a right-sided brachial plexus injury from a high-velocity motocross accident. Physical examination and electromyography were consistent with a pan-brachial plexopathy with no evidence of axonal continuity. The patient underwent a spinal accessory nerve to suprascapular nerve transfer and an intercostal nerve to musculocutaneous nerve transfer with interpositional sural nerve grafts. He recovered MRC 4/5 elbow flexion and MRC 2/5 shoulder abduction and external rotation. Twenty-two months post-injury the patient displayed a flicker of flexion of his flexor pollicis longus and flexor digitorum profundus to his index finger – he went on to recover a functional pinch. Thirty-six months post-injury the patient displayed a flicker of contraction in brachioradialis with motor unit potentials on electromyography. This case demonstrates that some patients may have capacity for functional recovery after prolonged denervation and highlights the potential impact of anatomical anomalies in the assessment and treatment of peripheral nerve injuries 1).


A 25-year-old man had a T11T12 fracture dislocation sustained in a motocross accident that resulted in a T11 American Spinal Injury Association Impairment Scale (ASIA) grade A traumatic spinal cord injury. He was treated with acute surgical decompression and spinal fixation with fusion, and enrolled in the spinal scaffold study. A 2 × 10 mm bioresorbable scaffold was placed in the spinal cord parenchyma at T12. The scaffold was implanted directly into the traumatic cavity within the spinal cord through a dorsal root entry zone myelotomy at the caudal extent of the contused area. By 3 months, his neurological examination improved to an L1 AIS grade C incomplete injury. At 6-month postoperative follow-up, there were no procedural complications or apparent safety issues related to the scaffold implantation.

Although longer-term follow-up and investigation are required, this case demonstrates that a polymer scaffold can be safely implanted into an acutely contused spinal cord. This is the first human surgical implantation, and future outcomes of other patients in this clinical trial will better elucidate the safety and possible efficacy profile of the scaffold 2).


Nearly half of all motocross competitors under the age of 18 reported concussion symptoms. Preventive measures are necessary to limit the negative impact from concussions. The risk of concussive injury can be decreased for pediatric motocross riders if they receive professional help with proper helmet fitting and through implementation of stricter guidelines regarding sponsorship 3).

Daniels et al. found a high occurrence of head injuries following pediatric off-road motorcycle riding or motocross accidents despite the use of helmets. Additionally, this study severely underestimates the rate of mild TBIs in this patient population. Our data indicate that motocross is a high-risk sport despite the use of protective gear. Riders and parents should be counseled accordingly about the risks prior to participation 4).

Increased degenerative changes in the cervical and thoracic spine were identified in adolescent motocross racers compared with age-matched controls. The long-term consequences of these changes are unknown; however, athletes and parents should be counseled accordingly about participation in motocross activities 5).

References

1)

Head LK, Wolff G, Boyd KU. Reinnervation of Extrinsic Finger Flexors and Brachioradialis 22 and 36 Months Following Traumatic Pan-Brachial Plexopathy: A Case Report. J Hand Surg Asian Pac Vol. 2019 Mar;24(1):118-122. doi: 10.1142/S2424835519720081. PubMed PMID: 30760136.
2)

Theodore N, Hlubek R, Danielson J, Neff K, Vaickus L, Ulich TR, Ropper AE. First Human Implantation of a Bioresorbable Polymer Scaffold for Acute Traumatic Spinal Cord Injury: A Clinical Pilot Study for Safety and Feasibility. Neurosurgery. 2016 Aug;79(2):E305-12. doi: 10.1227/NEU.0000000000001283. PubMed PMID: 27309344.
3)

Luo TD, Clarke MJ, Zimmerman AK, Quinn M, Daniels DJ, McIntosh AL. Concussion symptoms in youth motocross riders: a prospective, observational study. J Neurosurg Pediatr. 2015 Mar;15(3):255-60. doi: 10.3171/2014.11.PEDS14127. Epub 2015 Jan 2. PubMed PMID: 25555121.
4)

Daniels DJ, Clarke MJ, Puffer R, Luo TD, McIntosh AL, Wetjen NM. High occurrence of head and spine injuries in the pediatric population following motocross accidents. J Neurosurg Pediatr. 2015 Mar;15(3):261-5. doi: 10.3171/2014.9.PEDS14149. Epub 2015 Jan 2. PubMed PMID: 25555116.
5)

Daniels DJ, Luo TD, Puffer R, McIntosh AL, Larson AN, Wetjen NM, Clarke MJ. Degenerative changes in adolescent spines: a comparison of motocross racers and age-matched controls. J Neurosurg Pediatr. 2015 Mar;15(3):266-71. doi: 10.3171/2014.9.PEDS14153. Epub 2015 Jan 2. PubMed PMID: 25555120.

LINC 2019

Program

LINC represents an ambitious project to establish a unique for our region event that will periodically cover all aspects of vascular neurosurgery. Our aim is to provide trainees with a thorough and up to date review of a different subject each time, through theoretical lectures, debates as well as practical video sessions. Our inaugural course, the LINC2016, has been successfully completed on the 18th and 19th of March 2016. Its main theme being cerebral aneurysms, and with over 50 participants and 20 faculty members from both Europe and the U.S., LINC2016 proved to be a substantial educational experience for us all. For this event, we have chosen to concentrate on brain AVMs, a disease that still stirs controversy over what its management should be. My team and I, welcome you all in Athens for what we trust will

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