The Grizzly, February 15, 1994

Pledging Meeting: First in a Series • Berry Announces Plans for Candidacy • Ursinus Given Laboratory Glassware as Gift • Airband to Help Local • Northeast Still Being Hit by Winter • Professor Profile: Tom Whalen • The Power of the Postcard • GALA Retools • Censorship Sucks • UC Baseball to Hold 4th Annual Baseball Clinic • Freshman Black Belt Profiled in National Karate Magazine • New Track & Field Coaches Hired • Wrestling Destroys All Competitionhttps://digitalcommons.ursinus.edu/grizzlynews/1330/thumbnail.jp

An Evaluation of the Tolerability and Feasibility of Combining 5-Amino-Levulinic Acid (5-ALA) with BCNU Wafers in the Surgical Management of Primary Glioblastoma.

Background Glioblastoma (GBM) is the commonest primary malignant brain tumour in adults and effective treatment options are limited. Combining local chemotherapy with enhanced surgical resection using 5-aminolevulinic acid (5-ALA) could improve outcomes. Here we assess the safety and feasibility of combining BCNU wafers with 5-ALA-guided surgery. Methods We conducted a multicentre feasibility study of 5-ALA with BCNU wafers followed by standard-of-care chemoradiotherapy (chemoRT) in patients with suspected GBM. Patients judged suitable for radical resection were administered 5-ALA pre-operatively and BCNU wafers at the end resection. Post-operative treatment continued as per routine clinical practice. The primary objective was to establish if combining 5-ALA and BCNU wafers is safe without compromising patients from receiving standard chemoRT. Results Seventy-two patients were recruited, sixty-four (88.9%) received BCNU wafer implants, and fifty-nine (81.9%) patients remained eligible following formal histological diagnosis. Seven (11.9%) eligible patients suffered surgical complications but only two (3.4%) were not able to begin chemoRT, four (6.8%) additional patients did not begin chemoRT within 6 weeks of surgery due to surgical complications. Eleven (18.6%) patients did not begin chemoRT for other reasons (other toxicity (n = 3), death (n = 3), lost to follow-up/withdrew (n = 3), clinical decision (n = 1), poor performance status (n = 1)). Median progression-free survival was 8.7 months (95% CI: 6.4-9.8) and median overall survival was 14.7 months (95% CI: 11.7-16.8). Conclusions Combining BCNU wafers with 5-ALA-guided surgery in newly diagnosed GBM patients is both feasible and tolerable in terms of surgical morbidity and overall toxicity. Any potential therapeutic benefit for the sequential use of 5-ALA and BCNU with chemoRT requires further investigation with improved local delivery technologies

The role of the PAS-cap in the function of hEAG1 and the role of hEAG1 in cancer cell progression

Human ether-a-go-go 1 (hEAG1) is a voltage gated K+ channel that is sensitive to inhibition by Ca2+-calmodulin. hEAG1 is located presynaptically in brain neurons and regulates Ca2+ influx and neurotransmitter release. It is also ectopically expressed in >70% of human tumours. hEAG1 has been shown to increase cell proliferation. The research here aims to understand the mechanism for Ca2+-calmodulin regulation of gating and whether specific intracellular domains are also important for effects on proliferation. The role of hEAG1 on cell migration is studied here for the first time. hEAG1 contains an N-terminal EAG domain consisting of a Per-Arnt-Sim (PAS) domain and a 26 amino acid PAS-cap region. On the C-terminus is a cyclic nucleotide binding homology domain (cNBHD). hEAG1 channels were mutated and channels characterised by expression in Xenopus laevis oocyte expression system and two electrode voltage clamp. At a membrane potential of +60mV, WT hEAG1 shows activation kinetics of 309.1 ± 16.4ms and does not inactivate in control conditions. WT hEAG1 is inhibited 85.5 ± 2.9% when Ca2+ is raised. Deleting the PAS-cap (Δ2-26) slows the activation kinetics to 801 ± 122ms and allows the non-inactivating channel to inactivate. When Ca2+ is raised, the Δ2-26 hEAG1 current increases by 1272.7 ± 197.1%. In this study we address, at the amino acid level, the interactions behind the PAS-cap’s role in regulating hEAG1. We also address whether the Ca2+ sensitivity and intracellular domains of hEAG1 influence its effect on proliferation by using a BrdU incorporation assay. The EAG domain and the E600 residue are important for this role as mutation of either resulted in a reduction in the number of proliferating cells. Overall the results suggest that PAS-cap, EAG and cNBH domain interactions regulate current responses to Ca2+-calmodulin and that the EAG domain and E600 are important for increased proliferation

Mutant IDH in Gliomas: Role in Cancer and Treatment Options.

Peer reviewed: TrueAltered metabolism is a common feature of many cancers and, in some cases, is a consequence of mutation in metabolic genes, such as the ones involved in the TCA cycle. Isocitrate dehydrogenase (IDH) is mutated in many gliomas and other cancers. Physiologically, IDH converts isocitrate to α-ketoglutarate (α-KG), but when mutated, IDH reduces α-KG to D2-hydroxyglutarate (D2-HG). D2-HG accumulates at elevated levels in IDH mutant tumours, and in the last decade, a massive effort has been made to develop small inhibitors targeting mutant IDH. In this review, we summarise the current knowledge about the cellular and molecular consequences of IDH mutations and the therapeutic approaches developed to target IDH mutant tumours, focusing on gliomas

Mutant IDH in Gliomas: Role in Cancer and Treatment Options.

Altered metabolism is a common feature of many cancers and, in some cases, is a consequence of mutation in metabolic genes, such as the ones involved in the TCA cycle. Isocitrate dehydrogenase (IDH) is mutated in many gliomas and other cancers. Physiologically, IDH converts isocitrate to α-ketoglutarate (α-KG), but when mutated, IDH reduces α-KG to D2-hydroxyglutarate (D2-HG). D2-HG accumulates at elevated levels in IDH mutant tumours, and in the last decade, a massive effort has been made to develop small inhibitors targeting mutant IDH. In this review, we summarise the current knowledge about the cellular and molecular consequences of IDH mutations and the therapeutic approaches developed to target IDH mutant tumours, focusing on gliomas

Advances in Research of Adult Gliomas

Diffuse gliomas are the most frequent brain tumours, representing 75% of all primary malignant brain tumours in adults. Because of their locally aggressive behaviour and the fact that they cannot be cured by current therapies, they represent one of the most devastating cancers. The present review summarises recent advances in our understanding of glioma development and progression by use of various in vitro and in vivo models, as well as more complex techniques including cultures of 3D organoids and organotypic slices. We discuss the progress that has been made in understanding glioma heterogeneity, alteration in gene expression and DNA methylation, as well as advances in various in silico models. Lastly current treatment options and future clinical trials, which aim to improve early diagnosis and disease monitoring, are also discussed