bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using nanobiopsy of single brain tumour cells to investigate transcriptional reprogramming during standard treatment.
Authors: Elpidorou Marilena , Actis Paolo , Stead Lucy 
Published: October 2019

Abstract
Glioblastoma (GBM) is an incurable brain cancer because, despite aggressive standard treatment (consisting of surgery, radiation and Temozolomide chemotherapy), 100% of tumours recur. GBM tumours are characterised by significant intratumour heterogeneity, with genotypically or phenotypically distinct subpopulations of cells co-existing within each tumour. However, it is not yet known whether the inevitable recurrence of GBM is owing to Darwinian selection of inherently treatment resistant cells within the primary tumour, or the ability of cells to transcriptional reprogram and acquire treatment resistance properties. Knowing this is fundamental to developing more effective treatment for GBM: should we therapeutically target existing cells or their ability to reprogram? The only way to know this is to profile individual cells longitudinally, which has not been possible until now.
Here we present a pioneering technology, known as nanobiopsy, which can longitudinally track the transcriptional profile of single GBM cells through standard treatment. The nanobiopsy allows injection or extraction of cytoplasmic material by electrowetting. We have proved that this technique is able to sample cytoplasmic fractions from cells without killing them, giving us the advantage to capture the transcriptional changes occurring through treatment using optimised scRNA sequencing protocols. We are applying this novel technology to help us identify treatment resistance modes and mechanisms to reveal novel targets for drug development.
The ketogenic diet alters the epigenetic landscape of GBM to potentiate the effects of chemotherapy and radiotherapy
Authors: Zeng Qingyu , Stylianou Tzouliana , Preston Jessica , Glover Sophie , O’Neill Kevin , Woolf Eric C , Scheck Adrienne C , Syed Nelofer 
Published: October 2019

Abstract
Glioblastoma Multiforme (GBM) is the most aggressive form of primary brain tumour, with a median survival of 12–14 months after diagnosis. Although GBM has been extensively characterised on the molecular level during the past decades, many targeted therapies have been proved to be ineffective due to high heterogeneity of GBM. Thus, novel therapies targeting the altered metabolism which is exhibited by all cancer cells have gained more attentions. Our strategy is the therapeutic ketogenic diet (KD), a high fat, low carbohydrate and adequate protein diet, which has been recognized as a treatment for refractory paediatric epilepsy. Recent studies have shown that KD reduces tumour growth and potentiates the effects of radiotherapy in some glioma animal models. However, the underlying mechanism is still unclear. To unravel the mechanism of action, we carried out small-RNA sequencing and chromatin modifying enzyme analysis using brain tumour samples from GBM mice model, fed with either KD or standard diet (SD). Our results highlighted an overall upregulation of tumour suppressor miRNAs and key chromatin modifying enzymes that are typically downregulated in GBM in mice fed with KD compared with those fed with SD. We also observed a corresponding downregulation in target genes of these miRNAs and chromatin modifying enzymes. These genes have been reported as key regulators in tumour growth, tumour invasion and chemo/radio-resistance in previous publications. Therefore, our study indicates that targeting cancer metabolism using the KD alters the epigenetic landscape of GBM and induces changes in key genes that potentiate the effects of chemo/radiotherapy.
Characterising a SOX2+ OLIG2+ glioma stem cell using Crispr-engineered fluorescent reporters in primary patient-derived GBM and DIPG cells.
Authors: Finlay Jack , Hallou Clement , Dewari Pooran , Pollard Steven , Pathania Manav , Bulstrode Harry , Rowitch David 
Published: October 2019

Abstract
Malignant glioma can be understood as a cancer stem cell disease. There is strong evidence that expression of a core set of neural stem cell master regulators is necessary and sufficient for tumour initiation in both adult and childhood disease subtypes, and across a range of underlying mutation signatures and expression profiles. We hypothesise that a double positive SOX2+ OLIG2+ progenitor is the cancer stem cell in H3K27M diffuse intrinsic pontine glioma (DIPG) and adult glioblastoma (GBM) alike. We present expression data in 4 patient-derived cell lines (2 adult GBM, 2 DIPG) in vitro and in a defined mutation mouse model of the H3K27M disease, demonstrating high expression levels of SOX2 and OLIG2 in serum-free culture and especially in the invasive tumour. We then demonstrate derivation of patient-derived human dual reporter lines, using a CRISPR targeting approach to add fluorescent reporters at the endogenous SOX2 and OLIG2 loci. With these tools, we aim to characterise the tumour-initiating potential of the SOX2+ OLIG2+ fraction. We further aim to identify cell surface markers whose expression is driven by this transcription program and which might represent targets for novel molecular therapies.
Characterisation of the metabolomes of epigenetically distinct subgroups of paediatric ependymoma
Authors: Woodward Alison , Abdelrazig Salah , Ortori Catharine , Barrett David , Grundy Richard , Kim Dong-Hyun , Rahman Ruman 
Published: October 2019

Abstract
Paediatric ependymoma relapses in up to half of patients, with a five-year survival rate of only 25%. Comprehensive characterisation of the genetic/epigenetic mutation and transcriptome landscape has not yet translated to improved treatments. Metabolomics is a functional genomic approach, offering an opportunity to elucidate aberrant metabolic pathways and new therapeutic avenues. Metabolomics thus far has concentrated on 1H High-resolution Magic Angle Spinning, Magnetic Resonance Spectroscopy and Raman Spectroscopy, where low numbers of metabolites were identified compared to that feasible by Liquid Chromatography tandem Mass Spectrometry (LC-MS/MS).
Here we present broader metabolome coverage using LC-MS/MS to separately analyse ependymoma polar and non-polar metabolites, comparing two subgroups from distinct neuro-anatomical compartments with different genetic and epigenetic drivers. We homogenised surgically resected ependymoma tissue from two epigenetic subgroups, posterior fossa A (n=10) and supratentorial RELA fusion (n=5), and extracted polar metabolites and lipids using methanol/water/chloroform 1:1:3. LC-MS/MS using a quadrupole-Orbitrap revealed 167 putative metabolites and 400 putative lipids significantly altered in relative abundance between the two subgroups. The metabolites predominantly mapped onto the taurine and hypotaurine pathway. Grade II and III PF-A tumours could be distinguished by the abundances of 53 metabolites, with three metabolites in the protein-lysine degradation pathway increased in abundance.
The study presents a first-in-kind description of the paediatric ependymoma metabolome revealing PF-A and ST-RELA subgroups are metabolically distinct brain tumours and therefore warrant consideration of distinct anti-metabolite therapies. Paediatric ependymoma intra-tumour regions have been collected from 6 surgical resections and ongoing intra-tumour metabolomics/lipidomics integrated with transcriptomics will be discussed.
The Prevalence of BRAF Mutations in Patients with Glioma: A Systematic Review
Authors: Samir Saincher Saanwalshah , Higgins Julian P T , McAleenan Alexandra , Kurian Kathreena M 
Published: October 2019

Abstract

Background
The V600mutation in the v-raf murine sarcoma oncogene homologue B1 (BRAF) enzyme, is a potential clinically actionable target in gliomas. BRAF inhibitors are in wide clinical use for other tumour types, particularly melanoma. The prevalence of this mutation across all gliomas is not fully elucidated and is needed to inform potential screening and treatment.

Methods
A systematic review using articles on the MEDLINE and EMBASE databases (February 1, 2019) was carried out. A meta-analysis was conducted to calculate the prevalence of BRAF mutations in patients with gliomas across all populations and age groups in a clinical setting.

Preliminary Results
The review identified 75 studies including 6316 patients; the ages of participants ranged from 30 days to 90 years with a mean age of 32.75 years. Across all studies, the average prevalence of BRAF mutations was 16% (95% confidence interval (CI) from 12% to 20%) but estimates were highly variable across studies, ranging from 0% to 78%. The average prevalence of BRAF mutations in paediatric group was 15% (95% CI 10% to 20%) while the average prevalence in the adult group was 9% (95% CI 4% to 16%). Low grade gliomas had an average prevalence of 19% (95% CI 14% to 25%) compared with 7% (95% CI 4% to 11%) in high-grade gliomas.

Conclusions
BRAF mutations were found to be more prevalent in pediatric patients and in low grade gliomas. Screening these patients for BRAF mutations and treating them with BRAF inhibitors represents a promising area of future medical practice.
Factors affecting treatment strategy, completion of planned treatment and survival in older patients with glioblastoma
Authors: Goel Aimee , Shahabi Lillie , Narenthiran Ganesalingam , O’Neill Kevin , Peterson David , Nandi Dipankar , Williams Matthew , Saleem W , Falconer A , Camp Sophie 
Published: October 2019

Abstract

Introduction
For older patients with glioblastoma (GBM), age, extent of resection, and performance status are prognostic factors. However, an international survey conducted by our Unit found that >40% of neurosurgeons use age alone to discount surgery in older (65+) patients. The aim of this study was to review management in our Unit for 65+ GBM patients, to inform future approaches.

Methods
Patients 65+ with a new GBM diagnosis in our Unit, between 2014 and 2017, were identified. Demographic data, performance status (PS), comorbidity and frailty indices, together with details of surgical/oncological management and outcome were collected.

Results
78 patients were identified. 78% aged 65–74 underwent maximal safe resection, compared with 45% aged 75–84, and 10% aged 85+. Resection was undertaken in 68% PS1, 73% PS2 and 23% PS3 patients. No PS3 patient completed intended radiotherapy, compared with 79% PS1 and 74% PS2 patients. There was a significant difference in frailty scores of patients who completed scheduled oncological therapy compared with those who did not (median score 2 vs 4.5, p=0.0338).
Median survival was 10 months for patients 65–74, 4 months for aged 75 -84, and 40 days for 85+ (p<0.0167). Median survival was significantly lower for PS3 patients (44 days) compared with PS1 or 2 (9.5 months and 7 months respectively; p<0.0167).

Conclusion
There is considerable variability in performance status and frailty of 65+ GBM patients. PS3 patients at diagnosis are very unlikely to complete oncological treatment. These factors, rather than age alone, should be used to guide management decisions.
Glioblastoma multiforme in patients over 65 – should we operate?
Authors: Maleyko Igor , Hall Benjamin , Brodbelt Andrew , Lawson David , Jenkinson Michael , Chavredakis Emmanuel 
Published: October 2019

Abstract

Aim
Current standard of care for glioblastoma is maximum safe resection followed by radio chemotherapy with Temozolomide. Older patients are less likely to receive the full treatment. The aim was to determine treatment and outcomes in glioblastoma patients >65 years.

Methods
Single centre retrospective study from 2001–2016. Eligible patients had: (i) diagnosis of glioblastoma (ii) undergone biopsy or resection with radiotherapy ± adjuvant chemotherapy. Age at diagnosis, type of surgery, performance status, complications, adjuvant therapy and median survival (MS) were recorded. Patients were assigned to group A (age <65), B (age 65–69 years) or C (age >/= 70 years).

Results
637 patients met the eligibility criteria and 403 had complete records for analysis. Age distribution of the cohort was 17.9 – 91.6 years.
In the group A (n=259), those who had undergone resection had significantly longer MS compared to biopsy: 17.2 vs 13.2 months (P<0.05 CI: 444.043 – 561.957). 70 patients developed complications.
In the group B (n=79), those who had undergone resection had significantly longer MS compared to biopsy: 12.3 vs 5.1 months (P<0.05 CI: 194.354 – 335.646). 17 patients developed complications.
In the group C (n=64), analysis did not show statistically significant difference (P=0.066 CI: 220.476 – 321.524). Clinically, patients who had resection had longer MS (10.5 months vs 3.5 months). Furthermore, there was no significant difference in the rate of complications between resection and biopsy (Fisher’s exact test, P=0.755).

Conclusion
i) Patients >65 should be treated as per the Stupp protocol ii) In patients >70 surgical resection should be considered.:
Nanotherapeutics for neurosurgically-applied drug delivery
Authors: Vasey Catherine , Taresco Vincenzo , Smith Stuart , Alexander Cameron , Rahman Ruman 
Published: October 2019

Abstract
Despite multimodal treatment, the median survival of Glioblastoma multiforme (GBM) remains less than 15 months, in considerable part due to diffusely infiltrative disease. Better treatment methods are necessary to eradicate residual tumour burden remaining beyond the resection cavity boundary. Based on an increasing understanding of GBM intra-tumour heterogeneity, the capability to deliver multiple therapeutic moieties from single formulations is clinically-relevant. It is hypothesised that incorporating drug-loaded polymer pro-drugs, which are capable of transcytotic ‘hopping’, into a biodegradable microparticulate paste will lead to efficacious local delivery.
Here we report the formulation of numerous self-assembling cytocompatible nanoparticles, based on different linear and branched polymeric architectures. The polymers were synthesised by ring opening polymerisation with organic catalysts, leading to controlled reaction kinetics and greater potential biomedical applicability. We demonstrated that copolymerisation of a monomer with functional capability enabled the successful conjugation of doxorubicin to the polymer chain. We hypothesised that polymers with a greater degree of branching over traditional linear structures would lead to greater drug loading, and successfully tested this hypothesis through the encapsulation of olaparib.
We will discuss strategies to incorporate: i) pH-sensitive linkers to the polymeric backbone, which would allow controlled drug release in acidic microenvironments; ii) multiple combined chemotherapeutics, including doxorubicin and olaparib. Future work will assess the efficacy of the polymer pro-drugs against primary GBM lines derived from the invasive margin and safety/efficacy using orthotopic syngeneic allografts.
This is the first study incorporating polymer pro-drugs of this type into an existing localised micro-scale delivery system for GBM therapies.
Spontaneous glioma-induced seizures recorded in a living human brain tissue preparation
Authors: Kirby Alastair , Pedro Lavrador Jose , Brogna Christian , Vergani Francesco , Zebian Bassel , Chandler Christopher , Bodi Istvan , Bhangoo Ranjeev , Keyoumars Ashkan , Finnerty Gerald 
Published: October 2019

Abstract
Gliomas often present clinically with seizures. Tumour-associated seizures can be difficult to control with medication. A deeper understanding of the cellular mechanisms underlying tumour-associated seizures would provide a basis for developing new treatments. Here, we investigate epileptic discharges in peritumoral cortex using living human brain tissue donated by people having a craniotomy for glioma resection (REC approval, 18/SW/002). The brain tissue was cut into thin slices, which preserved the architecture of the glioma and the adjacent healthy brain. The brain slices were incubated in 5-aminolevulinic acid to make the glioma cells fluorescent. This enabled us to make electrophysiological recordings of brain activity across the boundary between glioma and brain. We recorded from brain slices of 5 participants with glioblastoma and 4 participants with oligodendroglioma (WHO grade II – III). Spontaneous “seizure-like” discharges were recorded in brain slices from 5/8 participants (3 GBM, 2 oligodendroglioma) who reported seizures and from one participant (GBM) who had not had any clinical seizures. Further analysis of the seizure-like discharges revealed that they could be subdivided into two distinct types based on the major frequencies in the discharge. We concluded that human brain slices from people with either a low-grade or a high-grade glioma can generate spontaneous seizure-like discharges. The living human brain tissue preparation gives us a platform to study the mechanisms of tumour-associated seizures and how abnormal neural activity affects glioma growth.
Relationship between travel time to primary and tertiary care centres and survival in glioblastoma: the NHS Grampian experience.
Authors: Veljanoski Damjan , Barlas Raphae , Jamjoom Aimun , Myint Phyo 
Published: October 2019

Abstract

Background
Studies have demonstrated a distance-decay effect, whereby patients who live further away from their healthcare facility have poorer health outcomes. The geographical catchment area served by the neurosurgical unit in Aberdeen, Grampian region, Scotland is one of the largest in the UK. We aimed to examine the relationship between travel time as a proxy of distance travelled, and survival outcome for glioblastoma.

Methods
We conducted a retrospective, cohort analysis of patients with glioblastoma referred for treatment from January 2009 to December 2018. Travel time was calculated from the patients’ home to their general practitioner (GP) and to the neurosurgical unit. Logistic regression models were constructed to estimate survival at three, six and 12 months, as well as treatment within 62 days of GP referral, and within 31 days of diagnosis controlling for age, sex and treatment type.

Results
There were 195 patients (mean age (SD) 64.4 ± 12.9 years)57.9% were men, 65.1% were treated surgically, and 48.2% were alive after one year. Longer time travelled to GP, but not to tertiary care centre, was associated with reduced odds of mortality at three months (OR 0.88 95%CI 0.79–0.98; p=0.005) and six months (OR 0.92 95%CI 0.85–0.99; p=0.01), for each incremental increase in one minute.

Conclusions
Patients with glioblastoma with longer travel times to their GP were more likely to be alive at three months and six months. Further work is required to identify other factors, including degrees of socio-economic deprivation and rurality, which may influence this finding.
A tale of two water markets in Australia: lessons for understanding participation in formal water markets
Authors: Ann Wheeler Sarah , Garrick Dustin E 
Published: October 2019

Abstract
Water markets are promoted as a demand-management strategy for addressing water scarcity. Although there is an increasing literature on the institutional preconditions required for successful formal water markets, there has been less focus on understanding what drives participation after establishment of the basic enabling conditions. Participation can be measured in terms of either trading activity (conducting either a permanent or temporary water trade) and/or trade volumes across time and market products. Australia’s water markets in the Southern and Northern Basins of the Murray-Darling Basin provide a notable example of a ‘tale of two water markets’, offering insights about the economic policy levers that can drive participation across different hydrological, irrigation, and socioeconomic contexts. Key lessons include: distribution of initial property rights in resource allocation; the need to prepare for and seize opportunities to strengthen property rights; and robust monitoring and compliance requirements—all of which will reduce transaction costs and increase participation.
Potassium disturbance associated with an inpatient childhood asthma pathway
Authors: Hung Jonathan , Kraft Timothy , Seefried Brent , Johnson David W , Bailey Michelle , Dersch-Mills Deonne 
Published: October 2019

AbstractBackgroundPaediatric asthma exacerbations in Alberta are treated via standardized order sets known as the Alberta Acute Childhood Asthma Pathway (ACAP). This pathway is utilized in paediatric tertiary hospitals and in remote and rural locations. Incidence, magnitude, and risk factors for hypokalemia in inpatients receiving salbutamol for asthma exacerbations via this pathway are presently unknown.ObjectiveEstablish incidence, magnitude, and risk factors for hypokalemia associated with salbutamol therapy as directed by a paediatric asthma pathway.MethodsRetrospective cohort study using visit-level electronic medical data. Inpatients aged &lt;18 years old receiving salbutamol via the ACAP with at least one potassium level were included. Hypokalemia was defined as mild (3.0 ≤ [K+] &lt; 3.5 mEq/L), moderate (2.5 ≤ [K+] &lt; 3.0 mEq/L), or severe ([K+] &lt; 2.5 mEq/L), as measured in serum or blood gas. Binomial logistic regression was utilized to examine risk factors for hypokalemia, route of administration, location of lowest [K+], nil per os (NPO) status during admission, potassium supplementation, gender, and age.ResultsThere were 821 patients screened for analysis and 433 patients were analyzed after exclusions. There was an incidence of hypokalemia of 38.8%. Of patients experiencing hypokalemia, 71.4% were mild, 25.6% moderate, and 3.0% severe. Risk factors included nebulized salbutamol, patient location (emergency department or paediatric intensive care unit), and age (&gt;5 years) although these risk factors may actually represent patients receiving higher doses of salbutamol.ConclusionsThe majority of the 38.8% of children experiencing hypokalemia associated with the ACAP were mild. Routine monitoring of potassium status in children receiving salbutamol per standardized pathway is recommended for children with described risk factors, and ideally within the first 12 hours of presentation.
Optimal Dynamic Carbon Taxes in a Climate–Economy Model with Distortionary Fiscal Policy
Authors: Barrage Lint 
Published: October 2019

Abstract
How should carbon be taxed as a part of fiscal policy? The literature on optimal carbon pricing often abstracts from other taxes. However, when governments raise revenues with distortionary taxes, carbon levies have fiscal impacts. While they raise revenues directly, they may shrink the bases of other taxes (e.g. by decreasing employment). This article theoretically characterizes and then quantifies optimal carbon taxes in a dynamic general equilibrium climate–economy model with distortionary fiscal policy. First, this article establishes a novel theoretical relationship between the optimal taxation of carbon and of capital income. This link arises because carbon emissions destroy natural capital: they accumulate in the atmosphere and decrease future output. Consequently, this article shows how the standard logic against capital income taxes extends to distortions on environmental capital investments. Second, this article characterizes optimal climate policy in sub-optimal fiscal settings where income taxes are constrained to remain at their observed levels. Third, this article presents a detailed calibration that builds on the seminal DICE approach but adds features essential for a setting with distortionary taxes, such as a differentiation between climate change production impacts (e.g. on agriculture) and direct utility impacts (e.g. on biodiversity existence value). The central quantitative finding is that optimal carbon tax schedules are 8–24% lower when there are distortionary taxes, compared to the setting with lump-sum taxes considered in the literature.