bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flow Cytometry in the Differential Diagnosis of CD10-Positive Nodal Lymphomas
Authors: Sorigue Marc , Santos-Gomez Mireia , Comes Martina , Raya Minerva , Vergara Sara , Tapia Gustavo , Navarro José-Tomas , Morales-Indiano Cristian , Junca Jordi 
Published: October 2019

Abstract

Background
Differences between follicular lymphoma (FL) and diffuse large B-cell lymphoma/high-grade B-cell lymphoma (DLBCL/HGBL) by flow cytometry are underexplored.

Methods
We retrospectively assessed flow cytometry results from 191 consecutive lymph node biopsies diagnosed with FL or DLBCL/HGBL.

Results
The only parameters that differed between the 2 groups in the derivation cohort were forward scatter and side scatter (P &lt; 10–6; area under the curve [AUC], 0.75–0.8) and %CD23 (P = .004; area under the receiver characteristic operating curve, 0.64). However, since light scatter characteristics did not distinguish between grade 3 FL and DLBCL/HGBL, we set out to develop a model with high sensitivity for the exclusion of the latter. Several models, including FS and %CD23, were tested, and 2 models showed a sensitivity of &gt;0.90, with negative predictive values of ≥0.95, albeit with low specificity (0.45 to 0.57).

Conclusion
Two simple models enable the exclusion of DLBCL/HGBL with a high degree of confidence.
DisProt: intrinsic protein disorder annotation in 2020
Authors: Hatos András , Hajdu-Soltész Borbála , Monzon Alexander M , Palopoli Nicolas , Álvarez Lucía , Aykac-Fas Burcu , Bassot Claudio , Benítez Guillermo I , Bevilacqua Martina , Chasapi Anastasia , Chemes Lucia , Davey Norman E , Davidović Radoslav , Dunker A Keith , Elofsson Arne , Gobeill Julien , Foutel Nicolás S González , Sudha Govindarajan , Guharoy Mainak , Horvath Tamas , Iglesias Valentin , Kajava Andrey V , Kovacs Orsolya P , Lamb John , Lambrughi Matteo , Lazar Tamas , Leclercq Jeremy Y , Leonardi Emanuela , Macedo-Ribeiro Sandra , Macossay-Castillo Mauricio , Maiani Emiliano , Manso José A , Marino-Buslje Cristina , Martínez-Pérez Elizabeth , Mészáros Bálint , Mičetić Ivan , Minervini Giovanni , Murvai Nikoletta , Necci Marco , Ouzounis Christos A , Pajkos Mátyás , Paladin Lisanna , Pancsa Rita , Papaleo Elena , Parisi Gustavo , Pasche Emilie , Barbosa Pereira Pedro J , Promponas Vasilis J , Pujols Jordi , Quaglia Federica , Ruch Patrick , Salvatore Marco , Schad Eva , Szabo Beata , Szaniszló Tamás , Tamana Stella , Tantos Agnes , Veljkovic Nevena , Ventura Salvador , Vranken Wim , Dosztányi Zsuzsanna , Tompa Peter , Tosatto Silvio C E , Piovesan Damiano 
Published: October 2019

Abstract
The Database of Protein Disorder (DisProt, URL: https://disprot.org) provides manually curated annotations of intrinsically disordered proteins from the literature. Here we report recent developments with DisProt (version 8), including the doubling of protein entries, a new disorder ontology, improvements of the annotation format and a completely new website. The website includes a redesigned graphical interface, a better search engine, a clearer API for programmatic access and a new annotation interface that integrates text mining technologies. The new entry format provides a greater flexibility, simplifies maintenance and allows the capture of more information from the literature. The new disorder ontology has been formalized and made interoperable by adopting the OWL format, as well as its structure and term definitions have been improved. The new annotation interface has made the curation process faster and more effective. We recently showed that new DisProt annotations can be effectively used to train and validate disorder predictors. We believe the growth of DisProt will accelerate, contributing to the improvement of function and disorder predictors and therefore to illuminate the ‘dark’ proteome.
Targeted DNA methylation of neurodegenerative disease genes via homology directed repair
Authors: Cali Christopher P , Park Daniel S , Lee Edward B 
Published: October 2019

Abstract
DNA methyltransferases (DNMTs) are thought to be involved in the cellular response to DNA damage, thus linking DNA repair mechanisms with DNA methylation. In this study we present Homology Assisted Repair Dependent Epigenetic eNgineering (HARDEN), a novel method of targeted DNA methylation that utilizes endogenous DNA double strand break repair pathways. This method allows for stable targeted DNA methylation through the process of homology directed repair (HDR) via an in vitro methylated exogenous repair template. We demonstrate that HARDEN can be applied to the neurodegenerative disease genes C9orf72 and APP, and methylation can be induced via HDR with both single and double stranded methylated repair templates. HARDEN allows for higher targeted DNA methylation levels than a dCas9-DNMT3a fusion protein construct at C9orf72, and genome-wide methylation analysis reveals no significant off-target methylation changes when inducing methylation via HARDEN, whereas the dCas9-DNMT3a fusion construct causes global off-target methylation. HARDEN is applied to generate a patient derived iPSC model of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) that recapitulates DNA methylation patterns seen in patients, demonstrating that DNA methylation of the 5′ regulatory region directly reduces C9orf72 expression and increases histone H3K9 tri-methylation levels.
Bidirectional neuron-glioma interactions: effects of glioma cells on synaptic activity and its impact on tumor growth
Authors: Tantillo Elena , Vannini Eleonora , Cerri Chiara , Maria Mazzanti Chiara , Costa Mario , Caleo Matteo 
Published: October 2019

Abstract
Gliomas grow in a neuronal environment, but little is known on the functional changes in peritumoral neurons during tumor development. Moreover, investigations on the role of neural activity in glioma progression have yielded contradictory results. Here, we monitored longitudinal changes in network activity by recording visual evoked potentials (VEP) and local field potentials (LFP) after transplant of GL261 glioma cells in mouse visual cortex. We detected a progressive deterioration of VEP amplitudes in glioma-bearing mice, accompanied by an increase in slow network oscillations. At the cellular level, the analysis of microdissected peritumoral neurons showed alterations in both pre- and post-synaptic markers. To investigate whether glioma-driven alterations in synaptic function may impact on tumor growth, we manipulated levels of afferent cortical activity in glioma-bearing mice. Specifically, we tested blockade of synaptic activity via botulinum neurotoxin A (BoNT/A), visual deprivation (dark rearing, DR) and visual stimulation (VS). Replicating cells were quantified via immunostaining for BrdU and Ki67. We found that manipulation of cortical activity bidirectionally regulated glioma proliferation. Silencing of cortical synapses with BoNT/A and DR increased tumor proliferation while daily VS had the opposite effect.
These findings demonstrate reduced responsiveness of peritumoral neurons which may in turn stimulate tumor cell proliferation, thus triggering a vicious loop that exacerbates glioma progression. Physiological stimulation of neural activity appears to restrain glioma proliferation so it could be implemented in the clinical setting as an adjuvant therapy.
Multi-colour lineage tracing to asses intra-tumour heterogeneity in glioblastoma multiforme
Authors: Innes James , Brandner Sebastian , Marino Silvia 
Published: October 2019

Abstract

Background
Glioblastoma multiforme (GBM) represents nearly 50% of all malignant brain tumours. Molecular and genomic diagnostics are beginning to unravel the variation between individual tumours. However, there is growing evidence that cellular heterogeneity exists within a single malignancy. Singe cell analysis has demonstrated the presence of subpopulations corresponding to distinct expression profiles.

Objective and experimental approach
characterisation of the intratumor heterogeneity is essential to understand biological behaviour and therapy response. Through combining a genetically labelled mouse model (rosa26-confetti lineage tracing locus) with genetically engineered GBM model we can label distinct cellular lineages.

Results
For three-dimensional imaging of these fluorescently labelled tumours we have optimised tissue clearing protocols. Fluorescence activated sorting of genetically labelled tumour cells identifies distinct populations within single tumours. With these techniques can now interrogate the spatial organisation of clones across large areas and we can compare distinct tumour lineages.

Outlook
Currently, we are engineering human glioblastoma cell lines with genetic fluorescent labels for lineage tracing. Several genetically characterised human cell lines are available for which novel therapeutic targets have been identified. We will apply our lineage tracing approach to investigate the clonal effects of these tailored therapeutics.
Introducing Fluorescence Guided Surgery into Neuro-Oncology Practice and Getting It Right First Time
Authors: Vaqas Babar , Hill Ciaran , Qin Cathy , Glover Sophie , Maniar Ruchi 
Published: October 2019

Abstract

Introduction
Fluorescence Guided Surgery (FGS) using 5-ALA is recommended for patients undergoing resection of suspected high grade glioma and this type of surgery is increasingly being used in more units throughout the UK. We report on our experience of introducing 5-ALA guided surgery for suspected HGG in a regional neurosciences unit.

Methods
Consecutive series of the first 24 patients in our unit to receive 5-ALA guided surgery for suspected HGG from June 2017 to October 2018. Data was prospectively collected.

Results
5-ALA fluorescence guided surgery was used for a range of histologically confirmed WHO grade III-IV gliomas. All but 1 tumour (GBM) fluoresced with 5-ALA, with strong fluorescence in recurrent GBM and anaplastic foci of grade 3 tumours. EOR varied according to the eloquence of the lesion with 70% of cases achieving gross total resection. 40% of cases used awake mapping or intraoperative neurophysiology. 5 patients (20.8%) had temporary neurological deficits which resolved in all cases. Individual surgeon learning curves resulted in 2 styles of practice- complete FGS with fluorescence used throughout the case, and intermittent use of fluorescence as an adjunct often at the end of debulking under white light.

Conclusions
Adopting 5-ALA use comes with specific challenges in terms of service organisation, learning curves and complication avoidance. Our experience is that it is useful both to improve EOR and as an adjunct to identify tumour tissue in eloquent region tumours with monitoring of function. This is possible through a day admission pathway in line with GIRFT.
Functionalised LRP1 targeted carbon nanotubes across the blood-brain barrier in vitro and in vivo after intravenous injection
Authors: Wang Julie , Kafa Houmam , Rubio Noelia , Bansal Sukhvinder , Festy Frederic , Sosabowski Jane , Abbott Joan , Al-Jamal Khuloud 
Published: October 2019

Abstract
Despite extensive research in drug development, brain cancer is still lacking an efficacious cure due to the inability to deliver current therapeutics to the brain across the blood-brain barrier (BBB). Chemically functionalized carbon nanotubes (f-CNT) constitute a novel class of nanomaterials with attractive physical, chemical and electronic properties. The key advantage of f-CNTs is the extremely high surface area to size ratio allowing a high degree of chemical functionalization making them invaluable tools for designing drug delivery systems to the brain. One of the most interesting characteristics of f-CNTs is their ability to translocate across plasma membranes and enter the cells either passively by direct translocation across membranes or actively via endocytosis.
Herein, we confirmed the ability of f-CNTs to cross the BBB and reach the brain in in vitro using a co-culture model of PBEC and primary rat astrocytes and in vivo after intravenous injection. Thanks to their unique optical properties, the uptake of f-CNT in brain was confirmed using state-of-the-art spectroscopic imaging techniques such as multi-photon luminescence imaging, fluorescence lifetime microscopy and Raman spectroscopy. Conjugation with angiopep-2 (ANG), a small peptide targeting the LRP1 receptor overexpressed in the BBB and glioma cells, further enhanced brain parenchyma accumulation in healthy brains. Higher uptake in glioma than brain parenchyma was also observed in glioma-bearing mice after intravenous administration.
The inherent brain accumulation ability of f-CNTs coupled with improved brain-targeting by ANG favours the future clinical applications of f-CNTs-ANG to deliver active therapeutics for brain glioma therapy.
Intra-tumoural perfusion habitats showed prognostic value in glioblastoma patients
Authors: Li Chao , Sun Chang , Wang Shuo , Price Stephen 
Published: October 2019

Abstract
The perfusion within glioblastoma is associated with tumour microenvironment and may create invasive tumor habitats that could potentially be revealed by perfusion imaging. The purpose of this study is to characterize the peritumoural habitats of glioblastoma for treatment target. Dynamic susceptibility contrast-enhancement (DSC) MRI was acquired pre-operatively on 115 newly-diagnosed glioblastoma patients. All images were co-registered to post-contrast T1-weighted images. The relative cerebral blood volume (rCBV), mean transit time (MTT) and relative cerebral blood flow (rCBF) maps were generated from the DSC images. The contrast-enhanced and peritumoural tumor regions were semi-automatically segmented from the post-contrast T1-weighted and FLAIR images. To delineate the habitats of different perfusion levels, a two clusters mixture model with Gaussian distribution was fitted to the rCBV, rCBF, and MTT within both contrast-enhanced and peritumoural regions. Perfusion parameters of the identified habitats were compared, and the prognostic values of habitats were investigated using survival analysis. The results showed that although non-enhanced, the peritumoral high perfusion (PHP) habitat demonstrated similar perfusion level with the contrast high perfusion (CHP) habitat, with similar rCBV (PHP: 1.13 ± 0.18, 95% CI [1.10, 1.15]; CHP: 1.21 ± 0.25, 95% CI [1.16, 1.21]) and rCBF (PHP: 1.08 ± 0.23, 95% CI [1.05, 1.08]; CHP: 1.08 ± 0.19, 95% CI [1.05, 1.08]). Multivariate Cox regression showed that the volumes of both habitats were associated with worse patient overall survival (PHP: P = 0.032; HR= 7.09; CHP: P = 0.008; HR= 12.01). Our results suggest that the intra-tumoural perfusion habitats may potentially offer treatment targets.
Primary Central Nervous System Lymphoma – Management and Outcome in the ‘haematology era’
Authors: Kumar Siddhant , Islim Abdurrahman , Ali Tamara , Smith Jeffery , Haylock Brian , Shenoy Aditya , Husband David , J Mills Samantha , Brodbelt Andrew , Chavredakis Emmanuel , Lawson David , Chapman Grace , Wickramaratne Nawani , Ridzuan-Allen Adam , Harrison Imogen , D Jenkinson Michael 
Published: October 2019

Abstract

Introduction
Primary CNS lymphoma (PCNSL) requires a biopsy for diagnosis but can be inconclusive when steroids are administered. Without treatment median survival is 1.5–3.3 months, improving to 10–20 months with oncological treatment. This study aimed to compare outcomes of PCNSL treated under haematology to those of clinical oncologists.

Methods
Retrospective casenote review of patients with PCNSL treated under oncologists (2006–2010) and haematologists (2011–2016).

Results
121 cases were identified (median age 63 years; range 19–84). Median WHO performance status (PS) was 1. 11.6% required repeat biopsy.
10 patients were managed palliatively due to poor PS.
67 cases were managed under haematology. Median symptom duration was 28 days (range 2–540). Median time from MRI to diagnosis was 18 days (range 6–232). 66 patients received chemotherapy, 1 received radiotherapy. Median overall survival (OS) was 8 months (95%CI: 0.7–15.3), 5-year OS was 22.4%.
44 cases were managed under oncology. Median symptom duration was 28 days (range 2–365). Median time from MRI to diagnosis was 16 days (range 6–309). 34 patients received radiotherapy first-line, 10 received chemotherapy. Median OS was 7 months (95%CI: 0–21.5), 5-year OS was 15.9%.
Multivariate analysis demonstrated PS (HR 2.02 (95%CI: 1.08–3.76)) and symptom duration (HR 0.63 (95%CI: 0.41–0.96)) to be significant prognostic indicators for OS.

Discussion
PCNSL carries poor prognosis and outcomes from the ‘haematology era’ are similar to those achieved by clinical oncologists. Delay in diagnosis leads to worse outcomes and highlights the ongoing need to streamline current clinical services to improve outcomes.
Using Neuro-oncology to teach GCSE students STEM-subjects
Authors: Shahabi Lillie , Shahabi Golnaz , Wilcox Emma , Campos Catarina , Shah Zahra , Holgate Daisy , Furssedonn Lilly , Al-Tai Dhuha , Jando Saavun , Ranny Aaron , Nagra Nirvan , Seksaria Eesha , Ferreira Diogo , Dadhania Seema , Soni Shivani , Wang James , Camp Sophie , Syed Nelofer , Williams Matt 
Published: October 2019

Abstract

Background
The profile of brain tumours in the wider community has recently been raised. In this project we explored whether we could link brain tumour awareness with STEM education for secondary school pupils. We aimed to inspire the next generation by bringing research into formal and informal learning contexts.

Method
We worked with a local school to co-design and co-create a set of blended learning sessions. Each session consisted of some “biological” teaching and a practical activity. These included using IDH, MGMT and 1p/19q as models of varying genetic disorder and a Jenga-based game to teach radiobiology. Sessions were delivered every 1–2 weeks using a multidisciplinary team. We assessed impact through informal weekly feedback, a structured feedback form and linkage to GCSE curriculum items. We assessed costs using a staff-free FEC model.

Results
We delivered a total of 12 hours over 10 sessions. Feedback was overwhelmingly positive from the students – “The project has been very enlightening and rewarding”. We were able to link 60% of taught material to GCSE curriculum items. We estimated costs (materials) at £260. Students presented their work at the Imperial Science Festival and an additional conference.

Discussion
We have co-developed and piloted an innovative multi-disciplinary toolkit to use neuro-oncology as a way of teaching STEM subjects, though a pupil-centred approach. We are now seeking to pilot the materials with other neuroscience centres/ universities to support secondary schools and neuroscience centres/ universities in working collectively to create structured, strategic, and sustainable mechanisms for engagement.
Characterisation of the anti-migratory activity of the 6-bromoindirubin-3’oxime (BIO) derivative VTIND42 in patient-derived GBM subpopulations
Authors: Peat Samuel , Bruning-Richardson Anke , Meijer Laurent , Lawler Sean , Thiéry Valérie , Morton Ruth 
Published: October 2019

Abstract

Introduction
Targeting the infiltrative nature of GBMs with anti-migratory drugs as combination treatment for prevention of tumour recurrence is an attractive disease management option. One such class of drugs are the GSK-3 inhibitors 6-bromoindirubin-3′-oximes (BIO). BIO has been proposed for use in combination therapy, however, the administration of indirubins remains problematic due to low solubility causing low bioavailability. We describe the characterisation of a BIO derivative, VTIND42, identified from a screen of 450 compounds with improved solubility.

Method
The compounds were initially screened on the following criteria, selective anti-migratory effect with enhanced potency over the lead compound BIO. Effect on cell migration in two cell subpopulations (core obtained, edge obtained) from the patient derived GBM40 was assessed by 3D migration/invasion assays and for cytoskeletal rearrangements by immunofluorescence.

Results
VTIND42 (1 µM) showed the best performance overall in terms of specificity and efficacy in comparison to BIO with a pronounced effect on GBM40 edge cell populations. Anti-migratory effects over 72 hours in GBM40 edge (24h, 10.74% p=0.04; 48h, 6.52% p=0.06, 72h, 4.26% p=0.06) in comparison to the control were observed; BIO (5 µM) significantly reduced migration over 72 hours (24h, 12.79% p<0.001; 48h 5.43% p<0.001; 72h 4.26% p<0.001). Immunofluorescence assays revealed cytoskeletal rearrangements; cells treated with VTIND42 showed an increased ratio of cells with stress fibres to cortical fibres and elongated cells.

Discussion
VTIND42 displayed increased efficacy in comparison to BIO, further investigations will determine its potential as a bioavailable anti-migratory drug for glioblastoma treatment potentially improving disease outcome in patients.
Cholesterol protects glioblastoma cells against premature mitosis
Authors: Gomez-roman Natividad , Jackson Mark , Chalmers Anthony J 
Published: October 2019

Abstract
Glioblastoma is the most common malignant primary tumour with a dismal prognosis. So far, no inhibitors targeting frequently altered pathways in GBM have improved patient survival. Premature entry to mitosis by small molecules that promote cancer cells to bypass the cell-cycle checkpoints have shown potent anti-tumour activity in vitro in a variety of cancers including GBM. We have reproduced these cytotoxic effects in our patient-derived GBM cell lines with the small molecule ME-344 and the Wee1-specific inhibitor AZ1775 both by by clonogenic survival and cell viability assays (EC50 values ranging from 0.003–0.02 μM and 0.2–0.4 μM, respectively). ME-344 and AZ1775 triggered profound morphological and cell cycle effects including mitotic induction, arrest and mitotic catastrophe. Bioinformatic analysis of global mRNA expression of our GBM cell lines stratified by ME-344 sensitivity showed a correlation between high ABCA1 and low cholesterol pathway gene expression with high sensitivity, and vice-versa. Cholesterol is a main component of membranes and is critical for cell growth and mitosis progression. GBM cells rely on cholesterol for survival. Due to the unique metabolic environment of the brain where a nearly unlimited supply of cholesterol is provided by astrocytes, targeting cellular activities regulated by cholesterol might lose their anti-tumour activity. Here we report that cholesterol confers cytoprotection to AZ1775 and ME344 in all GBM cell lines tested. These results suggest that cholesterol can override premature mitotic anti-tumour activity, indicating that mitotic induction and cholesterol inhibition might be a better therapeutic strategy for GBM than either treatment alone.