bluuebunny/crossref_metadata_2025 huggingface dataset:
Family Life Courses, Gender, and Mid-Life Earnings
Authors: Jalovaara Marika , Fasang Anette Eva
Published: October 2019

There is a long-standing debate on whether extensive Nordic family policies have the intended equalizing effect on family and gender differences in economic outcomes. This article compares how the combination of family events across the life course is associated with annual and accumulated earnings at mid-life for men and women in an egalitarian Nordic welfare state. Based on Finnish register data (N = 12,951), we identify seven typical family life courses from ages 18 to 39 and link them to mid-life earnings using sequence and cluster analysis and regression methods. Earnings are highest for the most normative family life courses that combine stable marriage with two or more children for men and women. Mid-life earnings are lowest for unpartnered mothers and never-partnered childless men. Earnings gaps by family lives are small among women but sizeable among men. Gender disparities in earnings are remarkably high, particularly between men and women with normative family lives. These gaps between married mothers and married fathers remain invisible when looking only at motherhood penalties. Results further highlight a large group of (almost) never-partnered childless men with low earnings who went largely unnoticed in previous research.
Gravity and magnetic field interpretation to detect deep buried paleobasinal fault lines contributing to intraplate earthquakes: a case study from Pohang Basin, SE Korea
Authors: Choi Sungchan , Ryu In-Chang , Lee Young-Cheol , Son Yujin
Published: October 2019

Potential field interpretation is a powerful method to locate deep buried tectonic fault lines that contribute to intraplate earthquakes. A magnitude 5.4 earthquake (2017, M5.4_PO) occurred in the Middle-Miocene Pohang Basin (PB), SE of the Korean Peninsula on 15 November 2017, in the area where no fault lines appear on geological and tectonic maps. To constrain fault locations, we calculate the gravity effect of the current basin fill with a gravity stripping method and used curvature analysis to identify former geological and tectonic structures, assumed formed in the Early-Miocene. The Early-Miocene PB is divided into two subregions (northern- and southern sub-basins) by a modelled NW–SE fault line, similar to the other Early-Miocene basins (e.g. Eoil basin). Fault line trends are NE–SW in the northern sub-basin, and NNE–SSW in the southern sub-basin. 2017M5.4_PO arose from a tectonic movement along the eastern boundary of the northern sub-basin, the cross-over area from the isolated high-magnetic/low-gravity region to low-magnetic/high-gravity region. The largest aftershock of the 2017M5.4_PO occurred along the NW–SE fault line bordering the northern- and southern sub-basin.
A unilateral pelvic kidney with variant vasculature: clinical significance
Authors: Gencheva Ralitsa , Gibson Bryce , Garugu Shruthi , Forrest Anthony , Sakthi-Velavan Sumathilatha
Published: October 2019

The incidence of ectopic pelvic kidney accounts for ~1 of 2500 live births. Although pelvic kidneys are most often asymptomatic, they may be associated with several pathologies including hypertension. As pelvic kidney results from a brief interference of the ascension of the developing kidney, it is frequently accompanied by an atypical and variable blood supply. The presence of multiple arteries and veins and their abnormal course and morphology are associated with surgical and radiological significance. Malrotation of the kidney with extrarenal calyces further predisposes the pelvic kidney to recurrent urinary tract infections. This report describes a rare case of a unilateral pelvic kidney with vascular and calyceal variations, and this case is reported to provide additional insight into this variation and its correlation to clinical practice.
Local Hole revisited: evidence for bulk motions and self-consistent outflow
Authors: Shanks T , Hogarth L M , Metcalfe N , Whitbourn J
Published: October 2019

We revisit our mapping of the ‘Local Hole’, a large underdensity in the local galaxy redshift distribution that extends out to redshift z ≈ 0.05 and a potential source of outflows that may perturb the global expansion rate and thus help mitigate the present ‘H0 tension’. First, we compare local peculiar velocities measured via the galaxy average redshift–magnitude Hubble diagram, $\overline{z}(m)$, with a simple dynamical outflow model based on the average underdensity in the Local Hole. We find that this outflow model is in good agreement with our peculiar velocity measurements from $\overline{z}(m)$ and not significantly inconsistent with Type Ia supernova peculiar velocity measurements from at least the largest previous survey. This outflow could cause an ≈2–3 per cent increase in the local value of Hubble’s constant. Second, considering anisotropic motions, we find that the addition of the outflow model may improve the $\overline{z}(m)$ fit of a bulk flow where galaxies are otherwise at rest in the Local Group frame. We conclude that the Local Hole plus neighbouring overdensities such as the Shapley Supercluster may cause outflow and bulk motions out to ≈150 h−1 Mpc that are cosmologically significant and that need to be taken into account in estimating Hubble’s constant.
Periodic orbits of the retrograde coorbital problem
Authors: Morais M H M , Namouni F
Published: October 2019

Asteroid (514107) Ka‘epaoka‘awela is the first example of an object in the 1/1 mean motion resonance with Jupiter with retrograde motion around the Sun. Its orbit was shown to be stable over the age of the Solar system, which implies that it must have been captured from another star when the Sun was still in its birth cluster. Ka‘epaoka‘awela orbit is also located at the peak of the capture probability in the coorbital resonance. Identifying the periodic orbits that Ka‘epaoka‘awela and similar asteroids followed during their evolution is an important step towards precisely understanding their capture mechanism. Here, we find the families of periodic orbits in the two-dimensional retrograde coorbital problem and analyse their stability and bifurcations into three-dimensional periodic orbits. Our results explain the radical differences observed in 2D and 3D coorbital capture simulations. In particular, we find that analytical and numerical results obtained for planar motion are not always valid at infinitesimal deviations from the plane.
Architectures of exoplanetary systems – I. A clustered forward model for exoplanetary systems around Kepler’s FGK stars
Authors: He Matthias Y , Ford Eric B , Ragozzine Darin
Published: October 2019

Observations of exoplanetary systems provide clues about the intrinsic distribution of planetary systems, their architectures, and how they formed. We develop a forward modelling framework for generating populations of planetary systems and ‘observed’ catalogues by simulating the Kepler detection pipeline (SysSim). We compare our simulated catalogues to the Kepler DR25 catalogue of planet candidates, updated to include revised stellar radii from Gaia DR2. We constrain our models based on the observed 1D marginal distributions of orbital periods, period ratios, transit depths, transit depth ratios, transit durations, transit duration ratios, and transit multiplicities. Models assuming planets with independent periods and sizes do not adequately account for the properties of the multiplanet systems. Instead, a clustered point process model for exoplanet periods and sizes provides a significantly better description of the Kepler population, particularly the observed multiplicity and period ratio distributions. We find that $0.56^{+0.18}_{-0.15}$ of FGK stars have at least one planet larger than 0.5R⊕ between 3 and 300 d. Most of these planetary systems ($\sim 98{{\ \rm per\ cent}}$) consist of one or two clusters with a median of three planets per cluster. We find that the Kepler dichotomy is evidence for a population of highly inclined planetary systems and is unlikely to be solely due to a population of intrinsically single planet systems. We provide a large ensemble of simulated physical and observed catalogues of planetary systems from our models, as well as publicly available code for generating similar catalogues given user-defined parameters.
Secondary CMB temperature anisotropies from magnetic reheating
Authors: Saga Shohei , Ota Atsuhisa , Tashiro Hiroyuki , Yokoyama Shuichiro
Published: October 2019

Spatially fluctuating primordial magnetic fields (PMFs) inhomogeneously reheat the Universe when they dissipate deep inside the horizon before recombination. Such an energy injection turns into an additional photon temperature perturbation. We investigate secondary cosmic microwave background (CMB) temperature anisotropies originated from this mechanism, which we call inhomogeneous magnetic reheating. We find that it can bring us information about non-linear coupling between PMFs and primordial curvature perturbations parametrized by bNL, which should be important for probing the generation mechanism of PMFs. In fact, by using current CMB observations, we obtain an upper bound on the non-linear parameter as log (bNL(Bλ/nG)2) ≲ − 36.5nB − 94.0 with Bλ and nB being a magnetic field amplitude smoothed over λ = 1 Mpc scale and a spectral index of the PMF power spectrum, respectively. Our constraints are far stronger than a previous forecast based on the future CMB spectral distortion anisotropy measurements because inhomogeneous magnetic reheating covers a much wider range of scales, i.e. 1 Mpc−1 ≲ k ≲ 1015 Mpc−1.
Constraining ν-process production of fluorine through cosmic ray nucleosynthesis
Authors: Olive Keith A , Vangioni Elisabeth
Published: October 2019

Fluorine is massive enough that it is not considered to be a light (Z ≤ 5) element, yet compared to its near neighbours, C, N, O, and Ne, it is far underproduced in the course of stellar evolution, making its origin more complex. In fact, the abundance of fluorine is the lowest among all elements between Z = 5 and 21 and is roughly 3–4 orders of magnitude below that of C, N, O, and Ne. There are several plausible sources for F beyond standard stellar evolution. These include the production in the asymptotic giant branch phase (AGB) in intermediate-mass stars, production in Wolf–Rayet stars, and the production through neutrino spallation in supernovae. The latter, known as the ν-process, is an important source for 11B, and may contribute to the abundance of 7Li as well. We combine a simple model of Galactic chemical evolution with a standard Galactic cosmic ray nucleosynthesis model to treat self-consistently the evolution of the Li, Be, and B isotopes. We include massive star production of F, as well as contributions from AGB stars, and the ν-process. Given the uncertainties in neutrino energies in supernovae, we normalize the ν-process using the observed 11B/10B ratio as a constraint. As a consequence, we are able to determine the relative importance of each contribution to the F abundance. We find that although the ν-process dominates at early times (low metallicity), the present-day F abundance is found to originate primarily from AGB stars.
LnCeVar: a comprehensive database of genomic variations that disturb ceRNA network regulation
Authors: Wang Peng , Li Xin , Gao Yue , Guo Qiuyan , Ning Shangwei , Zhang Yunpeng , Shang Shipeng , Wang Junwei , Wang Yanxia , Zhi Hui , Fang Ying , Shen Weitao , Zhang Guangmei , Chen Steven Xi , Li Xia
Published: October 2019

LnCeVar (http://www.bio-bigdata.net/LnCeVar/) is a comprehensive database that aims to provide genomic variations that disturb lncRNA-associated competing endogenous RNA (ceRNA) network regulation curated from the published literature and high-throughput data sets. LnCeVar curated 119 501 variation–ceRNA events from thousands of samples and cell lines, including: (i) more than 2000 experimentally supported circulating, drug-resistant and prognosis-related lncRNA biomarkers; (ii) 11 418 somatic mutation–ceRNA events from TCGA and COSMIC; (iii) 112 674 CNV–ceRNA events from TCGA; (iv) 67 066 SNP–ceRNA events from the 1000 Genomes Project. LnCeVar provides a user-friendly searching and browsing interface. In addition, as an important supplement of the database, several flexible tools have been developed to aid retrieval and analysis of the data. The LnCeVar–BLAST interface is a convenient way for users to search ceRNAs by interesting sequences. LnCeVar–Function is a tool for performing functional enrichment analysis. LnCeVar–Hallmark identifies dysregulated cancer hallmarks of variation–ceRNA events. LnCeVar–Survival performs COX regression analyses and produces survival curves for variation–ceRNA events. LnCeVar–Network identifies and creates a visualization of dysregulated variation–ceRNA networks. Collectively, LnCeVar will serve as an important resource for investigating the functions and mechanisms of personalized genomic variations that disturb ceRNA network regulation in human diseases.
The PATRIC Bioinformatics Resource Center: expanding data and analysis capabilities
Authors: Davis James J , Wattam Alice R , Aziz Ramy K , Brettin Thomas , Butler Ralph , Butler Rory M , Chlenski Philippe , Conrad Neal , Dickerman Allan , Dietrich Emily M , Gabbard Joseph L , Gerdes Svetlana , Guard Andrew , Kenyon Ronald W , Machi Dustin , Mao Chunhong , Murphy-Olson Dan , Nguyen Marcus , Nordberg Eric K , Olsen Gary J , Olson Robert D , Overbeek Jamie C , Overbeek Ross , Parrello Bruce , Pusch Gordon D , Shukla Maulik , Thomas Chris , VanOeffelen Margo , Vonstein Veronika , Warren Andrew S , Xia Fangfang , Xie Dawen , Yoo Hyunseung , Stevens Rick
Published: October 2019

The PathoSystems Resource Integration Center (PATRIC) is the bacterial Bioinformatics Resource Center funded by the National Institute of Allergy and Infectious Diseases (https://www.patricbrc.org). PATRIC supports bioinformatic analyses of all bacteria with a special emphasis on pathogens, offering a rich comparative analysis environment that provides users with access to over 250 000 uniformly annotated and publicly available genomes with curated metadata. PATRIC offers web-based visualization and comparative analysis tools, a private workspace in which users can analyze their own data in the context of the public collections, services that streamline complex bioinformatic workflows and command-line tools for bulk data analysis. Over the past several years, as genomic and other omics-related experiments have become more cost-effective and widespread, we have observed considerable growth in the usage of and demand for easy-to-use, publicly available bioinformatic tools and services. Here we report the recent updates to the PATRIC resource, including new web-based comparative analysis tools, eight new services and the release of a command-line interface to access, query and analyze data.
ClinVar: improvements to accessing data
Authors: Landrum Melissa J , Chitipiralla Shanmuga , Brown Garth R , Chen Chao , Gu Baoshan , Hart Jennifer , Hoffman Douglas , Jang Wonhee , Kaur Kuljeet , Liu Chunlei , Lyoshin Vitaly , Maddipatla Zenith , Maiti Rama , Mitchell Joseph , O’Leary Nuala , Riley George R , Shi Wenyao , Zhou George , Schneider Valerie , Maglott Donna , Holmes J Bradley , Kattman Brandi L
Published: October 2019

ClinVar is a freely available, public archive of human genetic variants and interpretations of their relationships to diseases and other conditions, maintained at the National Institutes of Health (NIH). Submitted interpretations of variants are aggregated and made available on the ClinVar website (https://www.ncbi.nlm.nih.gov/clinvar/), and as downloadable files via FTP and through programmatic tools such as NCBI’s E-utilities. The default view on the ClinVar website, the Variation page, was recently redesigned. The new layout includes several new sections that make it easier to find submitted data as well as summary data such as all diseases and citations reported for the variant. The new design also better represents more complex data such as haplotypes and genotypes, as well as variants that are in ClinVar as part of a haplotype or genotype but have no interpretation for the single variant. ClinVar's variant-centric XML had its production release in April 2019. The ClinVar website and E-utilities both have been updated to support the VCV (variation in ClinVar) accession numbers found in the variant-centric XML file. ClinVar's search engine has been fine-tuned for improved retrieval of search results.
Targeting brain tumours: apoferritin nanocage for delivery of novel analogues of temozolomide
Authors: Bouzinab Kaouthar , Thomas Neil R , Turyanska Lyudmila , Gershkovich Pavel , Weston Nicola , Ashford Marianne B , Bradshaw Tracey D
Published: October 2019

Treatment for glioblastoma multiforme (GBM) consists of surgery, radiotherapy and temozolomide (TMZ) chemotherapy. Nevertheless, patient prognosis remains poor; in England 5-year survival is < 10%. Resistance to TMZ is a major obstacle thwarting successful treatment, due to overexpression of the O6-methylguanine DNA-methyltransferase (MGMT) and deficiency in mismatch repair (MMR). To overcome resistance, novel N3-substituted analogues of TMZ have been developed. An N3-propargyl analogue, T3, has promising activity irrespective of MGMT or MMR status. However, poor brain drug bioavailability and systemic toxicity remain to be resolved. We use apoferritin (AFt) as a biocompatible nano-delivery system for encapsulation of therapeutic agents via molecular diffusion, through channels in the AFt cage. Around 520 molecules of TMZ and T3 per AFt cage were encapsulated. AFt`s small size (diameter: 12 nm) and numerous transferrin receptor recognition sites on its surface; alongside enhanced expression of transferrin receptors (TfR1; which sequester AFt) on the membranes of cancer cells, offer a dual targeting approach towards greater cancer-selectivity. The encapsulated agents have demonstrated significantly increased anti-tumour activity in brain cancer GBM cell lines, U373V (vector control) and U373M (MGMT over-expressing), with growth inhibition GI50 values < 1 μM, compared to > 30 μM for naked drugs. Clonogenic and cell cycle analyses further corroborate these findings. Hence, the AFt nano-delivery system offers a promising route for enhanced specificity, selectivity and potency of TMZ analogues.
Advanced molecular characterization using Digital Spatial Profiling Technology on immuno-oncology targets in methylated compared with unmethylated IDH-wildtype glioblastoma
Authors: Barber Hannah , Lander Beatrice , Daniels Aled , Tofias Antonis , Jing Gong Jing , Ren Yuqi , Ren Xing , Liang Yan , White Paul , Kurian Kathreena M
Published: October 2019

Introduction

Glioblastoma (GBM) is the most common primary adult brain tumour with 12–15 months median overall survival. Molecular characterization of multiple immuno-onology targets in GBM is required to optimise immunotherapeutic strategies. Advanced molecular characterisation using Digital Spatial Profiling Technology allows assessment of multiple immuno-oncology protein targets in methylated compared with unmethylated Glioblastoma IDH-wildtype.

Methods

Nanostring DSP uses multiple primary antibodies conjugated to indexing DNA oligos with a UV photocleavable linker. Tissue Regions of interest (ROI) are selected with bound fluorescent antibodies, oligos are released via a UV-mediated linker and quantitated. We used DSP multiplex analysis of 31 immuno-oncology proteins and controls (PD-1, PD-L1, B7-H3, VISTA, CD45, CD45RO, CD3, MS4A1 (CD20), CD4, CD8A, CD68, STAT3, STAT3 (Phopshory705), GZMB, Beta-2-microglobulin, CD56, Beta-catenin, FOXP3, CD14, CD19, AKT, P-AKT, PTEN, Bcl-2, CD44, Histone H3, S6, IgG Rabbit Control, Mouse IgG Control, Pan-Cytokeratin, Ki67) from ROIs in a cohort of 10 Glioblastomas IDH-wildtype (5 methylated, 5 unmethylated). An nCounter platform allowed quantitative comparisons of antibodies between ROIs in MGMT methylated and unmethylated tumours. Mean protein expression counts between methylated and unmethylated GBM were compared using a linear mixed effect model for technical and biological replicates.

Results

GeoMx DSP showed 10/27 immuno-oncology target proteins were significantly increased in methylated versus unmethylated Glioblastoma IDH-wildtype (false discovery rate FDR <0.1 by Benjamini-Hocheberg Procedure).

Conclusions

Increased immuno-oncology protein target expression in methylated versus unmethylated glioblastoma IDH-wildtype using DSP platform has been identified. Advanced multiplex immuno-oncological biomarker analysis is required to identify predictive biomarkers for novel immunotherapeutic agents in GBMs.
Ketogenic diet and metabolic regulation of brain microglia
Authors: Benito Adrian , Hajji Nabil , O’Neill Kevin , Keun Hector C , Syed Nelofer
Published: October 2019

Ketogenic diet (KD) has been proposed as a coadjuvant therapy in the treatment of brain tumours. Reduction of blood glucose and increase in ketone bodies concentration are amongst the most important changes induced by KD in patients. Preliminary data collected in our lab indicates that KD induces substantial changes in the immune system in mice bearing brain tumours. Microglia are brain-resident immune cells that account for around 30% of the tumour mass and play a major role in controlling tumour progression by adopting a protumour (M2 polarisation) or antitumour (M1 polarisation) phenotype. We are interested in understating the molecular and metabolic determinants of microglia polarisation and how these can be modulated by the metabolic microenvironment and KD. We report some initial findings that indicate microglia adapt to changes in the metabolic microenvironment and that nutrient availability can modulate microglia activation and polarisation. We believe that the study of microglia metabolism and nutritional interventions like KD can provide new knowledge about the regulation of the brain immune system and unveil novel routes for brain cancer treatment.
Choroid plexus papillomas are induced by c-Myc overexpression in the choroid plexus via a T-cell inflammatory mechanism
Authors: Merve Ashirwad , Zhang Xinyu , Pomella Nicola , Acquati Serena , Hoeck Joerg , Dumas Anaelle , Rosser Gabriel , Li Yichen , Jeyapalan Jennie , Vicenzi Silvia , Sabò Arianna , Sheer Denise , Behrens Axel , Marino Silvia
Published: October 2019

Choroid plexus tumours (CPT) account for up to 20% of brain tumours in children under 2 years of age. Histologically CPTs are classified into three categories - Choroid Plexus Papilloma (CPP), Atypical Choroid Plexus Papilloma (ACPP) and Choroid Plexus Carcinoma (CPC). Recent literature demonstrates that CPP and ACPP are molecularly distinct from CPC. Initial management for CPT include surgery followed by adjuvant therapy in selected patients. Currently there are no disease-specific chemotherapeutic agents available, possibly because of their rarity and paucity of faithful pre-clinical experimental models.

In this study we show that c-Myc overexpression in the choroid plexus epithelium induces T-cell inflammation-dependent choroid plexus papillomas in a mouse model. We demonstrate that c-MYC is expressed in a substantial proportion of human choroid plexus tumours and that this subgroup of tumours is characterised by an inflammatory transcriptome and significant inflammatory infiltrates. We observed that triple transgenic compound mutant mouse model with c-Myc overexpression in an immune-suppressed background led to a decreased incidence of CPP and reduced tumour bulk. A reduced tumour size was also observed when c-Myc overexpressing mice were treated with anti-CD3 antibodies.

Our data raise the possibility that benign choroid plexus tumours expressing c-MYC could be amenable to medical therapy with anti-inflammatory drugs.
Reliability of DCE MRI data in primary brain tumours: a comparison of Tofts and Shutter Speed Models
Authors: Inglese Marianna , Honeyfield Lesley , Aboagye Eric , Waldman Adam , Grech-Sollars Matthew
Published: October 2019

The accuracy of quantitative measurements of perfusion parameters by DCE-MRI is crucial as it can significantly impact the clinical care of cancer patients. In this study, we provide a method to identify reliable DCE-MRI brain data for perfusion quantification with different pharmacokinetic models.

We analysed DCE-MRI data of 14 patients with primary brain tumours using the Tofts model (TM), the extended-Tofts model (ETM), the shutter speed model (SSM) and the extended shutter speed model (ESSM). Due to the presence of the blood brain barrier, which can block the leakage of the CA into the interstitium, we also implemented the no-exchange model (NEM). For each lesion, we produced a 3D model selection map with the evaluation of the Akaike Information Criteria. The variability of each pharmacokinetic parameter extracted from the fitting of the model of choice was assessed with a noise propagation procedure, resulting in distributions of the coefficient of variation (CV).

Results showed the NEM to be the most frequent model of choice (35.5%), followed by the ETM (32%), the TM (28.2%), the SSM (4.3%) and the ESSM (<0.1%). In analysing the reliability of Ktrans, when considering regions with a CV<20%, ≈25% of voxels were found to be stable. The remaining 75% of voxels were considered to be unreliable.

In conclusion, an appropriate model selection, considering tissue biology and its effects on BBB permeability and exchange conditions, together with an analysis on the reliability and stability of the calculated parameters, is critical in the identification of reliable brain DCE-MRI data.
Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exhibit single agent therapeutic activity and sensitize glioblastoma cells to ionizing radiation
Authors: Jackson Mark , Gomez-Roman Natividad , Chalmers Anthony
Published: October 2019

Objective

The lack of an effective therapy for glioblastoma (GBM) largely results from the intrinsic resistance of GBM cells. The radiosensitizing activity of inhibitors of poly(ADP-ribose) polymerases (PARPs) highlights the important role of poly(ADP-ribose) (PAR) in the DNA damage response. In contrast to PARPs, inhibition of poly(ADP-ribose) glycohydrolase (PARG), the enzyme responsible for degrading PAR chains, has shown single agent therapeutic activity in non-glioma cancer cells. This work aims to validate the therapeutic potential of PARG inhibitors (PARGi) in GBM.

Results

Baseline PAR levels were found to vary between different primary and commercial GBM cells, with PARylation increasing upon exposure of cells to ionizing radiation (IR), as expected. Target engagement of a novel PARGi, PDD00017273, was confirmed by the accumulation of nuclear PAR in treated cells. Inhibitor specificity was demonstrated using an inactive control compound and by combining PARGi with the PARP inhibitor olaparib, which blocked the effect. Single agent treatment with PARGi reduced the clonogenic survival of GBM cells in a concentration-dependent manner. Importantly, PARGi also sensitized GBM cells to IR (sensitizer enhancement ratios, SER, ≥ 1.40)

Conclusion

In contrast to PARP inhibitors, novel PARGi exhibit single agent activity against a panel of GBM cell lines, and also show robust radiosensitizing activity. PARGi therefore have therapeutic potential in this cancer of unmet need.
Role of diffusional kurtosis imaging in grading of brain gliomas: A diagnostic test accuracy systematic review and meta-analysis
Authors: Abdalla Gehad , Sanverdi Eser , Machado Pedro M , Kwong Joey S W , Panovska-Griffiths Jasmina , Rojas-Garcia Antonio , Yoneoka Daisuke , Yousry Tarek , Bisdas Sotirios
Published: October 2019

Aim and objectives

We aim to illustrate the diagnostic performance of diffusional kurtosis imaging (DKI) in the diagnosis of gliomas.

Methods and materials

A review protocol was developed according to the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P), registered in the international prospective register of systematic reviews, PROSPERO and published. Literature search in 4 databases was performed using the keywords “glioma” and “diffusional kurtosis”.After applying a robust inclusion/exclusion criteria, included articles were independently evaluated according to the QUADAS-2 tool.Data extraction was done in a pre-designed pro forma.Reported sensitivities and specificities were used to construct 2x2 tables and paired forest plots using the Review Manager (RevMan®) software.Random-effect model was pursued using the hierarchical summary receiver operator characteristics.

Results

Initially, 216 hits were retrieved. Considering duplicates and inclusion criteria; 23 articles were eligible for full-text reading. Ultimately, 19 studies were deemed to be eligible for final inclusion. Quality assessment revealed 9 studies with low risk of bias in the 4 domains. Using a bivariate random-effect model for data synthesis; summary ROC curve showed pooled area under the curve (AUC) of 0.92 and estimated sensitivity of 0.87 (95% CI: 0.78 - 0.92) in high/low grade gliomas’ differentiation.A mean difference in Mean Kurtosis (MK) value between HGG and LGG of 0.22 [95% CI: 0.25 - 0.19] was illustrated (p value = 0.0014) and a moderate degree of heterogeneity (I²= 73.8%).

Conclusion

DKI shows good diagnostic accuracy in high/low grade gliomas’ differentiation; which might qualify it to be part of the routine clinical practice, however; further evidence is deemed for technique standardization.
Use of pre-treatment MRI scans to predict toxicity from radiotherapy in patients with Glioblastoma (GB)
Authors: Gill Ramandeep , Mills Samantha , Chalmers Anthony , Lorimer Cressida
Published: October 2019

Median life expectancy of patients with Glioblastoma (GB) is 24.4 weeks. Current best treatment involves concurrent use of Temozolomide and radiotherapy. However, toxicity from radiotherapy can limit patient benefit. The objective of this study was to determine the ability of pre-treatment MRI scans of the brain to predict radiotoxicity.

This pilot study collected survival and toxicity data from 10 patients aged 65 years or older with a histopathological or radiological diagnosis of GB. Brain MRI scans were used to collect information on tumour characteristics alongside imaging scoring systems to assess medial temporal lobe atrophy, global cortical atrophy and small vessel disease. Scans were analysed by two independent readers.

Median survival for this cohort was 35.2 weeks (range 19–59.3 weeks). The beta correlation scores for total contralateral white matter score, global cortical atrophy and T1 contrast volume and survival were all found to equal 1. Beta-correlation coefficients for microanatomical rating score and Schelten’s medial temporal atrophy score were 0.4 and 0.9 respectively. The sum of CTCAE scores for nausea, fatigue and confusion was calculated to provide an overall toxicity score. The mean beta-correlation co-efficient for all scores against toxicity was 1. Use of Bland-Altmann plots showed significant inter-rater reliability for all scores excluding global cortical atrophy. Results from this study suggest a moderate relationship between scan characteristics and increasing toxicity. However, high inter-rater reliability suggests these scoring systems have the potential to be used accurately in clinical practice. A larger study will be conducted to confirm results from this study.
Survival of patients with melanoma metastatic brain metastases in the era of novel systemic therapies in Cardiff, Wales
Authors: Pasquale Joseph , Ocen Joanita , Powell James , Kumar Satish
Published: October 2019

The incidence of malignant melanoma (MM) is increasing in the UK; it’s projected to rise by 7% by 2035. MM has high predisposition to developing brain metastases (BM) with 50–60% of patients being affected. Stereotactic radiosurgery (SRS) and surgery, key interventions in managing patients with BM, have been shown to improve survival outcomes of patients. Patients’ prognosis and survival has also significantly improved with the advent of novel therapies in the last few years. It was noted that the Cardiff Neuro-Oncology multidisciplinary team were receiving increasing amount of referrals for consideration of surgery or SRS in patients with MM. 106 MDT referrals were retrospectively reviewed. 31 patients had surgery, 20 patients had SRS and the remaining 54 patients had WBRT. There was no significant difference in the patient distribution. The majority of patients had 1 brain lesion in both groups (in similar proportions). The 12 month survival for the surgical cohort was 65% for immunotherapy group, 55%- targeted therapy and 30%- no therapy. For the SRS group the 12 month survival for immunotherapy was 45%, targeted therapy- 40% and 20%- no therapy. The median OS for surgery versus SRS was 8 and 7 months respectively. The results suggest that simultaneous treatment with surgery or SRS in conjunction with SACT does improve survival. Interpretation of results will have to be taken with caution due to the retrospective nature and the small sample size. Going forward, we will delve deeper and review local progression rates and SACT timing/sequencing in our practice.
Exploring the lived experience of a high grade glioma
Authors: Soni Shivani , Williamas Matthew , Lannie Antonia
Published: October 2019

Introduction

Brain tumour patients face a variety of challenges during diagnosis and treatment. Although most treating clinicians are familiar with these, it can be difficult to obtain a comprehensive overview of which are the most common problems, which patients they affect and how to address them.

Methods

We conducted a systematic review of all work relating to the lived experience of patients and carers of a glioblastoma. We identified articles published between 2008 and 2018 these had to be published in English, using the search terms cares and patients, lived experience, glioblastoma and perspective with relative alternative terms. We excluded articles that were previous systematic reviews, included low grade/brain metastasis from another primary site and articles that combined results for patients and carers. We extracted key theme and concerns, and summarised and tabulated and developed a discussion/recommendation.

Results

We identified 405 potential studies. We rejected 374 after screening abstract and titles, and a further 23 on further review. This left a set of 8 unique publications. The 8 publications included were comprised of qualitative studies that explored patient and carers experience at different points in the patient pathway. The main concerns/themes identified were issues around communication specifically the shock of diagnosis, re-negotiating relationships and finally accessing support.

Conclusions

This is the first systematic review that collates the lived experience of patients with high grade gliomas. It differs from the palliative care literature and from the James Lind Alliance, and is more specific than generic health needs assessments that are being used in practice.
Contrasting multidisciplinary clinic follow up for patients with high and low grade glioma.
Authors: Critchley Giles , Bucur Sorin , Walsh Gill , Smith Ruth , Creak Antonia , Brock Juliet
Published: October 2019

Patients with high grade glioma (HGG) and low grade glioma (LGG) may enter a period of stability in their disease when surveillance is required; during this time they often require different forms of support. We describe two different multidisciplinary clinics approaches to patients with gliomas, both of which are linked to the relevant multidisciplinary meetings (MDMs).

Since 1987 the ‘joint glioma clinic’ (HGG clinic) has been run with a neurosurgeon, neurooncologist and clinical nurse specialist seeing patients and their carers in one room. Patients under surveillance undergo MRI scans and if there is evidence of recurrence then an immediate discussion can be held with the patient regarding options for further management.

Since 2011 the Low grade glioma clinic (LGG clinic) has run with a multi room model. There are two neurosurgeons, a neurooncologist, a neuroradiologist, a neuropsychologist, a neurologist and a clinical nurse specialist present who discuss patients in a MDM. Subsequently a patient may then see one or more of the team in sequence in different rooms as needed. This allows issues such as epilepsy, neuropsychology, treatment options and surveillance intervals to be discussed with patients at one visit.

There is a cohort of 106 patients under surveillance in the HGG joint glioma clinic and 270 patients in the LGG clinic.

We believe a single visit can minimize the impact of the disease and provide different forms of support a needed. Both models allow rapid decision making when the period of surveillance ends due to transformation or recurrence.
The Glioma Elephant in The Room
Authors: Davis Charles
Published: October 2019

Radiotherapy is the most effective treatment of glioblastoma, radical surgery and chemotherapy will help some patients. Tumour Treating Fields (TTF) is used in many countries in the developed world. Thousands of patients have been treated.

Methods

A survey at a neuro-oncology meeting of clinicians, scientists and charity members asking them about TTF.

Results

1. 7 out of 8 clinicians did not discuss TTF with patients.: 2. The reasons being “not available”, “very expensive”, “don’t know enough”.: 3. Out of 17 non clinicians, 14 stated that TTF should be discussed with all patients.: 4. Out of 22 clinicians and non clinicians, 16 said they would consider trying to raise £200.000 for treatment from crowd funding.

Discussion

The report of the chief scientific officer of the department of health on brain tumours, the report of the Tessa Jowell funding, BNOS, do not discuss TTF.?why. NICE guidelines for NHS patients state “Do not offer TTF” but do not say “Do not discuss”.

Conclusion

Sadly, clinicians are not telling the patients about options for treatment. TTF is controversial and expensive and is now being used in several cancer treatments. The UK is one of the few developed countries that is not researching or discussing this treatment.
The impact of the neuro-oncology research radiographer role in the effective facilitation of an advanced imaging study in glioblastoma
Authors: Fernandez Sharon , Murray Louise , Scarsbrook Andrew , Broadbent David , Shelley David , Currie Stuart , Short Susan
Published: October 2019

Background

A neuro-oncology research radiographer was included in the multi-disciplinary study team (MDT) from the set-up stage of a new advanced imaging study in glioblastoma, as it was envisaged that this would enhance progress and provide better patient-centred care.

Aims

This pilot study aimed to include 12 participants. This specialist radiographer role was to support recruitment, co-ordinate appointments and monitor patients’ progress. We aimed to ensure that optimal treatment and patient-centred care remained at the forefront of the study pathway.

Method

Patients were identified and approached by the radiographer prior to consent by a trial investigator. Additional scans were planned prior to radiotherapy (RT), 2 weeks into RT and 6 weeks post RT. The radiographer ensured streamlined appointments and was present during each study visit to liaise with health professionals, provide a specific point of contact with the patient and to ensure continuity.

Results

6 patients have been recruited since November 2018. The specialist radiographer has attended 28 study scans to date. Over 40 face-to-face interactions have been undertaken, 30 email communications and 18 telephone consultations. Patient feedback has been extremely positive, all patients convey that they feel supported and value continuity throughout the pathway. Enhanced communication across the entire study team has also guaranteed efficient recruitment.

Conclusion

The research radiographer has a key role in the multi-disciplinary team delivering this study. Effective liaison between the radiotherapy and imaging departments has been crucial and patients value a consistent point of contact through the study and treatment pathways.
Cavernous Malformations in and Around the Third Ventricle: Indications, Approaches, and Outcomes
Authors: Woodall M Neil , Catapano Joshua S , Lawton Michael T , Spetzler Robert F
Published: October 2019

BACKGROUND

Cavernous malformations in structures in and around the third ventricle are a challenging conceptual and surgical problem. No consensus exists on the ideal approach to such lesions.

OBJECTIVE

To perform a retrospective review of our institutional database to identify and evaluate approaches used to treat cavernous malformations located in and around the third ventricle.

METHODS

Information was extracted regarding lesion size and location, extent of resection, time to last follow-up, surgical approach, presenting symptoms, preoperative and postoperative neurological status, and specific approach-related morbidity.

RESULTS

All 39 neurosurgical operations (in 36 patients) were either an anterior interhemispheric (AIH) (44%, 17/39) or a supracerebellar infratentorial (SCIT) (56%, 22/39) approach. Gross-total resection was achieved in 23 of 39 procedures (59%), a near-total resection in 1 (3%), and subtotal resection in 15 (38%). For the 31 patients with at least 3 mo of follow-up, the mean modified Rankin Scale (mRS) score was 1.5. Of the 31 patients, 25 (81%) had an mRS score of 0 to 2, 4 had a mRS score of 3 (13%), and 1 each had a mRS score of 4 (3%) or 5 (3%).

CONCLUSION

Most approaches to cavernous malformations in and around the third ventricle treated at our institution have been either an AIH or a SCIT approach. The AIH approach was used for lesions involving the lateral wall of the third ventricle or the midline third ventricular floor, whereas the SCIT approach was used for lesions extending from the third ventricle into the dorsolateral midbrain, with acceptable clinical results.
Differences in the Clinical Characteristics of Persistent Idiopathic Facial Pain (Atypical Odontalgia) Patients with or Without Neurovascular Compression of the Trigeminal Nerve
Authors: Kawasaki Kaoru , Sugawara Shiori , Watanabe Kazuya , Hong Chaoli , Tu Trang Thi Huyen , Watanabe Takeshi , Sakamoto Junichiro , Yoshino Norio , Suga Takayuki , Mikuzuki Lou , Takenoshita Miho , Takada Satoshi , Kurabayashi Tohru , Toyofuku Akira
Published: October 2019

Background

Persistent idiopathic facial pain (PIFP) is the unexplained pain along the territory of the trigeminal nerve, including nonorganic tooth pain called atypical odontalgia (AO). Though PIFP is debilitating to patients’ livelihood and well-being, its pathophysiology remains poorly understood. Although neurovascular compression (NVC) of the trigeminal nerve is known to be associated with trigeminal neuralgia (TN), the relationship between NVC and other orofacial pains has not been fully elucidated.

Methods

In this study, we investigated the differences in the characteristics of PIFP (primarily AO) patients in the presence or absence of NVC. A retrospective analysis was performed on data from 121 consecutive patients who had been diagnosed with unilateral PIFP according to the criteria of the International Classification of Headache Disorders (ICHD)–3 and underwent magnetic resonance imaging scans of the head.

Results

In the group without NVC, characteristic findings were significant for psychiatric morbidity, somatization, and pain disability, when compared with the group with NVC. Furthermore, the group without NVC exhibited significant headache, noncardiac chest pain, shortness of breath, and pain catastrophizing.

Conclusions

These results suggest that PIFP patients can be divided into two groups: one consistent with a neuropathic pain phenotype when NVC is present and a functional somatic symptom phenotype when presenting without NVC. Our findings may enable a more precise understanding of pathophysiology of PIFP and lead to better treatment strategies.
An unbiased high-throughput drug screen reveals a potential therapeutic vulnerability in the most lethal molecular subtype of pancreatic cancer
Authors: Pan Chun-Hao , Otsuka Yuka , Sridharan BanuPriya , Woo Melissa , Babu Sruthi , Leiton Cindy V. , Bai Ji Dong K. , Chang David K. , Biankin Andrew , Scampavia Louis , Spicer Timothy , Escobar-Hoyos Luisa F. , Shroyer Kenneth R.
Published: October 2019

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related deaths in the United States by 2020, due in part to innate resistance to widely used chemotherapeutic agents and limited knowledge about key molecular factors that drive tumor aggression. We previously reported a novel negative prognostic biomarker, keratin 17 (K17), whose overexpression in cancer results in shortened patient survival. In this study, we aimed to determine the predictive value of K17 and explore the therapeutic vulnerability in K17-expressing PDAC, using an unbiased high-throughput drug screen. Patient-derived data analysis showed that K17 expression correlates with resistance to Gemcitabine (Gem). In multiple in vitro models of PDAC, spanning human and murine PDAC cells, we determined that the expression of K17 results in a more than two-fold increase in resistance to Gem and 5-fluorouracil, key components of current standard-of-care chemotherapeutic regimens. Furthermore, through an unbiased drug screen, we discovered that Podophyllotoxin (PPT), a microtubule inhibitor, showed at least two-fold higher sensitivity in K17-expressing compared to K17-negative PDAC cells. In the clinic, another microtubule inhibitor, Paclitaxel (PTX), is used in combination with Gem as a first line chemotherapeutic regimen for pancreatic, breast, lung, and ovarian cancer. Surprisingly, we found that when combined with Gem, PPT but not PTX, was synergistic in inhibiting the viability of K17-expressing PDAC cells. This provides evidence that PPT or its derivatives could potentially be combined with Gem to enhance treatment efficacy for the approximately 50% of PDACs that express high levels of K17. In summary, we reported that K17 is a novel target for developing a biomarker-based personalized treatment for PDAC.
Engineering cooperative patterns in multi-species bacterial colonies
Authors: Curatolo A. I. , Zhou N. , Zhao Y. , Liu C. , Daerr A. , Tailleur J. , Huang J.
Published: October 2019

Self-organization is a hallmark of all living systems [1]. In particular, coordinated cellular behavior, commonly orchestrated at the population level through reciprocal interactions among different cell species [2–4], regulates the spatial arrangement of specialized cell types to generate tissue patterning and form complex body layouts [5, 6]. The overwhelming complexity of living systems, however, makes deciphering the underlying mechanisms difficult and limits our knowledge of basic pattern-forming mechanism in vivo [7, 8]. A successful strategy is then to work with synthetic, engineered systems, in which cellular interactions can be more easily tailored and studied [9–13]. Here, we demonstrate a simple mechanism through which different populations of cells can self-organize in periodic patterns. Programmed population interactions are shown to lead to coordinated out-ofphase spatial oscillations of two engineered populations of Escherichia coli. Using a combination of experimental and theoretical approaches, we show how such patterns arise autonomously from reciprocal density-dependent activation of cellular motility between the two species, without the need of any preexisting positional or orientational cues. Moreover, by re-designing the interaction, the original out-of-phase spatial oscillation rhythm of the two populations can be accordingly turned into in-phase oscillations. The robustness and versatility of the underlying pattern-formation process suggest that it could both be generically encountered in nature, for instance in the complex bacterial ecosystems found in biofilms [14–16], and used to promote the mixing or demixing of active particles in a controlled way.