bluuebunny/crossref_metadata_2025 huggingface dataset:
34 Extent of resection in glioblastoma: Incorporating clinical and molecular data
Authors: Semenchuk Julie , Pitz Marshall , Essig Marco , Lambert Pascal , Galloway Katie
Published: July 2018

Background: The benefits of increasing extent of resection (EOR) for both overall survival and progression-free survival (PFS) in glioblastoma has been well documented. However, models predicting surgical outcomes have failed to incorporate a patient’s IDH status, a known prognostic factor. We isolate the impact of IDH on surgical outcomes. We determine the effect modification of increasing EOR and decreasing residual tumor volume (RTV) on IDH status. Methods: We performed a retrospective cohort study of 98 patients with glioblastoma who had undergone either biopsy or surgical resection. Tumor volumes were determined by volumetric analysis. Univariable and multivariable Cox PH Regression models were built using overall survival and PFS as endpoints. Results: Increasing EOR and decreasing RTV were both associated with prolonged overall survival and PFS. When IDH status was added to multivariable models, the model utilizing RTV provided a slightly better fit compared to EOR. An interaction term between RTV and IDH status was characterized, such that at low RTVs the prognosis of an IDH mutant is significantly better than that of an IDH wild-type, an effect that is less important as RTV increases. The significance of this term was confirmed by improved fit upon insertion into multivariable models. Conclusion: Minimizing RTV and increasing EOR are important prognostic factors for both IDH wild-type and IDH mutant glioblastoma. The protective benefit of the IDH mutation at lower RTVs suggests these patients are the best candidates for aggressive surgical resection.
40 Prognostic significance of PD-L1 expression in meningioma for tumor recurrence; associated with hypoxia and NFKB2 activation
Authors: Karimi Shirin , Suppiah Suganth , Nassiri Farshad , Mamatjan Yasin , Liu Jeff , Zadeh Gelareh , Aldape Kenneth
Published: July 2018

Estimation of tumor recurrence in meningioma patients is one of the important clinical challenges. The prognostic impact of immune modulatorymolecule PD-L1 in several malignancies has been demonstrated. We studied the association of PD-L1 expression in meningioma with tumor recurrence and the underlying mechanism of its activation. Immunohistochemical staining(IHC) was performed for detection of PD-L1and NFKB2 on whole sections of meningiomas diagnosed between1998-2016 at TorontoWesternHospital. The biologic role of hypoxia in activation of PD-L1 in meningioma was investigated using gene set enrichment analysis(GSEA)-based on RNAseq data in validation cohorts. We analyzed a total of 93 meningioma cases: F/M ratio58/35;WHOgrade I(41),II(43),III(9),42(47%)cases with tumor recurrence and median follow up was 6.97yrs. PD-L1 expression on tumor cells(PD-L1TC) in 33(35%) cases was identified with distinctive patchy distribution. Univariate analysis indicated expression of PD-L1TC as a prognostic factor for tumor recurrence(p<0.0001). Multivariate analysis showed that PD-L1TC expression is an independent prognostic factor for tumor recurrence after adjusting for extent of resection(EOR),WHO grade and maximum tumor diameter(p<0.0001). Analysis of RNAseq data of two GEOmeningioma studies demonstrated prominent expression of NFKB activation associated with PD-L1expression. IHC analysis confirmed increased expression of NFKB2 protein in 26(30%)cases,which correlated with PD-L1TC expression(p=0.02). Furthermore,GSEAon a RNAseq data of 88 sporadic meningiomas using Hypoxia gene signature of HUVEC cells we found that the hypoxic sporadic meningiomas have significantly elevated PD-L1 expression(p<0.001). Our data strongly suggest that PD-L1TCexpression serves as a significant prognostic marker for tumor recurrence and. We found that hypoxia andNFKB2 activation are potential underlying mechanisms. These results also provide a rationale for potential adjuvant therapeutic role for PD-L1 inhibitors in meningioma.
47 Preclinical studies of dianhydrogalactitol (VAL-083) in DIPG, as single agent or as a combination with AZD1775 or radiation
Authors: Yang Xiaodong , Steino Anne , Bacha Jeffrey , Brown Dennis , Mueller Sabine
Published: July 2018

Despite decades of trials, the prognosis for diffuse intrinsic pontine gliomas (DIPG) remains dismal. DIPG is inoperable and standard treatment is radiation alone, as the addition of chemotherapeutic agents, such as temozolomide, have not improved survival. In addition to inherent chemoresistance, treatment of DIPG is impeded by an intact blood-brain barrier (BBB). VAL-083 is a structurally unique bi-functional DNA-targeting agent that readily crosses the BBB. VAL-083 forms interstrand DNA crosslinks at N7-guanine, resulting in DNA double-strand breaks (DSB), S/G2-phase cell-cycle arrest, and ultimately cancer cell death. We have previously demonstrated that VAL-083 is able to overcome temozolomide-resistance in vitro and in vivo, and that its cytotoxicity is independent of the DNA-repair enzyme O6-methylguanine DNA-methyltransferase (MGMT). MGMT is almost universally expressed in DIPG and its expression is strongly correlated with temozolomide-resistance. VAL-083’s distinct mechanism-of-action suggests the potential for combination with inhibitors of DNA DSB repair or S/G2 cell-cycle progression (e.g. Wee1 inhibitor AZD1775). Here, we investigated the effects of VAL-083 in combination with radiation, AZD1775 or irinotecan (topoisomerase inhibitor) in three DIPG cell-lines: SF10693 (H3.1), SF8628 (H3.3) and NEM157 (H3.3). VAL-083 showed activity at low uM-concentration in all three cell-lines. In addition, VAL-083 showed synergy with AZD1775 in all three cell-lines. Combined with its ability to cross the BBB, accumulate in brain tumor tissue and overcome MGMT-related chemoresistance, these results suggest VAL-083 as a potentially attractive treatment option for DIPG as single agent or in combination with AZD1775. Combination studies with radiation are ongoing and will be presented at the meeting.
60 Are gangliogliomas in children and adults disorders of nervous system development?
Authors: Jiang Qiang , Zagozewski Jamie , Nozza Paolo , Wilson Beverly , Van Landeghem Frank , Eisenstat David
Published: July 2018

INTRODUCTION: Gangliogliomas (GGs) are neuroepithelial tumours of the central nervous system (CNS) composed of mature ganglion cells or a mixed population of ganglion and glial cells. Microarray data of low grade gliomas (LGG) including GGs revealed overexpression of the Dlx2 gene, a homeobox gene essential for interneuron migration and differentiation. We hypothesized that GGs are arrested in development, and began to explore the role of the Dlx2 gene. BRAF rearrangements and BRAF V600E point mutations have been reported in pediatric LGG. METHODS: DLX2 expression was examined in GGs using immunofluorescence (IF) and immunohistochemistry (IHC) labelling of formalin fixed paraffin embedded (FFPE) tissue sections, along with staining of glial and neuronal markers. BRAF mutations were detected using a commercial antibody and/or sequence verification of the DNA extracted from the FFPE blocks. RESULTS: In the Discovery cohort 10/30 were DLX2+ (33.3%) and in the Validation cohort 15/40 were DLX2+ (37.5%). Of these 15 cases, 15 were GFAP+ (100%), 15 were synaptophysin and/or NeuN+ (100%), and 13 were OLIG2+ (86.7%); 6 had a BRAF V600E mutation (40.0%). For the Validation cohort of 40 GGs, 28 were OLIG2+ (70.0%); 13/28 co-expressed DLX2 (46.4%). 18/40 cases had a BRAF V600 mutation(17 V600E, 1 V600G; 45.0%) and 6/18 were DLX2+ (33.3%). CONCLUSIONS: DLX2 is expressed in GGs in both neuronal and glial marker expressing tumour cells. Our results support that GGs arise from CNS progenitors arrested at the neuronal-glial cell fate “decision” point.
25 Durable complete responses observed in patients with recurrent high grade glioma treated with Toca 511 & Toca FC
Authors: Mikkelsen T , Cloughesy TF , Landolfi J , Vogelbaum MA , Ostertag D , Elder JB , Chen CC , Kalkanis SN , Kesari S , Lai A , Lee IY , Liau LM , Nghiemphu PL , Piccioni D , Accomando WP , Diago O , Hogan D , Jolly DJ , Kheoh T , Gruber HE , Das A , Walbert T
Published: July 2018

Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that selectively infects dividing cancer cells, integrates into the genome and replicates due to immune defects in tumors. Toca 511 spreads through tumors and stably delivers the gene encoding an optimized yeast cytosine deaminase that converts the prodrug Toca FC (investigational, extended-release of 5-fluorocytosine) into 5-fluorouracil. In preclinical models, 5-fluorouracil kills infected dividing cancer cells, myeloid derived suppressor cells and tumor associated macrophages, enabling immune activation against the tumor. In this dose ascending Ph1 trial (NCT01470794), Toca 511 was injected into the resection cavity wall of patients with rHGG, followed by courses of oral Toca FC. Additional cohorts included combination with bevacizumab or lomustine. Across the Ph1 program, the safety profile remains favorable. Objective responses (ORs) were assessed by IRR using MRI scans prior to Toca FC treatment as baseline. ORs occurred 6-19 months after Toca 511 administration, suggesting an immunologic mechanism. The ORs were observed in 4 patients with IDH1-wildtype and 2 patients with IDH1-mutant tumors, including 5 complete responses (CRs) with the investigational therapy alone, and 1 CR in combination with bevacizumab. The median duration of response (mDoR) was 35.1+ months. As of AUG2017, all responders were CR and remain alive. In a 23-patient subgroup who received high doses of Toca 511 and met Ph3 trial criteria, mOS was 14.4 months, 3-year survival rate was 26.1%, and mDoR was 35.7+ months with a durable response rate of 21.7%. Data suggest a positive association of durable response with OS.
51 Timing of adjuvant treatments on glioblastoma survival: A retrospective cohort analysis based on the national cancer database
Authors: Zhu Ping , Du Xianglin L. , Esquenazi Yoshua , Zhu Jay-Jiguang
Published: July 2018

Few studies investigated the associations between intervention modalities, timing, and survival in glioblastoma (GBM) patients. A total of 20511 eligible GBM patients underwent biopsy and craniotomy surgeries followed by adjuvant treatments (2005-2014) were derived from the National Cancer Database (NCDB). The time intervals (days) from the date of diagnosis to the initiation date of adjuvant treatment [radiation therapy only (RT), chemotherapy only, concurrent chemoradiation (CRT), or non-concurrent RT and chemotherapy] were categorized into quartiles (Q1-Q4). Kaplan-Meier method and Cox proportional hazards regression were applied for survival analysis. Multivariate logistic regression was performed to compare differences in treatment timing, intervention modalities, and secondary outcomes. The patients underwent biopsy obtained significant survival benefit by having delayed adjuvant treatment [comparing to Q1, Q2: HR (hazard ratio), 0.88, Q3: HR, 0.86]. For patients underwent resection, the prolonged waiting time of adjuvant treatment had 5-6% reduced risk of death [comparing to Q1, Q2: HR, 0.95; Q3: HR, 0.94]. Patients received more RT fractions [comparing to 10-29 fractions, 30-33 fractions: HR: 0.62 (biopsy), 0.62 (resection); ≥34 fractions: HR: 0.53 (biopsy), 0.62 (resection)] and high-dose RT [comparing to 34-46 Gy, 50-60 Gy: HR: 0.91 (biopsy), 0.95 (resection); ≥ 60 Gy: HR: 0.77 (biopsy), 0.88 (resection)] experienced significantly superior survival in both biopsy and resection groups. The impact of timing to adjuvant treatment on GBM survival varied by surgery procedures. Having adjuvant treatment initiated within 21 days for both biopsy and craniotomy groups may not guarantee a significant survival benefit. More RT fractions and high-dose RT are associated with better GBM survival.
13 The genetic landscape of pediatric low-grade gliomas: Incidence, prognosis and response to therapy - a SickKids pLGG Task Force update
Authors: Ryall S , Zapotocky M , Fukuoka K , Guerreiro-Stucklin A , Bennett J , Arnoldo A , Kowalski P , Johnson M , Lassaletta A , Bouffet E , Bartels U , Ellison D , Tabori U , Hawkins C
Published: July 2018

Molecular characterization of pediatric low-grade glioma (pLGG) over the last decade has identified recurrent alterations, most commonly involving BRAF, and less frequently other pathways including MYB and MYBL1. Many of these molecular markers have been exploited clinically to aid in diagnosis and treatment decisions. However, their frequency and prognostic significance remain unknown. Further, a significant portion of cases do not have any of these alterations and what underlies these cases remains unknown. To address this we compiled a cohort of 562 patients diagnosed at SickKids from 1990-2017. We identified molecular alterations in 454 cases (81% of the cohort). The most frequent events were those involving BRAF; either as fusions (most commonly with KIAA1549 (30%)) or V600E mutations (17%) and NF-1 (22%). Less frequently, we identified recurrent FGFR1 fusions and mutations (3%), MYB/MYBL alterations (2%), H3F3AK27M (2%) or IDH1R132H (0.5%) mutations, as well as other novel rare events. Survival analysis revealed significantly better progression-free survival (PFS) and overall survival (OS) of KIAA1549-BRAF fused patients compared to BRAFV600E with 10-year OS 97.7% (95%, CI 95.5-100) and 83.9% (95%, CI 72.5-95.6), respectively. In addition to survival, molecular alterations predicted differences in response to conventional therapeutics; BRAF fused patients showed a 46% response-rate, versus only 14% in V600E patients. pLGGs harboring H3F3AK27M progressed early with median PFS of 11 months. In patients with MYB/MYBL1, FGFR1/FGFR2 alterations, we observed only one death (FGFR1N546K case). The work here represents the largest cohort of pLGGs with molecular profiling and their impact on the clinical behaviour of the disease.
31 Intracranial growing teratoma syndrome (IGTS): An international retrospective study
Authors: Michaiel George , Strother Douglas , Gottardo Nicholas , Bartels Ute , Coltin Hallie , Eisenstat David D. , Hukin Juliette , Johnston Donna L. , Wilson Beverly , Zelcer Shayna , Hansford Jordan R. , Wells Olivia , AbdelBaki Mohamed S. , Abu-Arja Mohammad H. , Cole Kristina A. , Dhall Girish , Fisher Paul G. , Hoffman Lindsey , Leary Sarah E.S. , Owens Pickle Emily E. , Smiley Natasha P. , Smith Amy , Vinitsky Anna , Vitanza Nicholas A. , Wright Avery , Yeo Kee K. , Chow Lionel M.L. , Kirby Maria , Valvi Santosh , Vanan Magimairajan I. , Wong Grace , Ziegler David , Bouffet Eric , Lafay-Cousi Lucie
Published: July 2018

BACKGROUND: IGTS is a rare phenomenon of paradoxical germ cell tumor (GCT) growth during or following treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of IGTS in patients in 21 North-American and Australian institutions. METHODS: Patients with IGTS diagnosed from 2000-2017 were retrospectively evaluated. RESULTS: Out of 739 GCT diagnoses, IGTS was identified in 33 patients (4.5%). IGTS occurred in 9/191 (4.7%) mixed-malignant GCTs, 4/22 (18.2%) immature teratomas (ITs), 3/472 (0.6%) germinomas/germinomas with mature teratoma, and in 17 secreting non-biopsied tumours. Median age at GCT diagnosis was 10.9 years (range 1.8-19.4). Male gender (84%) and pineal location (88%) predominated. Of 27 patients with elevated markers, median serum AFP and Beta-HCG were 70 ng/mL (range 9.2-932) and 44 IU/L (range 4.2-493), respectively. IGTS occurred at a median time of 2 months (range 0.5-32) from diagnosis, during chemotherapy in 85%, radiation in 3%, and after treatment completion in 12%. Surgical resection was attempted in all, leading to gross total resection in 76%. Most patients (79%) resumed GCT chemotherapy/radiation after surgery. At a median follow-up of 5.3 years (range 0.3-12), all but 2 patients are alive (1 succumbed to progressive disease, 1 to malignant transformation of GCT). CONCLUSION: IGTS occurred in less than 5% of patients with GCT and most commonly after initiation of chemotherapy. IGTS was more common in patients with IT-only on biopsy than with mixed-malignant GCT. Surgical resection is a principal treatment modality. Survival outcomes for patients who developed IGTS are favourable.
1450-1545 Young Investigator Awards & Presentations

Basic/Translational

Exploring cellular subpopulations in glioblastoma and matched organoids using single-cell RNA-seq 52
Authors: LeBlanc VG , Trinh D , Hughes M , Luthra I , Livingstone D , Blough MD , Cairncross JG , Kelly JJ , Marra MA
Published: July 2018

Glioblastomas (GBMs) account for nearly half of all primary malignant brain tumours, and current therapies are often only marginally effective. Our understanding of the underlying biology of these tumours and the development of new therapies have been complicated in part by widespread inter- and intratumoural heterogeneity. To characterize this heterogeneity, we performed regional subsampling of primary glioblastomas and derived organoids from these tissue samples. We then performed single-cell RNA-sequencing (scRNA-seq) on these primary regional subsamples and 1-3 matched organoids per sample. We have profiled samples from six tumour sets to date and have obtained sequencing data for 21,234 primary tissue cells and 14,742 organoid cells. While the most apparent differences in gene expression appear to be between individual tumours, we were also able to identify similar cellular subpopulations across tissue samples and across organoids. Importantly, organoids derived from the same tissue sample appeared to be composed of similar cellular subpopulations and were highly comparable to each other, indicating that replicate organoids faithfully represent the original tumour tissue. Overall, our scRNA-seq approach will help evaluate the utility of tumour-derived organoids as model systems for GBM and will aid in identifying cellular subpopulations defined by gene expression patterns, both in primary GBM regional subsamples and their associated organoids. These analyses will allow for the characterization of clonal or subclonal populations that are likely to respond to different therapeutic approaches and may also uncover novel therapeutic targets previously unrevealed through bulk analyses.
Exploring cellular subpopulations in glioblastoma and matched organoids using single-cell RNA-seq
Authors: Nassiri F , Nejad R , Yasheng M , Torchia J , Aldape K , Zadeh G
Published: July 2018

Background: Gliomas are the most common and fatal adult brain tumor with distinct genomic subgroups defined by isocitrate dehydrogenase (IDH) mutation status. Mutations in IDH result in overproduction of the oncometabolite 2-hydroxyglutarate (2HG). The landscape of metabolic changes that define gliomas has not previously been explored. Methods: We performed liquid chromotography-mass spectrometry (LC-MS) to examine over 700 metabolites on 90 fresh-frozen glioma samples (30 IDH-wildtype, 30 IDH-mutant 1p/19q codeleted, 30 IDH-mutant 1p/19q non-codeleted) from our institutional biobank. R and S enantiomers of 2HG were quantified using high pressure liquid chromatography tandem mass spectrometry coupled with a CHIROBIOTIC R column. Genome wide DNA methylation was performed on all tumors using Illumina 850k EPIC array. Unsupervised consensus clustering of differentially expressed metabolites and methylated post-processed probes was performed. Copy number variations were determined based on intensity values of the methylation array. Survival of unsupervised cluster groups was determined using the Kaplan-Meier Estimate. Results: Unsupervised clustering of 689 metabolites revealed 2 distinct subgroups of gliomas associated with recurrence-free survival (RFS, P = 0.021). IDH mutant tumours were found in both cluster groups where as IDH-wildtype tumors were found only in Group 2. Group 2 IDH-mutant tumors had unfavourable PFS, higher R/S-2HG levels, and higher proportion of copy number alterations (4q, 9p, 13q, 17q) compared to group 1 IDH-mutant tumors (P=0.048, P=0.0194, P<0.0001 respectively) compared to group 1 IDH-mutant tumors. (P= p=0.048). . Conclusions: Metabolic profiling of gliomas reveals 2 distinct subtypes of IDH-mutant independent of 1p/19q codeletion status with differing survival patterns and large scale chromosomal alterations that may be driven by varying levels of R/S-2HG.
49 Dianhydrogalactitol (VAL-083) reduces glioblastoma tumor progression in vivo, upon bevacizumab-induced hypoxia
Authors: Golebiewska A , Oudin A , Steino A , Bacha JA , Brown DM , Niclou S
Published: July 2018

Standard-of-care for glioblastoma (GBM) includes surgery, radiation and temozolomide. Nearly all tumors recur and 5-year survival is less than 3%. Unmethylated promoter status O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for temozolomide-resistance. Second-line treatment with bevacizumab has not only failed to improve survival, but has also been shown to induce intratumor hypoxia and increased chemoresistance. VAL-083 is a bi-functional DNA-targeting agent that readily crosses the blood-brain barrier. VAL-083 targets N7-guanine, causing DNA double-strand breaks and cancer cell-death in GBM cancer stem cells (CSCs) and non-CSCs, independent of MGMT. To investigate the in vivo anti-tumor effect of VAL-083+bevacizumab, we used an orthotopic GBM T16 PDX model. All mice carried MGMT-unmethylated, temozolomide-resistant recurrent GBM tumors detected by MRI 35 days post-implantation. Tumor progression was measured by MRI on days 49 and 56, and was calculated for the entire study (day 35 vs. 56) and for the last 7 days (day 49 vs. 56). Mice were grouped into control, bevacizumab, VAL-083, and VAL-083+bevacizmab. VAL-083 treatment started 3 days after bevacizumab treatment to ensure induction of hypoxia. Results: Tumors were significantly smaller in VAL-083-treated mice both compared to control (-83%, p<0.001) and compared to bevacizumab-treated (-75%, p<0.001) mice. Additionally, analysis of tumor growth in-time showed significantly reduced tumor progression for VAL-083+bevacizumab compared to VAL-083 alone (p<0.01). Conclusions: These results show strong in vivo anti-tumor efficacy of VAL-083 against MGMT-unmethylated, recurrent GBM. This effect was further augmented in combination with bevacizumab, providing rationale of clinical investigation of VAL-083+bevacizumab in GBM.
29 Unraveling molecular drivers of brain cancers at the clinical setting
Authors: Wong D. , Shen Y. , Levine A. B. , Hoon Lee T. , Pleasance E. , Jones M. , Thiessen B. , Toyota B. , Laskin C.M, J. , Jones S. , Marra M. A , Yip S.
Published: July 2018

Brain tumor behavior is driven by aberrations in the genome and epigenome. Many of these changes, such as IDH mutations in diffuse low-grade glioma (DLGG), are common amongst the same class of tumour and can be incorporated into the diagnostic criteria. However, any given tumor may have other, less common genomic aberrations that are essential for its biological behavior and may inform on underlying aberrant cellular pathways, and potential therapeutic agents. Precision oncology is a genomics-based approach which profiles these alterations to better manage cancer patients and has established itself within the practice of oncology and is slowly making its way into neuro-oncology. The BC Cancer’s Personalized OncoGenomics (POG) program has profiled 16 adult tumours originating from the central nervous system using whole genome and transcriptome analysis (WGTA), for the first time, within a meaningful clinical timeframe/setting. As expected, primary genomic drivers were consistent with their respective diagnoses, though secondary drivers were found to be unique to each tumour. Although these analyses did not result in altered clinical management for these patients, primarily due to availability of drug or clinical trials, they highlight the heterogeneity of secondary drivers in cancers and provide clinicians with meaningful biological information. Lastly, the data generated by POG has highlighted the frequency and complexity of novel driver fusions which are predicted to behave similarly to canonical driver events in their respective tumours. The information available to clinicians through POG has provided paramount knowledge into the biology of each unique tumour.
09 Could DLX2 regulation of neural progenitor cell fate contribute to differentiation of diffuse intrinsic pontine glioma (DIPG)?
Authors: Nevin M , Song X , Japoni S , Zagozewski J , Jiang Q , Becher O , Godbout R , Underhill DA , Eisenstat DD
Published: July 2018

Introduction: Diffuse intrinsic pontine glioma (DIPG) is refractory to therapy. The identification of histone H3.1/H3.3 K27M mutations in most DIPG has provided new insights. The DLX homeobox genes are expressed in the developing forebrain. The Dlx1/Dlx2 double knockout (DKO) mouse loses tangential GABAergic interneuron migration to the neocortex. We have identified genes that encode glutamic acid decarboxylase (GAD) enzymes as direct targets of DLX1/DLX2. In DIPG patients with H3.3 K27M mutations there is decreased Dlx2 and increased expression of the myelin transcription factor, Myt1. Methods and Results: We used bioinformatics approaches and chromatin immunoprecipitation (ChIP) assays to identify Olig2, Nkx2.2 and Myt1 promoter sequences as candidate DLX2 targets in vivo. DNA binding specificity was confirmed. The functional consequences of Dlx2 co-expression with reporter constructs of ChIP-isolated promoter fragments of Olig2 and Nkx2.2 demonstrated repression of gene targets in vitro. qPCR showed increased Olig2 and Nkx2.2 expression in the DKO forebrain. Stable transfection of a murine DIPG cell line with Dlx2 resulted in increased Gad1 and Gad2 and decreased Olig2 and Nkx2.2 expression. Of significance, we demonstrated decreased expression of H3.3 K27M and restoration of H3.3 K27 tri-methylation (me3). Conclusions: DLX transcription factors promote GABAergic interneuron and concomitant inhibition of oligodendroglial differentiation in neural progenitors by repression of a suite of genes including Olig2 and Nkx2.2. Restoration of H3 K27me3 expression in DIPG provides a promising lead towards exploration of differentiation as a therapeutic strategy for DIPG.
21 Inhibiting PARP-1 to restore temozolomide sensitivity and prevent resistance in glioblastoma
Authors: Bering E. A. , Yuan A. L. , Cairncross J. G. , Blough M. D.
Published: July 2018

Adult Glioblastomas (GBMs) remain one of the least curable brain cancers despite the discovery and use of DNA alkylating agent Temozolomide (TMZ). TMZ provides a moderate survival benefit to sensitive patients whose O6-methylguanine-methyltransferase (MGMT) gene is silenced by promoter methylation. Unfortunately, TMZ potential is stunted because of the rapid onset of tumour recurrence and acquired resistance believed to result from the upregulation of DNA damage repair by the base excision repair (BER), mismatch repair (MMR), or homologous recombination (HR) systems. Our laboratory previously demonstrated that cell lines obtained from recurrent, TMZ-resistant GBMs could be re-sensitized to TMZ when treated with an inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1) – a protein instrumental in the recruitment of BER machinery. From this preliminary research, we postulate that PARP-1 inhibition may not only be used to overcome established resistance in GBM but may also be used to prevent its emergence altogether. To test this hypothesis, we utilized the MGMT-methylated GBM cell line U251N and developed an in vitro model of inducible TMZ resistance. We verified that prolonged treatment of U251N cells with TMZ resulted in the emergence of resistant colonies that resembled recurrent GBM clinically observed in TMZ-treated patients. However, when the parental U251N line was co-treated with TMZ and PARP-1 inhibitor ABT-888, resistant colonies failed to appear. Therefore, PARP-1 inhibition may possess the potential to maintain tumour sensitivity to TMZ as well as evade the otherwise inevitable development of resistance in GBM.
What the future holds for the Netherlands Journal of Geosciences
Authors: ten Veen Johan
Published: July 2018

My first year as Editor-in-Chief of the Netherlands Journal of Geosciences / Geologie en Mijnbouw turned out to be a steep learning curve which showed me all the facets this task brings. It has been a productive year, though. A total of 49 papers were published in three regular and two special issues. The special issues, on the Meuse Valley and on Seismicity of the Groningen Gas Field, were well received and contain papers authored by members of academic and applied institutions, including universities, consultants, advisory institutions, provinces, energy operators and regulatory authorities. This once again proves that thematic issues are a great strength of the Journal and it is good to notice that the Journal has become a medium for a broad geoscientific research community.
Juste part, boycott et loi spéciale. Le cadrage gouvernemental d'un printemps de crise sociale
Authors: Giasson Thierry , Dubois Philippe
Published: July 2018

Cet article étudie la stratégie de communication gouvernementale lors du mouvement de grève étudiante de 2012 au Québec. Six ans après la fin du conflit, et malgré la production d'un volume important d'analyses et de réflexions sur cette crise sociale, aucune étude empirique n'a recensé systématiquement le contenu de la stratégie communicationnelle du gouvernement. Par le biais d'une analyse de contenu quantitative des interventions publiques des membres de l'exécutif, cette étude relève les cadres argumentaires au cœur de la stratégie de communication gouvernementale. S'inspirant de la théorie de l'activation en cascade d'Entman, l'analyse montre comment le gouvernement a tenté de définir les problèmes, les solutions et les protagonistes impliqués dans le conflit sociétal qu'a traversé le Québec en 2012. Notre analyse met en lumière l’échec gouvernemental à maintenir au fil des évènements l'initiative du cadrage de la crise, et le changement de stratégie communicationnelle qui en résulte.
EXTREME POINTS FOR COMBINATORIAL BANACH SPACES
Authors: BEANLAND KEVIN , DUNCAN NOAH , HOLT MICHAEL , QUIGLEY JAMES
Published: July 2018

A norm ‖ċ‖ on c00 is called combinatorial if there is a regular family of finite subsets $\mathcal{F}$, so that $\|x\|=\sup_{F \in \mathcal{F}} \sum_{i \in F} |x(i)|$. We prove the set of extreme points of the ball of a combinatorial Banach space is countable. This extends a theorem of Shura and Trautman. The second contribution of this article is to exhibit many new examples of extreme points for the unit ball of dual Tsirelson's original space and give an explicit construction of an uncountable collection of extreme points of the ball of Tsirelson's original space. We also prove some stability properties of the intermediate norms used to define Tsirelson's space and give a lower bound of the stabilization function for these intermediate norms.
Frequency effects in Subject Islands
Authors: CHAVES RUI P. , DERY JERUEN E.
Published: July 2018

This work provides evidence that Subject Island violation effects vanish if subject-embedded gaps are made as frequent and pragmatically felicitous as non-island counterpart controls. We argue that Subject Island effects are caused by the fact that subject-embedded gaps are pragmatically unusual – as the informational focus does not usually correspond to a dependant of the subject phrase – and therefore are highly contrary to comprehenders’ expectations about the distribution of filler–gap dependencies (Chaves 2013, Hofmeister, Casasanto & Sag 2013). This not only explains why sentences with subject-embedded gaps often become more acceptable ‘parasitically’, in the presence of a second gap outside the island, but also explains why some Subject Island violations fail to exhibit any amelioration with repetition (Sprouse 2009, Crawford 2011, Goodall 2011); some ameliorate marginally (Snyder 2000, 2017) or moderately (Hiramatsu 2000, Clausen 2011, Chaves & Dery 2014), and others become fully acceptable, as in our case. This conclusion extends to self-paced reading Subject Island studies (Stowe 1986, Kurtzman & Crawford 1991, Pickering, Barton & Shillcock 1994, Phillips 2006), which sometimes find evidence of gap filling and sometimes do not.
Approaches used to estimate bioavailability when deriving dietary reference values for iron and zinc in adults
Authors: Fairweather-Tait Susan J. , de Sesmaisons Agnès
Published: July 2018

This review aims to describe approaches used to estimate bioavailability when deriving dietary reference values (DRV) for iron and zinc using the factorial approach. Various values have been applied by different expert bodies to convert absorbed iron or zinc into dietary intakes, and these are summarised in this review. The European Food Safety Authority (EFSA) derived zinc requirements from a trivariate saturation response model describing the relationship between zinc absorption and dietary zinc and phytate. The average requirement for men and women was determined as the intercept of the total absorbed zinc needed to meet physiological requirements, calculated according to body weight, with phytate intake levels of 300, 600, 900 and 1200 mg/d, which are representative of mean/median intakes observed in European populations. For iron, the method employed by EFSA was to use whole body iron losses, determined from radioisotope dilution studies, to calculate the quantity of absorbed iron required to maintain null balance. Absorption from the diet was estimated from a probability model based on measures of iron intake and status and physiological requirements for absorbed iron. Average dietary requirements were derived for men and pre- and post-menopausal women. Taking into consideration the complexity of deriving DRV for iron and zinc, mainly due to the limited knowledge on dietary bioavailability, it appears that EFSA has made maximum use of the most relevant up-to-date data to develop novel and transparent DRV for these nutrients.
Human–wildlife coexistence: attitudes and behavioural intentions towards predators in the Maasai Mara, Kenya
Authors: Broekhuis Femke , Kaelo Michael , Sakat Dominic Kantai , Elliot Nicholas B.
Published: July 2018

Living alongside predators can entail substantial costs both in terms of livelihoods and personal safety. Negative interactions with predators can lead to negative attitudes and behavioural intentions such as retaliatory or pre-emptive killing. As a result, conservation strategies are increasingly adopting human–wildlife coexistence approaches aimed at minimizing the costs associated with living with predators by providing direct or indirect benefits. This is done in the hope that people will foster positive attitudes and behavioural intentions towards predators. However, people's attitudes and their behavioural intentions are not necessarily linked, and both need to be understood for conservation actions to be effective. We conducted 747 semi-structured interviews with community members in the Maasai Mara, Kenya, to determine which factors influenced people's attitudes and behavioural intentions towards predators and whether the two were linked. Most interviewees (57.52%) had a positive attitude towards predators as measured by their assertion that people, livestock and predators should coexist. Their attitude was dependent on benefits, occupation, conservancy membership and perceived community ownership of predators, but was not influenced by the costs of livestock depredation. Most respondents who were members of a conservancy had positive attitudes towards predators but this differed by conservancy, suggesting that, in addition to benefits, conservation politics could influence attitudes. In total, 10.3% of respondents said that they would kill a predator if it killed their livestock. This behavioural intention was only influenced by the respondent's attitude. Understanding the factors that influence attitudes and behavioural intentions will aid future management and coexistence strategies.
The meaning of a claim is its reproducibility
Authors: de Ruiter Jan P.
Published: July 2018

A scientific claim is ageneralizationbased on a reported statistically significant effect. The reproducibility of that claim is its scientific meaning. Anything not explicitly mentioned in a scientific claim as a limitation of the claim's scope means that it implicitly generalizes over these unmentioned aspects. Hence, so-called “conceptual” replications that differ in these unmentioned aspects from the original study are legitimate, and necessary to test the generalization implied by the original study's claim.
Bayesian belief updating after a replication experiment
Authors: Holcombe Alex O. , Gershman Samuel J.
Published: July 2018

Zwaan et al. and others discuss the importance of the inevitable differences between a replication experiment and the corresponding original experiment. But these discussions are not informed by a principled, quantitative framework for taking differences into account. Bayesian confirmation theory provides such a framework. It will not entirely solve the problem, but it will lead to new insights.
An argument for how (and why) to incentivise replication
Authors: Howe Piers D. L. , Perfors Amy
Published: July 2018

Although Zwaan et al. (2018) have made a compelling case as to why direct replications should occur more frequently than they do, they do not address how such replications attempts can best be encouraged. We propose a novel method for incentivising replication attempts and discuss some issues surrounding its implementation.
Direct replications in the era of open sampling
Authors: Paolacci Gabriele , Chandler Jesse
Published: July 2018

Data collection in psychology increasingly relies on “open populations” of participants recruited online, which presents both opportunities and challenges for replication. Reduced costs and the possibility to access the same populations allows for more informative replications. However, researchers should ensure the directness of their replications by dealing with the threats of participant nonnaiveté and selection effects.
You are not your data
Authors: Pennycook Gordon
Published: July 2018

Scientists should, above all else, value the truth. To do this effectively, scientists should separate their identities from the data they produce. It will be easier to make replications mainstream if scientists are rewarded based on their stance toward the truth – such as when a scientist reacts positively to a failure to replicate – as opposed to a particular finding.
The importance of exact conceptual replications
Authors: Petty Richard E.
Published: July 2018

Although Zwaan et al. argue that original researchers should provide a replication recipe that provides great specificity about the operational details of one's study, I argue that it may be as important to provide a recipe that allows replicators to conduct a study that matches the original in as many conceptual details as possible (i.e., an exact conceptual replication).
Holding replication studies to mainstream standards of evidence
Authors: Wegener Duane T. , Fabrigar Leandre R.
Published: July 2018

Replications can make theoretical contributions, but are unlikely to do so if their findings are open to multiple interpretations (especially violations of psychometric invariance). Thus, just as studies demonstrating novel effects are often expected to empirically evaluate competing explanations, replications should be held to similar standards. Unfortunately, this is rarely done, thereby undermining the value of replication research.
Interactive and automated proofs for graph transformations
Authors: STRECKER MARTIN
Published: July 2018

This article explores methods to provide computer support for reasoning about graph transformations. We first define a general framework for representing graphs, graph morphisms and single graph rewriting steps. This setup allows for interactively reasoning about graph transformations. In order to achieve a higher degree of automation, we identify fragments of the graph description language in which we can reduce reasoning about global graph properties to reasoning about local properties, involving only a bounded number of nodes, which can be decided by Boolean satisfiability solving or even by deterministic computation of low complexity.
RACE, CRIME, AND THE CHANGING FORTUNES OF URBAN NEIGHBORHOODS, 1999–2013
Authors: Krivo Lauren J. , Vélez María B. , Lyons Christopher J. , Phillips Jason B. , Sabbath Elizabeth
Published: July 2018

For over a century, scholars have traced higher levels of serious crime in minority compared to White neighborhoods to stark socioeconomic inequality. Yet, this research is largely cross-sectional and does not assess how ethnoracial differences in crime patterns evolve over time in response to shifting structural conditions. The new century witnessed substantial changes to the circumstances that undergird the ethnoracial divide in neighborhood crime as well as a national crime decline. How are the changing dynamics of urban inequality reinforcing or diminishing racial and ethnic disparities in neighborhood crime in the context of the “Great American Crime Decline”? We address this question by first identifying distinct paths of violent and property crime change between 1999 and 2013 for almost 2700 neighborhoods across eighteen cities. We then assess how initial and changing levels of disadvantage, housing instability, and demographics explain divergent crime trajectories within neighborhoods. We find that most neighborhoods have lower levels of homicide and burglary than fifteen years ago. However, homicide and burglary increased in some neighborhoods, and this trend is largely limited to Black neighborhoods. Disadvantage and the housing crisis are critical in accounting for the heightened risk of neighborhoods having increasing rather than decreasing crime trends. In contrast, immigration is linked with declining and stable trends in violent and property crime. Overall, results indicate a widening of the racial-spatial divide for the most marginalized communities in the United States.
AN ELABORATION AND CRITIQUE OF “REASSESSING ‘TOWARD A THEORY OF RACE, CRIME, AND URBAN INEQUALITY’”
Authors: Vélez María B.
Published: July 2018

In the prior article in this volume, Robert Sampson and colleagues (2018) take theoretical and empirical stock of a framework they presented twenty years ago. They find broad empirical support for its core tenets. Differences in disadvantage explain most, if not all, observed gaps in violent crime between Black and White neighborhoods; disadvantage also operates similarly to foster crime in Black and White areas. The authors also lament the limited research on the key intervening mechanism of community social organization, particularly its cultural and political sources, that links disadvantage to crime. I have two primary goals in commenting on this article. First, in keeping with their assessment, I provide my take on their agenda for extending the framework beyond the Black-White divide, giving greater attention to the political sources of community social organization, and considering reciprocal relationships between crime, race, and disadvantage. Second, I elaborate on how my views differ from Sampson and colleagues’ regarding strategies to empirically validate the racial invariance thesis, the breadth of support for the thesis beyond its core tenets, and the role of culture. I provide these critiques to encourage further work exploring the explanatory power of Sampson and colleagues’ thesis, and, to thereby foster a better understanding of enduring inequities in violent crime between racialized minority populations and Whites. Without their ecologically-based approach, we run the risk of essentializing minorities as criminogenic, like recent work espousing cultural (devoid of structural) and biological (devoid of social) explanations for the race-crime link.
Toxicity of Shirazi thyme, Zataria multiflora essential oil to the tomato leaf miner, Tuta absoluta (Lepidoptera: Gelechiidae)
Authors: Chegini Samira Goudarzvande , Abbasipour Habib , Karimi Jaber , Askarianzadeh Alireza
Published: July 2018

The tomato leafminer,Tuta absoluta(Meyrick) is a destructive pest of tomato, potato and other solanaceous crops of economic importance. One of the primary tools in its management is the use of conventional synthetic insecticides; however, this overreliance on synthetic insecticides quickly leads to the problem of insecticide resistance. In recent years, essential oils (EOs) of medicinal plants have received much attention as pest control chemical agents. If found, active compounds that are less persistent will be beneficial for both the environment and agricultural product consumers. In the current study, we studied the fumigant toxicity of EO of the Shirazi thyme,Zataria multifloraBoiss on the eggs, the second larval instars and adults. We analysed the composition of the EO by gas chromatography–mass spectrometry. The major component in the oil was thymol (33.52%). The EO showed strong adulticidal, larvicidal and ovicidal activity. Results show that by increasing the oil concentration, mortality will increase. By Probit analysis, the LC50values for eggs, second larvae (inside leaf, outside leaf) and adults were 60.26, 4.44, 1.26 and 1.38 µl/L air, respectively. The EO ofZ. multifloramay be suitable as a fumigant, because of its high volatility and safety.
Opening the black box of diagnosis-related groups (DRGs): unpacking the technical remuneration structure of the Dutch DRG system
Authors: van Herwaarden Sam , Wallenburg Iris , Messelink Joris , Bal Roland
Published: July 2018

While we know that upcoding of diagnosis-related groups (DRGs) regularly occurs, we have little knowledge of the role of the technical features of coding systems in inducing coding behaviour. This paper presents methods for investigating the financial structure of the Dutch DRG system, and more in particular the grouper software, to gain such insight. The paper describes a system for investigating the robustness of the reward structure, by simulating the response of the DRG system to small changes in individual coding. The results from these analyses are used to visualise some data on coding behaviour, and to investigate how this behaviour is affected by incentives in the technical features of the DRG system. A number of technical weaknesses in the system are also identified.
Is Suicidal Behavior in Mood Disorders Altered by Comorbid PTSD?
Authors: Lento René M. , Carson-Wong Amanda , Green Jonathan D. , AhnAllen Christopher G. , Kleespies Phillip M.
Published: July 2018

Abstract. Background: Suicide is a leading cause of death among US veterans. Associations between depression, posttraumatic stress disorder (PTSD), and suicidal behaviors have been found in this population, yet minimal research has explored how manifestations of self-injurious behavior (SIB) may vary among different diagnostic presentations. Aims: This study aimed to identify clinically useful differences in SIB among veterans who experience comorbid mood disorder and PTSD (CMP) compared with those who experience a mood disorder alone (MDA). Method: Participants were 57 US military veterans who reported an incident of intentional SIB. The semistructured Post Self-Injury/Attempted Self-Injury Debriefing Interview was used to examine characteristics of the SIB. Results: Veterans diagnosed with CMP were more likely than those with MDA to (a) report that the SIB was impulsive and (b) to be under the influence of substances at the time of self-injury. Limitations: Generalizability may be limited by small sample size and predominantly European American, male demographics. While highly relevant to routine clinical practice, caution is recommended, as study diagnoses were attained from medical records rather than structured interviews. Conclusion: Safety planning that emphasizes protection against impulsive suicide attempts (e.g., means restriction) may be especially important among veterans with comorbid mood disorder and PTSD.