bluuebunny/crossref_metadata_2025 huggingface dataset:
Building capacity in remote sensing for conservation: present and future challenges
Authors: Palumbo Ilaria , Rose Robert A. , Headley Rachel M. K. , Nackoney Janet , Vodacek Anthony , Wegmann Martin
Published: October 2016

Remote sensing (RS) has made significant contributions to conservation and ecology; however, direct use of RS‐based information for conservation decision making is currently very limited. In this paper, we discuss the reasons and challenges associated with using RS technology by conservationists and suggest how training in RS for conservationists can be improved. We present the results from a survey organized by the Conservation Remote Sensing Network to understand the RS expertise and training needs of various categories of professionals involved in conservation research and implementation. The results of the survey highlight the main gaps and priorities in the current RS data and technology among conservation practitioners from academia, institutions, NGOs and industry. We suggest training to be focused around conservation questions that can be addressed using RS‐derived information rather than training pure RS methods which are beyond the interest of conservation practitioners. We highlight the importance of developing essential biodiversity variables (EBVs) and how this can be achieved by increasing the RS capacity of the conservation community. Moreover, we suggest that open‐source software is adopted more widely in the training modules to facilitate access to RS data and products in developing countries, and that online platforms providing mapping tools should also be more widely distributed. We believe that improved RS capacity among conservation scientists will be essential to improve conservation efforts on the ground and will make the conservation community a key player in the definition of future RS‐based products that serve conservation and ecological needs.
Asymptotic properties of adaptive group Lasso for sparse reduced rank regression
Authors: He Kejun , Huang Jianhua Z.
Published: October 2016

This paper studies the asymptotic properties of the penalized least squares estimator using an adaptive group Lasso penalty for the reduced rank regression. The group Lasso penalty is defined in the way that the regression coefficients corresponding to each predictor are treated as one group. It is shown that under certain regularity conditions, the estimator can achieve the minimax optimal rate of convergence. Moreover, the variable selection consistency can also be achieved, that is, the relevant predictors can be identified with probability approaching one. In the asymptotic theory, the number of response variables, the number of predictors and the rank number are allowed to grow to infinity with the sample size. Copyright © 2016 John Wiley & Sons, Ltd.
Protein S Regulates Neural Stem Cell Quiescence and Neurogenesis
Authors: Zelentsova Katya , Talmi Ziv , Abboud-Jarrous Ghada , Sapir Tamar , Capucha Tal , Nassar Maria , Burstyn-Cohen Tal
Published: October 2016

Neurons are continuously produced in brains of adult mammalian organisms throughout life—a process tightly regulated to ensure a balanced homeostasis. In the adult brain, quiescent Neural Stem Cells (NSCs) residing in distinct niches engage in proliferation, to self-renew and to give rise to differentiated neurons and astrocytes. The mechanisms governing the intricate regulation of NSC quiescence and neuronal differentiation are not completely understood. Here, we report the expression of Protein S (PROS1) in adult NSCs, and show that genetic ablation of Pros1 in neural progenitors increased hippocampal NSC proliferation by 47%. We show that PROS1 regulates the balance of NSC quiescence and proliferation, also affecting daughter cell fate. We identified the PROS1-dependent downregulation of Notch1 signaling to correlate with NSC exit from quiescence. Notch1 and Hes5 mRNA levels were rescued by reintroducing Pros1 into NCS or by supplementation with purified PROS1, suggesting the regulation of Notch pathway by PROS1. Although Pros1-ablated NSCs show multilineage differentiation, we observed a 36% decrease in neurogenesis, coupled with a similar increase in astrogenesis, suggesting PROS1 is instructive for neurogenesis, and plays a role in fate determination, also seen in aged mice. Rescue experiments indicate PROS1 is secreted by NSCs and functions by a NSC-endogenous mechanism. Our study identifies a duple role for PROS1 in stem-cell quiescence and as a pro-neurogenic factor, and highlights a unique segregation of increased stem cell proliferation from enhanced neuronal differentiation, providing important insight into the regulation and control of NSC quiescence and differentiation.
“It's Only Sport”—The Symbolic Neutralization of “Violence”
Authors: Matthews Christopher R. , Channon Alex
Published: October 2016

Within the commodified world of professional ice hockey, athletes sell their bodily performances in return for a salary. A central feature of this transaction is the very real risk of physical injury—a risk inherent within most contact sports, but particularly so within those that feature seemingly “violent” confrontations between competitors, as ice hockey is widely reputed to do. Yet, within the spectacle of sport, where physicality can be constructed as playful and unserious, it is possible for the consequences of such action to be concealed behind a symbolic, ludic veneer. Within this article, we explore this process with a particular focus on ice hockey spectators, for whom notions of sport violence as in some important way “mimetic” of the “real” enabled their propensity to both enjoy, and find moral validation through, potentially deleterious behaviors among athletes.
Generalized Timoshenko‐Reissner models for beams and plates, strongly heterogeneous in the thickness direction
Authors: Tovstik Petr E. , Tovstik Tatiana P.
Published: October 2016

The paper is concerned with a thin beam and a thin plate made of a transversally isotropic linearly elastic material heterogeneous in the thickness direction. The ordinary Kirchhoff–Love and Timoshenko–Reissner models are known to be unacceptable for a strongly heterogeneous material or for a multilayered material with large ratio between the Young moduli of layers. A generalized Timoshenko–Reissner model is proposed for bending and free vibrations of such beams/plates. A multilayered beam/plate is reduced to one‐layer one with the equivalent elastic parameters. The range of application of such a model is very wide.
Spatial characteristics of extreme rainfall over China with hourly through 24-hour accumulation periods based on national-level hourly rain gauge data
Authors: Zheng Yongguang , Xue Ming , Li Bo , Chen Jiong , Tao Zuyu
Published: October 2016

Hourly rainfall measurements of 1919 national-level meteorological stations from 1981 through 2012 are used to document, for the first time, the climatology of extreme rainfall in hourly through 24-h accumulation periods in China. Rainfall amounts for 3-, 6-, 12- and 24-h periods at each station are constructed through running accumulation from hourly rainfall data that have been screened by proper quality control procedures. For each station and for each accumulation period, the historical maximum is found, and the corresponding 50-year return values are estimated using generalized extreme value theory. Based on the percentiles of the two types of extreme rainfall values among all the stations, standard thresholds separating Grade I, Grade II and Grade III extreme rainfall are established, which roughly correspond to the 70th and 90th percentiles for each of the accumulation periods. The spatial characteristics of the two types of extreme rainfall are then examined for different accumulation periods. The spatial distributions of extreme rainfall in hourly through 6-h periods are more similar than those of 12- and 24-h periods. Grade III rainfall is mostly found over South China, the western Sichuan Basin, along the southern and eastern coastlines, and in the large river basins and plains. There are similar numbers of stations with Grade III extreme hourly rainfall north and south of 30°N, but the percentage increases to about 70% south of 30°N as the accumulation period increases to 24 hours, reflecting richer moisture and more prolonged rain events in southern China. Potential applications of the extreme rainfall climatology and classification standards are suggested at the end.
FkbN and Tcs7 are pathway-specific regulators of the FK506 biosynthetic gene cluster in Streptomyces tsukubaensis L19
Authors: Zhang Xiao-Sheng , Luo Hong-Dou , Tao Yang , Wang Yue-Yue , Jiang Xin-Hang , Jiang Hui , Li Yong-Quan
Published: October 2016

FK506 (tacrolimus), which is produced by many Streptomyces strains, is clinically used as an immunosuppressive agent and for treatment of inflammatory skin diseases. Here, we identified that the FK506 biosynthetic gene cluster in an industrial FK506-producing strain Streptomyces tsukubaensis L19 is organized as eight transcription units. Two pathway-specific regulators, FkbN and Tcs7, involved in FK506 biosynthesis from S. tsukubaensis L19 were characterized in vivo and in vitro. FkbN activates the transcription of six transcription units in FK506 biosynthetic gene cluster, and Tcs7 activates the transcription of fkbN. In addition, the DNA-binding specificity of FkbN was determined. Finally, a high FK506-producing strain was constructed by overexpression of both fkbN and tcs7 in S. tsukubaensis L19, which improved FK506 production by 89 % compared to the parental strain.
Parent-Endorsed Sex Differences in Toddlers with and Without ASD: Utilizing the M-CHAT
Authors: Øien Roald A. , Hart Logan , Schjølberg Synnve , Wall Carla A. , Kim Elizabeth S. , Nordahl-Hansen Anders , Eisemann Martin R. , Chawarska Katarzyna , Volkmar Fred R. , Shic Frederick
Published: October 2016

Sex differences in typical development can provide context for understanding ASD. Baron-Cohen (Trends Cogn Sci 6(6):248–254, 2002) suggested ASD could be considered an extreme expression of normal male, compared to female, phenotypic profiles. In this paper, sex-specific M-CHAT scores from N = 53,728 18-month-old toddlers, including n = 185 (32 females) with ASD, were examined. Results suggest a nuanced view of the “extreme male brain theory of autism”. At an item level, almost every male versus female disadvantage in the broader population was consistent with M-CHAT vulnerabilities in ASD. However, controlling for total M-CHAT failures, this male disadvantage was more equivocal and many classically ASD-associated features were found more common in non-ASD. Within ASD, females showed relative strengths in joint attention, but impairments in imitation.
Calcium‐induced apoptosis of developing cerebellar granule neurons depends causally on NGFI‐B
Authors: Austdal Lars Peter Engeset , Mathisen Gro H. , Løberg Else Marit , Paulsen Ragnhild E.
Published: October 2016

Immediate early gene nerve growth factor‐induced clone B (NGFI‐B), a nuclear receptor important for differentiation and apoptosis, is expressed in mice and rat cerebellum from an early stage of postnatal development. Following apoptotic stimuli NGFI‐B translocates to mitochondria to initiate cell death processes. Controlled cell death is critical for correct cerebellar development. Immunohistochemical analysis of NGFI‐B in sections of mice cerebella showed NGFI‐B to be expressed in granule neurons in vivo at a time (P8‐11) when apoptosis is known to occur. The importance of NGFI‐B for apoptosis of cultured rat cerebellar granule neurons was investigated by inducing apoptosis with calcium ionophore A23187 (CaI, 0.1 μM). Imaging studies of gfp‐tagged NGFI‐B confirmed that mitochondrial translocation of NGFI‐B occurred following treatment with CaI and was reduced by addition of 9‐cis‐retinoic acid (1 μM), a retinoid X receptor (RXR) agonist that prevents dimerization of RXR and NGFI‐B that is known to occur before translocation. Consequently, 9‐cis‐retinoic acid partly reduced cell death. To address the causality of NGFI‐B in apoptosis further, knock‐down by siRNA was performed and it removed 85% of the NGFI‐B protein. This resulted in a complete inhibition of apoptosis after CaI exposure. Together these findings suggest that NGFI‐B plays a role in controlling correct cerebellar development.
El papel de la rehabilitación tras las reparaciones de las inestabilidades de muñeca
Authors: Lerma E. , Baixauli V. , Selma F. , García F.
Published: October 2016

De las patologías de muñeca más frecuentes en la consulta del cirujano de la mano, las inestabilidades carpianas ocupan un lugar importante junto con el dolor en la vertiente ulnocarpiana cuya causa más frecuente son las lesiones del complejo fibrocartílago triangular, que en ocasiones van a condicionar una inestabilidad de la articulación radiocubital distal. Analizando los datos anatómicos y biomecánicos que diponemos de la muñeca y tomando como punto de partida los escasos protocolos rehabilitadores de las inestabilidades escafolunares y lunopiramidales que existen en la bibliografía, se exponen los programas rehabilitadores específicos para cada una de ellas. Se describen también los protocolos existentes para la rehabilitación tras las reparaciones del complejo fibrocartílago triangular y exponemos los protocolos con los que trabajamos en la actualidad.

Definimos también la importancia de la reeducación propioceptiva en este tipo de lesiones y describimos un programa detallado de introducción progresiva de determinados ejercicios encaminados a ello.
Autorreporte del rendimiento en exámenes: un informe exploratorio
Authors: Dominguez-Lara Sergio Alexis
Published: October 2016

En la investigación educativa, una de las principales limitaciones es la obtención de datos que escapan del anonimato: el rendimiento académico (rendimiento en exámenes o el promedio general).
Modelling Therapy Resistance for the Identification of Treatment-Refractory Cell Population(s) in Human Glioblastoma
Authors: Qazi M.A. , Vora P. , Venugopal C. , Bakhshinyan D. , Nixon A. , McFarlane N. , Subapanditha M.K. , Murty N.K. , Hallett R.M. , Moffat J. , Singh S.K.
Published: October 2016

Despite aggressive multimodal therapy, human glioblastoma (hGBM), a highly malignant grade IV astrocytic tumour, remains incurable and inevitably relapses. Recent data has implicated intratumoral heterogeneity as the driver of therapy resistance and tumour relapse in hGBM. Thus models that capture the evolving hGBM biology in response to chemoradiotherapy will allow for the identification of cellular pathways that govern GBM therapy failure. In this study, we have developed a novel model to profile the clonal evolution of treatment naïve brain tumour initiating cell (BTIC) enriched hGBMs through chemoradiotherapy using: stem cell assays, BTIC marker expression and transcriptome analysis, immunohistochemistry, and cellular DNA barcoding technology. We report that treatment of hGBM BTICs leads to increased self-renewal capacity and higher transcript expression of stem cell genes Bmi1 and Sox2. Based on global transcriptome analysis of the in vitro treated hGBM, we also identify a hyper-aggressive form of glioma. Using our therapy-adapted hGBM-mouse xenograft model, we discover that despite tumour regression and increased mouse survival post-therapy, tumour relapse remains inevitable. The treatment-refractory cells again have increased self-renewal capacity and higher expression of Bmi1 and Sox2. Furthermore, by combining cellular DNA barcoding technology, which barcodes hGBM at single cell resolution, with our novel in vitro and in vivo therapy models, we are able to determine whether a pre-existing or a therapy driven subpopulation(s) seeds hGBM tumour relapse. Profiling the dynamic nature of heterogeneous hGBM subpopulations through disease progression and treatment may lead to the identification of novel therapeutic targets for the treatment of recurrent hGBM.
OS4 - 161 Activated Wnt Signaling for the Therapeutic Targeting of Treatment-Refractory Medulloblastoma Stem Cells
Authors: Manoranjan B. , Mahendram S. , Bakhshinyan D. , Kameda-Smith M. , Venugopal C. , Doble B.W. , Singh S. K.
Published: October 2016

Brain tumours represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant pediatric brain tumour. Current molecular Nsubgroups of MB recognize distinct disease entities of which activated Wnt signaling (monosomy 6, exon 3 mutations in CTNNB1, and Wnt gene signature) is associated with a distinct subgroup and the best overall outcome. In contrast, only non-Wnt MBs are characterized by metastatic disease, increased rate of recurrence, and poor overall survivorship. Given the excellent clinical outcome in patients with Wnt-driven MB, we aimed to convert treatment-resistant MB subgroups into an ostensibly benign tumour through selective targeting by small molecule Wnt agonists (Wnt3A), GSK3 inhibitors (CHIR99021), and transgenic lines containing a stabilized beta-catenin mutant. Activated Wnt signaling resulted in decreased in vitro self-renewal and promoted differentiation within primary human MB stem cells. The clinical relevance of these findings were demonstrated with an in vivo survival advantage in mice containing orthotopic injections of cells containing a stabilized beta-catenin mutant representative of constitutively active Wnt signaling. Xenografts generated from Wnt-activated tumours were much smaller in size, maintained a much lower rate of proliferation, and reduction in key MB stem cell self-renewal genes (Bmi1, Sox2, Msi1, FoxG1). Our work establishes activated Wnt signaling as a novel treatment paradigm in childhood MB, while providing evidence for the context-specific tumour suppressive function of the canonical Wnt pathway.
OS8 - 150 Encouraging Survival with Toca 511 and Toca FC Compared to External Lomustine Control
Authors: Huang T.T , Aghi M.K , Chen C.C , Elder J.B , Kesari S , Kalkanis S , Kaptain G , Landolfi J , Mikkelsen T , Portnow J , Robbins J.M , Ostertag D , Das A , Chu A , Vogelbaum M.A
Published: October 2016

Recurrent glioblastoma (GBM) has an unmet need for effective therapies. Toca 511 (vocimagene amiretrorepvec), a retroviral replicating vector with the transgene cytosine deaminase, selectively infects, persists and spreads in tumor. Subsequent oral administration of 5-fluorocytosine (Toca FC) produces 5-fluorouracil (5-FU) within infected cells. 5-FU kills cancer cells and myeloid derived suppressor cells, inducing robust antitumor immune responses in animal models. In 2 Phase 1 studies, Toca 511 was administered into the cavity wall after surgical resection (NCT01470794) or intratumoral injection by biopsy needle (NCT01156584). To provide context to the results observed, subjects were compared to an external lomustine treated control (Courtesy Denovo Biopharma; Wick 2010). Treatment with Toca 511/Toca FC from 2 Phase I studies showed significant improvement in OS HR equals to 0.48, p less than 0.001, with similar effect in the surgical resection (OS HR 0.45, p equals to 0.003) and intratumoral injection (OS HR 0.56, p equals to 0.060). Fewer related greater or equal to Grade 3 adverse events (AEs) were reported for Toca 511/Toca FC (2.5 percent) vs. lomustine (36.9 percent). There was a virtual absence of hematologic toxicity for Toca 511/Toca FC vs. lomustine (Grade greater or equal to 3 thrombocytopenia 23.8 percent). Discontinuations for AEs occurred in 0percent for Toca 511/Toca FC vs. 4.8 percent for lomustine. Toca 511 is surgically delivered and treatment-emergent AEs regardless of attribution included incision site pain (20 percent), procedural pain (12.5 percent), and wound infection (5 percent) vs. 0percent, 1.2 percent, 1.2 percent respectively for lomustine. Toca 511/Toca FC significantly improved survival and safety relative to lomustine. A Phase 2/3 trial has launched (NCT02414165).
OS11 - 165 Brain Cancer Survival and Conditional Survival Rates in Canada (1992-2008)
Authors: Davis F. G. , Yuan Y. , Shi Q. , Nagamuthu C. , Andres E. , Ross J.
Published: October 2016

To investigate patterns of survival and estimate conditional survival rates among brain cancer patients in Canada. METHODS: Canadian Cancer Registry data were obtained for all patients with primary brain cancer diagnosed between 1992 and 2008 (n=38,095). Follow-up ended with patient death or December 31, 2008, whichever occurred first. Crude Kaplan-Meier estimates were calculated at one, two, and five years post-diagnosis and also used to estimate conditional survival (restricted to 2000-2008). Age group, sex, residence and microscopic confirmation were considered in estimating rates for major histology types using multivariate models. RESULTS: The overall five-year survival rate was 27%. Oligodendrogliomas had the highest 5-year survival rate (65%, 95% CI: 62.5-67.4%) and glioblastomas the lowest (4.0%, 95% CI: 3.7-4.3%). Compared to Ontario, the age- and sex-adjusted 5-year glioblastoma survival estimates were lower in British Columbia, Alberta and Manitoba-Saskatchewan, lower in all other regions for diffuse astrocytoma, and lower in Manitoba-Saskatchewan for anaplastic astrocytomas. Estimates were significantly higher for oligodendrogliomas in Alberta, and for anaplastic oligodendrogliomas in Alberta and Quebec (P<0.05). Longer term conditional survival rates (surviving an additional 2 years 1-4 years after diagnosis) varied by histologic group. CONCLUSION: There is a need to further explore the underlying reasons for the observed variation in survival rates by region in an effort to improve the prognosis of brain cancer in the Canadian patient population. Conditional survival information has value for clinicians as they plan the course of treatment and follow-up for individual patients.
PS1 -131 Dosimetric Feasibility of the Hybrid Magnetic Resonance Imaging (MRI)-LINAC System for Brain Metastases
Authors: Tseng C.
Published: October 2016

We aimed to investigate the feasibility of delivering stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiotherapy with the hybrid MRI-LINAC (MRL) system for patients with single brain metastases, and to characterize the dosimetric impact at tissue-air interfaces resulting from the electron return effect (ERE). Material/Methods: 24 patients treated for intact single brain metastases were selected for analysis. Three optimized radiotherapy plans with the same prescribed dose were generated for each case: 1) standard noncoplanar volumetric modulated arc therapy (VMAT), 2) coplanar step-and-shoot intensity modulated radiotherapy (IMRT) on the MRL in the absence (MRL_B=0), and 3) in the presence of the transverse magnetic field (MRL_B=1.5). The plans were evaluated using cumulative dose-volume histograms (DVHs) and by calculation of Paddick conformity index (PCI), V100%, V12Gy minus gross tumor volume (V12Gy – GTV), and V2Gy. The dosimetric impact of ERE to the skin and air cavities was quantified using a 5 mm rim of tissue around tissue-air boundaries. Results: All plans met the objectives with respective to target coverage and OAR constraints. Differences between all investigated dosimetric parameters significantly favored the VMAT plans as compared to the MRL_B=0 and MRL_B=1.5 plans, except for V2Gy. The VMAT plans showed a higher mean (±standard deviation) PCI compared to the MRL_B=0 and MRL_B=1.5 plans (0.85±0.08 vs. 0.79±0.09 vs. 0.78±0.11). In the presence of the magnetic field, ERE resulted in a statistically significant but small increase in mean dose and D2cc in the skin (0.08 Gy, p < 0.0001 and 0.66 Gy, p < 0.0001, respectively) and around air cavities (0.07 Gy, p = 0.0092 and 0.25 Gy, p = 0.0004, respectively). Conclusions: Stereotactic radiation to single brain metastases is feasible using the MRL Monaco treatment planning system; however, in its current iteration, application to small targets deserve careful consideration given the technical limitations resulting in less favorable plan quality compared to that of a noncoplanar standard VMAT technique. The dosimetric impact of ERE at tissue-air boundaries is minor and does not compromise target conformity or dose gradient.
PS1 - 189 A Universal Predictive Model for Dose Fall-Off in MLC-Based Stereotactic Brain Radiosurgery
Authors: Ruschin M. , Sahgal A. , Soliman H. , Chugh B. , Myrehaug S. , Tsao M. , Sarfehnia A. , Yeboah C. , Lee Y.
Published: October 2016

Predictive modeling of dose fall-off in radiosurgery could assist in clinical decision-making when prescribing a treatment plan with minimized toxicity risk. The purpose of this study is to develop a predictive dose fall-off model. Materials/Methods: We retrospectively reviewed treatment plans from 257 patients (365 lesions) with total doses ranging from 20 to 35Gy in 5 fractions. For each plan, we measured both total volume of the external contour (EXT) and BrainMinusPTV (BMP) receiving P=20% to P=80% of the prescription dose. The model has form y=Fa(PTV)b+/-delta. y=volume of EXT or BMP (cc’s); a and b are curve-fitting coefficients; PTV=total planning target volume (cc’s); F is an adjustment factor (>1) to account for number of targets; delta is the 95% prediction band. F, a, b, and delta were modeled such that dose-fall can be forecast for any PTV and dose level. Results: The model coefficients were as follows: Coefficient EXT BMP a 19927(100×P)exp(-2) 17122(100×P)exp(-2) b 0.42(100×P)exp(0.17) 0.63 F -0.0156×(100×P)+2.5517 delta 384467×(100×P)exp(-2.3159) The table can be used to determine the model for any P from 20% to 80%. Example: the EXT receiving 50%, P=0.5, a=8.0, b=0.82, F=1.8, delta=45. Thus, EXT-50=8(PTV0.82) or 1.8×8(PTV0.82) for 1-3 or >3 targets, respectively,+/-45cc’s. The model was verified against published values of dose fall-off from linacs. Conclusion: A predictive dose fall-off model was generated for linac-based radiosurgery. The model can be used for quality assurance or for inter-institutional comparisons. Ongoing work is being conducted to extend the model to a SRS cones system.
PS1 - 163 Engaging in Difficult Discussions with Neuro-Oncology Patients: A Case Conference Based Quality Improvement Initiative
Authors: Mueller C. , Bilodeau D.B. , Chakraborty A.C. , Ellis J.E. , Gibson L.G. , Isenberg-Grzeda E.I. , Moroney C.M. , Myers J.M. , Scalco A.S. , Speke A.S.
Published: October 2016

Due to the non-curative nature of high grade brain tumours “difficult discussions” about goals of care, advance care planning, palliative care, and end of life are inherent to the practice of the neuro-oncology team. Clinician and patient barriers are common and may include anxiety about destroying hope, lack of readiness to discuss end of life topics, difficulty managing emotional responses, and concerns over competency in facilitating difficult discussions. Nonetheless, clinician comfort and skill in facilitating these discussions is critical and can impact patient perception of illness, coping response, and ability to make decisions about care. Methods At our regional cancer centre, a novel quality improvement initiative was designed to bring monthly case presentation of “difficult discussions” into a pre-existing weekly multi-disciplinary case conference (MCC). We will describe the rationale and developmental processes behind this initiative. Roughly 15 neuro-oncology clinicians attended each case conference, with guest attendance from palliative care and psychosocial oncology. Clinician groups represented included physicians (77%), nurses (8%), nurse practitioners (10 %), and occupational therapists (5%). Baseline and monthly surveys were administered to determine clinicians’ self- rated practices, skills, and attitudes towards “difficult discussions”. Results Early findings indicate that the initiative has been well-received. Physicians indicated highest levels of agreement with the statement “I feel that having difficult discussions is part of my responsibility”. Non physician groups indicated the greatest agreement that the intervention is beneficial to their practice. Discussion: Our challenges and successes may help guide others to incorporate a similar initiative at disease-site meetings.
PS1 - 158 The Role of LIN28A in Neoplastic Transformation of Human Embryonic Stem Cells (hESCs)
Authors: Kaur R. , Liang L. , Werbowetski-Ogilvie T.
Published: October 2016

Human embryonic stem cells (hESCs) are known for their indefinite self-renewal ability and pluripotent nature. However, during long-term culture, normal hESCs can undergo neoplastic transformation and acquire enhanced self-renewal ability and aberrant differentiation potential. These transformed-hESCs (trans-hESCs) exhibit high expression of the pluripotent gene, LIN28A. LIN28A, an RNA binding protein, is known: for its role in self-renewal of hESCs, as a reprogramming factor for generating induced-pluripotent stem cells and as a potent oncogene in several poorly differentiated, highly malignant human cancers. Despite its multiple functions, how LIN28A contributes to neoplastic transformation of normal hESCs is poorly understood. Our preliminary data demonstrate that following LIN28A knockdown, trans-hESCs display normal hESCs morphology consisting of both pluripotent colony cells surrounded by more differentiated fibroblast-like cells. Neural precursors derived from LIN28A knockdown trans-hESCs also revert back to a state of normal cell morphology and growth. Further analyses revealed that the expression levels of stage-specific embryonic antigen (SSEA3), OCT3/4 and NANOG decreases and are comparable to that observed in normal hESCs following LIN28A downregulation. Expression of miRNA targets of LIN28A such as let7i and mir125b was increased to levels seen in normal hESCs. These preliminary results indicate that LIN28A is a major contributing factor to neoplastic transformation of hESCs and that this process can be reversed by cellular “reprogramming”. This study will enhance our understanding of role of LIN28A in the transformation process in various human cancers thus, underscoring the value of hESCs and their neoplastic-derivatives as cellular and molecular model for studying tumor progression.
PS2 - 194 Bcl-2 Family Member Mcl-1 Expression is Reduced Under Hypoxia by the E3 Ligase FBW7 Contributing to BNIP3 Induced Cell Death In Glioma Cells
Authors: Chen Y. , Henson E. , Shome E. , Xiao W. , Eisenstat D.D. , Gibson S.B.
Published: October 2016

Mcl-1 is an anti-apoptotic Bcl-2 family member that is often over-expressed in the malignant brain tumour glioblastoma (GBM). It has been previously shown that epidermal growth factor receptors (EGFR) up-regulate Mcl-1 expression contributing to a cell survival response. Hypoxia is a poor prognostic marker in glioblastoma despite the fact that hypoxic regions have areas of necrosis. Hypoxic regions of GBM also highly express the pro-cell death Bcl-2 family member BNIP3, yet when BNIP3 is over-expressed in glioma cells, it induces cell death. The reasons for this discrepancy are unclear. METHODS: Using malignant glioma cell lines +/- hypoxia, gain and/or loss of function assays of BNIP3 or Mcl-1 were performed. BNIP3 and MCL-1 expression was assessed in GBM tumours from adult patients and human gliomas grown as xenografts in immunocompromised mice. RESULTS: Mcl-1 expression is reduced under hypoxia due to degradation by the E3 ligase FBW7 leading to increased hypoxia-induced cell death. This cell death is augmented by EGFR activation leading to increased Mcl-1 expression under hypoxia. Conversely, BNIP3 is over-expressed in hypoxia at times when Mcl-1 expression is decreased. Knocking down BNIP3 expression reduces hypoxia cell death and Mcl-1 expression effectively blocks BNIP3-induced cell death. Of significance, BNIP3 and Mcl-1 are co-localized under hypoxia in glioma cells, GBM tumours and in xenograft glioma tumours expressing mutant EGFR (EGFRvIII). CONCLUSION: These results support that Mcl-1 can block the ability of BNIP3 to induce cell death under hypoxia in GBM tumours
PS2 - 209 RXFP1 Promotes Temozolomide Chemoresistance by STAT3 Signaling Pathway Activation
Authors: Thanasupawat T. , Glogowska A. , Burg M. , Krcek J. , Beiko J. , Pitz M. , Hombach-Klonisch S. , Klonisch T.
Published: October 2016

We identified the G protein coupled relaxin receptor RXFP1 in glioblastoma (GB) and discovered C1q-tumor necrosis factor related protein 8 (CTRP8) as a novel ligand of RXFP1 in this common and most aggressive form of brain tumor. The known RXFP1 ligand relaxin isoform 2 (RLN2) is not expressed in the brain indicating that RXFP1 signaling in GB is activated by auto-/paracrine secretion of CTRP8. In GB, RXFP1 signaling included PI3K and PKC activation and resulted in the increased production and secretion of lysosomal protease cathepsin B, a known prognostic marker of GB. In the present study, we have investigated the potential role of RXFP1 in chemoresistance to the commonly used DNA alkylating drug temozolomide (TMZ) in human GB. Upon TMZ treatment, CTRP8/RLN2 mediated activation of RXFP1 was able to mitigate DNA damage in human primary GB cells and enhanced their survival. Activation of RXFP1 resulted in STAT3 pathway activation and the RXFP1- and STAT3-dependent up-regulation of proteins and their activity deemed important for TMZ-induced DNA damage repair. Furthermore, RXFP1 activation resulted in the up-regulation of key anti-apoptotic factors in human GB cells. Our results indicate a novel role for the CTRP8-RXFP1 ligand-receptor system in STAT3-dependent cell invasion, TMZ chemoresistance, and survival and identify RXFP1 as a new protective G protein coupled receptor in GB cells.
PC3 - 151 Toca 5: A Phase 2/3 Randomized, Open-Label Study of Toca 511, a Retroviral Replicating Vector, Combined with Toca FC versus Standard of Care in Patients Undergoing Planned Resection for Recurrent Glioblastoma (GBM) or Anaplastic Astrocytoma (AA) (NCT02414165)
Authors: Zadeh G. , Bota D. , Cachia D. , Landolfi J. , Schiff D. , Vogelbaum M.A. , Walbert T. , Tran D. , Chu A. , Das A. , Jolly D.J. , Ibañez C.E. , Ostertag D. , Sully S. , Cloughesy T.F.
Published: October 2016

Recurrent GBM and AA have a dismal prognosis and a high unmet need for effective therapies. Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that encodes the transgene cytosine deaminase (CD). Toca 511 selectively infects, persists and spreads in tumor. Subsequent oral administration of 5-fluorocytosine (Toca FC) produces 5-fluorouracil (5-FU) by CD within infected cells. 5-FU kills cancer cells and myeloid derived suppressor cells, inducing robust antitumor immune responses in animal models. Clinical data from phase 1 trials are consistent with this mechanism of action, and show extended survival compared to historical controls. Toca 5 is a multicenter, randomized, open-label Phase 2/3 trial of Toca 511 and Toca FC versus standard of care administered to patients undergoing resection for first or second recurrence of GBM or AA. Phase 2 will enroll 170 patients. Primary endpoint is overall survival (OS). Key secondary endpoints are safety, objective response rate, clinical benefit rate, progression-free survival, and landmark OS. Key inclusion criteria are age 18-75 years, histologically proven GBM or AA, measurable disease preoperatively of less than 5cm, candidate for equal or greater 80% resection of enhancing tumor based on pre-operative evaluation, and KPS equal or greater to 70. Assays for immune monitoring will be performed and molecular profiling of resected tumor samples will be correlated efficacy.
PC3 - 180 Is Conventional and Perfusion MRI Useful in Predicting Histopathology Defined Percentage of Recurrence in High Grade Gliomas
Authors: Nguye T.B.
Published: October 2016

New enhancing lesions after surgery and chemoradiation for high grade glioma commonly contain variable proportions of tumor recurrence (TR), tissue necrosis and treatment related changes. Our purpose is to determine whether the pattern of contrast enhancement and perfusion MR parameters correlate with the percentage of TR in these lesions. Methods: We prospectively enrolled 30 patients with high grade gliomas who presented with a new enhancing lesion suspicious for tumor recurrence. Each patient underwent conventional MRI with DCE and DSC perfusion MRI. The pattern of enhancement was classified by a blinded neuroradiologist in 5 different categories (solid, focal nodular, peripheral rim, hazy, punctate). A hot spot region-of-interest analysis was performed for each parametric map (Ktrans, AUC, Vp, corrected CBV). TR percentage was defined histopathologically. The lesions were categorized into predominant TR (=tumor>70%), predominant treatment related changes (T=<35%) and mixed lesions (35 %< T=<70%). Differences between the groups were assessed via Kruskal-Wallis and Mann-Whitney U tests. Results: There were 32 lesions (4 predominantly treatment related lesions,5 mixed lesions,23 predominant tumor recurrence). There is no significant difference in the enhancement pattern between the three groups (p=0.18).Statistically significant difference was only seen for corrected CBV between the three groups (p=0.01), mainly between the mixed and predominant tumor groups. The rest of the perfusion parameters did not show a statistically significant difference between the groups(p>0.05). Conclusion: Corrected CBV might be useful in predicting the proportion of tumor recurrence in post-treatment high grade gliomas.
PC3 - 130 A Meta-Analysis on the use of High-Dose Methotrexate Only Versus Combination Chemotherapy for the Treatment of Newly-Diagnosed Patients with Primary CNS Lymphoma
Authors: Concepcion Sales M.C.
Published: October 2016

Primary CNS Lymphoma (PCNSL) is an unusual extranodal form of Non-Hodgkin’s Lymphoma with a locally aggressive course but a rare tendency to disseminate systemically. There are various modalities available for the treatment of PCNSL which include chemotherapy, radiotherapy, surgery and immunotherapy. The effectiveness of adding another anti-neoplastic agent to HD-MTX have been optimized in small scale studies yet the “ perfect combination” has yet to be elucidated Objectives: This study aims to 1) compare the response to treatment of monotherapy with high-dose Methotrexate (HD-MTX) versus HD-MTX and an additional anti-neoplastic agent by evaluating complete response, partial response, stable disease and disease progression and 2) to compare the hematologic and non-hematologic side effects among patients subjected to monotherapy vs combination chemotherapy. Methodology: Journals from Medline, EMBASE, Cochrane Central Register of Control Trials (CENTRAL) and other relevant websites (www.clinicaltrials.org) without any restrictions in the year, language and status of publication were searched. Literatures cited by eligible studies and systemic reviews were also checked to identify useful articles. The following Medical Subject Headings (MeSH) were used: ‘primary CNS lymphoma’, ‘treatment’, ‘chemotherapy’ and ‘randomized control trial’. Statistical analysis was performed using the RevMan software version 5.1. Odds ratio (OR) and 95 % confidence interval (95% CI) were used as summary statistics. Results and Conclusion: The use of high-dose methotrexate and another anti-neoplastic agent showed benefit in terms of achieving complete response and delaying disease progression among patients diagnosed with PCNSL. However, the risks of hematologic toxicities such as anemia, neutropenia, thrombocytopenia and infection was higher in patients treated with the combination chemotherapy. Significant non-hematologic side effects such as mucositis was also observed in patients receiving an add-on to high dose methotrexate.
PC3 - 138 Stereotactic Radiosurgery for Intracranial Hemangiopericytomas – A Multicenter Study
Authors: Cohen-Inbar O.
Published: October 2016

Hemangiopericytomas (HPC) are widely recognized for their aggressive clinical behavior. We report a large multicenter study, through the International Gamma Knife Research Foundation reviewing management and outcome following stereotactic radiosurgery (SRS) for recurrent or newly-discovered HPC’s. Methods: Eight centers participated, reviewing a total of 90 patients harboring 133 tumors. Prior treatments included embolization (n = 8), chemotherapy (n=2), and fractionated radiotherapy (n=34). The median tumor volume at the time of SRS was 4.9 ml (range 0.2-42.4 ml). WHO-grade II (typical) HPC’s formed 78.9% (n=71) of the cohort. The median margin and maximal doses delivered were 15 Gy (2.8-24) and 32 Gy (8-51), respectively. The median clinical and radiographic follow-up period was 59 months (6-190) and 59 months (6-183), respectively. Results: At last follow-up, 55% of tumors and 62.2% of patients demonstrated local tumor control. New remote intracranial tumors were found in 27.8%. 24.4% of patients developed extra-cranial metastases. Adverse radiation effects were noted in 6.7%. The overall survival was 91.5%, 82.1%, 73.9%, 56.7%, and 53.7% at 2, 4, 6, 8, and 10 years, respectively, after initial SRS. Local progression free survival was 81.7%, 66.3%, 54.5%, 37.2%, and 25.5% at 2, 4, 6, 8, and 10 years, respectively, after initial SRS. In our cohort, 32 patients underwent 48 repeat SRS procedures for 76 lesions. Margin dose greater than 16 Gy (p=0.037) and tumor histology (p=0.006) were shown to influence PFS. Conclusions: SRS provides a reasonable rate of local tumor control and a low risk of adverse effects
PC3 - 216 Presentation of Intradural Extramedullary Plasmacytoma with Intratumoral Hemorrhage: Case Report and Review of Literature
Authors: Ghare A. , Haji F. , MacDougall K.
Published: October 2016

Plasmacytomas are solitary tumours characterized by neoplastic proliferation of plasma cells and can be found isolated or in associated with multiple myeloma. Plasmacytomas uncommonly occur intracranially, and dural plasmacytomas without involvement of the calvarium are exceedingly rare. Reported cases indicate durally-based plasmacytomas mimick the appearance of meningioma, lymphoma or sarcoma of the dura. The authors report a case of a 77-year-old male with known multiple myeloma who presented with a 3-week history of confusion, speech impediment, and right sided weakness. A non-contrast CT scan revealed a dense extra-axial mass in the left frontal lobe with initial concerns of an extra-axial hemorrhage. A subsequent MRI demonstrated a contrast enhancing mass with a broad-based dural tail and no underlying calvarial lesion. Differential diagnosis included meningioma or intracranial plasmacytoma. The patient underwent surgical resection and was found to have intratumoural hemorrhage, with pathology confirming plasmacytoma. In the published literature, there are only 20 prior reports of dural plasmacytomas (with and without primary calvarial infiltration), of which only five previous cases reported associated intratumoural hemorrhage. Our case, along with this literature, suggests that new onset of focal neurologic deficits in patients with a history of multiple myeloma merits careful investigation, and that intracranial plasmacytoma should be considered on the differential diagnosis even when imaging reveals masses consistent with hemorrhage or meningioma.
LOCAL COHOMOLOGY OF MULTI-REES ALGEBRAS, JOINT REDUCTION NUMBERS AND PRODUCT OF COMPLETE IDEALS
Authors: SARKAR PARANGAMA , VERMA J. K.
Published: October 2016

We find conditions on the local cohomology modules of multi-Rees algebras of admissible filtrations which enable us to predict joint reduction numbers. As a consequence, we are able to prove a generalization of a result of Reid, Roberts and Vitulli in the setting of analytically unramified local rings for completeness of power products of complete ideals.
Low-protein diet supplemented with ketoacids ameliorates proteinuria in 3/4 nephrectomised rats by directly inhibiting the intrarenal renin–angiotensin system
Authors: Zhang Jia-ying , Yin Ying , Ni Li , Long Quan , You Li , Zhang Qian , Lin Shan-yan , Chen Jing
Published: October 2016

Low-protein diet plus ketoacids (LPD+KA) has been reported to decrease proteinuria in patients with chronic kidney diseases (CKD). However, the mechanisms have not been clarified. As over-activation of intrarenal renin–angiotensin system (RAS) has been shown to play a key role in the progression of CKD, the current study was performed to investigate the direct effects of LPD+KA on intrarenal RAS, independently of renal haemodynamics. In this study, 3/4 subtotal renal ablated rats were fed 18 % normal-protein diet (Nx-NPD), 6 % low-protein diet (Nx-LPD) or 5 % low-protein diet plus 1 % ketoacids (Nx-LPD+KA) for 12 weeks. Sham-operated rats fed NPD served as controls. The level of proteinuria and expression of renin, angiotensin II (AngII) and its type 1 receptors (AT1R) in the renal cortex were markedly higher in Nx-NPD group than in the sham group. LPD+KA significantly decreased the proteinuria and inhibited intrarenal RAS activation. To exclude renal haemodynamic impact on intrarenal RAS, the serum samples derived from the different groups were added to the culture medium of mesangial cells. It showed that the serum from Nx-NPD directly induced higher expression of AngII, AT1R, fibronectin and transforming growth factor-β1 in the mesangial cells than in the control group. Nx-LPD+KA serum significantly inhibited these abnormalities. Then, proteomics and biochemical detection suggested that the mechanisms underlying these beneficial effects of LPD+KA might be amelioration of the nutritional metabolic disorders and oxidative stress. In conclusion, LPD+KA could directly inhibit the intrarenal RAS activation, independently of renal haemodynamics, thus attenuating the proteinuria in CKD rats.
The phonetics and phonology of lexical prosody in San Jerónimo Acazulco Otomi
Authors: Turnbull Rory
Published: October 2016

San Jerónimo Acazulco Otomi (SJAO) is an underdescribed and endangered Oto-Manguean language spoken in central Mexico. This paper provides an analysis of the phonology of tonal contrasts in SJAO and the phonetics of their realization based on pitch pattern data derived from audio recordings of citation forms of SJAO words. Each SJAO lexical word has one and only one tonal sequence – either /H/ or /HL/. This sequence is underlyingly associated with one syllable in the word. Other syllables are not specified for tone, and their phonetic realization is predictable depending on their position relative to the tonal syllable. A phonetic analysis revealed that underlyingly-tonal syllables are phonetically distinct from non-tonal syllables: those with /H/ are produced with greater vocal effort (measured by spectral tilt), and those with /HL/ are longer, louder, and bear a higher f0 (fundamental frequency), compared with non-tonal syllables. This analysis differs from previous accounts of lexical prosody in other Otomi varieties, which have either described a three-way system of high, low, and rising tones contrasting on every stem syllable, or a system where one syllable per word is assigned a stress-like ‘accent’. This difference from previous analyses suggests that there is a third possible characterization of lexical prosody for Otomi, which is appropriate for SJAO and potentially other understudied varieties.