bluuebunny/crossref_metadata_2025 huggingface dataset:
Portfolio Entrepreneurship and Resource Orchestration
Authors: Baert Caroline , Meuleman Miguel , Debruyne Marion , Wright Mike
Published: October 2016

Research summary

This study examines the role of resource orchestration for the exploration and exploitation of opportunities through portfolio entrepreneurship. Adopting a single‐case study approach, we identify eight distinctive resource orchestration subprocesses that we group into three aggregate resource orchestration processes that enable the development and exploitation of a set of resources and capabilities across a portfolio of ventures. Our findings extend the literature on enduring entrepreneurship by building theory on how resource orchestration across a portfolio of ventures facilitates the emergence of synergies when exploring and exploiting opportunities.

Managerial summary

This study examines the processes through which an entrepreneur structures and rearranges resources and capabilities across multiple firms as he/she grows a portfolio of firms to engage in the exploration and exploitation of market opportunities. Entrepreneurs can obtain insights for building their businesses from the eight processes we identify; these processes allow entrepreneurs to develop synergies as they create and put to use a set of resources and capabilities across their businesses. Through these synergies, entrepreneurs can share, transform, and harmonize resources and capabilities across their firms. This can enable them to continuously and simultaneously explore and exploit market opportunities, which ultimately facilitates the sustainability of their businesses. Copyright © 2016 Strategic Management Society.
Nanopore Sensing in Aqueous Two‐Phase System: Simultaneous Enhancement of Signal and Translocation Time via Conformal Coating
Authors: Lee Sang Jun , Kang Ji Yoon , Choi Wonjoon , Kwak Rhokyun
Published: October 2016

Nanofluidic resistive pulse sensing (RPS) has been extensively used to measure the size, concentration, and surface charge of nanoparticles in electrically conducting solutions. Although various methods have been explored for improving detection performances, intrinsic problems including the extremely low particle‐to‐pore volume ratio (<0.01%) and fast nanoparticle translocation (10–1000 µs) still induce difficulties in detection, such as low signal magnitudes and short translocation times. Herein, we present an aqueous two‐phase system (ATPS) in a nanofluidic RPS for amplifying translocation signals and decreasing translocation speeds simultaneously. Two immiscible aqueous liquids build a liquid‐liquid interface inside nanopores. As particles translocate from a high‐affinity liquid phase into a lower‐affinity one, the high‐affinity liquid forms a conformal coating on the particles, which increases the effective particle size and amplifies the current‐blockage signal. The translocation time is also increased, as the ATPS interface impedes the particle translocation. For 20 nm particles, 7.92‐fold and 5.82‐fold enhancements of signal magnitude and translocation time can be achieved. To our knowledge, this is the first attempt to improve nanofluidic RPS by treating an interface of solution reservoirs for manipulating target particles rather than nanopores. This direct particle manipulation allows us to solve the two intrinsic problems all at once.
Metallic Nanowire‐Based Transparent Electrodes for Next Generation Flexible Devices: a Review
Authors: Sannicolo Thomas , Lagrange Mélanie , Cabos Anthony , Celle Caroline , Simonato Jean‐Pierre , Bellet Daniel
Published: October 2016

Transparent electrodes attract intense attention in many technological fields, including optoelectronic devices, transparent film heaters and electromagnetic applications. New generation transparent electrodes are expected to have three main physical properties: high electrical conductivity, high transparency and mechanical flexibility. The most efficient and widely used transparent conducting material is currently indium tin oxide (ITO). However the scarcity of indium associated with ITO's lack of flexibility and the relatively high manufacturing costs have a prompted search into alternative materials. With their outstanding physical properties, metallic nanowire (MNW)‐based percolating networks appear to be one of the most promising alternatives to ITO. They also have several other advantages, such as solution‐based processing, and are compatible with large area deposition techniques. Estimations of cost of the technology are lower, in particular thanks to the small quantities of nanomaterials needed to reach industrial performance criteria. The present review investigates recent progress on the main applications reported for MNW networks of any sort (silver, copper, gold, core‐shell nanowires) and points out some of the most impressive outcomes. Insights into processing MNW into high‐performance transparent conducting thin films are also discussed according to each specific application. Finally, strategies for improving both their stability and integration into real devices are presented.
Pre-Transplantation Blockade of TNF-α-Mediated Oxygen Species Accumulation Protects Hematopoietic Stem Cells
Authors: Ishida Takashi , Suzuki Sachie , Lai Chen-Yi , Yamazaki Satoshi , Kakuta Shigeru , Iwakura Yoichiro , Nojima Masanori , Takeuchi Yasuo , Higashihara Masaaki , Nakauchi Hiromitsu , Otsu Makoto
Published: October 2016

Hematopoietic stem cell (HSC) transplantation (HSCT) for malignancy requires toxic pre-conditioning to maximize anti-tumor effects and donor-HSC engraftment. While this induces bone marrow (BM)-localized inflammation, how this BM environmental change affects transplanted HSCs in vivo remains largely unknown. We here report that, depending on interval between irradiation and HSCT, residence within lethally irradiated recipient BM compromises donor-HSC reconstitution ability. Both in vivo and in vitro we demonstrate that, among inflammatory cytokines, TNF-α plays a role in HSC damage: TNF-α stimulation leads to accumulation of reactive oxygen species (ROS) in highly purified hematopoietic stem/progenitor cells (HSCs/HSPCs). Transplantation of flow-cytometry—sorted murine HSCs reveals damaging effects of accumulated ROS on HSCs. Short-term incubation either with an specific inhibitor of tumor necrosis factor receptor 1 signaling or an antioxidant N-acetyl-L-cysteine (NAC) prevents TNF-α-mediated ROS accumulation in HSCs. Importantly, pre-transplantation exposure to NAC successfully demonstrats protective effects in inflammatory BM on graft-HSCs, exhibiting better reconstitution capability than that of nonprotected control grafts. We thus suggest that in vivo protection of graft-HSCs from BM inflammation is a feasible and attractive approach, which may lead to improved hematopoietic reconstitution kinetics in transplantation with myeloablative conditioning that inevitably causes inflammation in recipient BM.
On modeling of a thickness‐shear vibrating quartz crystal plate attached with micro‐beams immersed in liquid with considering couple stress effects
Authors: Xie Xuan , Xie Jiemin , Chen Xuedong , Hu Yuantai
Published: October 2016

A coupling model for a compound quartz crystal resonator (QCR) system, consisting of a QCR under the thickness‐shear mode (TSM) vibrations and surface micro‐beam arrays immersed in liquid, is developed using the modified couple stress theory and the Hamilton's variational principle. Couple stresses are included in both governing equations of micro‐beams and the quartz crystal plate. Incorporating the boundary conditions, a set of homogeneous equations is numerically solved to get the frequency shift caused by micro‐beams for different material parameters, such as Young's modulus and material characteristic length. The normalized beam deflections are plotted and discussed. Influence of couple stresses of both micro‐beams and QCR together with their interaction on frequency shift is discussed in detail. The obtained results are useful in measuring geometrical and physical properties of micro‐beams using plate‐like acoustic wave sensors.
Implementierung des Ökosystemleistungs-Ansatzes in deutschen Biosphärenreservaten
Authors: Plieninger Tobias , Woltering Manuel , Job Hubert
Published: October 2016

To safeguard ecosystem services has been defined as a central goal for large protected areas in several international agreements. This study investigates the importance of the ecosystem services approach for biosphere reserves in Germany. The ecosystem services approach can be useful in various fields for large protected areas, e. g. as approach in communication, fundraising, monitoring, planning and management. The analysis of the evaluation reports of the currently 15 UNESCO biosphere reserves in Germany shows a high variation in the degree of implementing the ecosystem services approach. The biosphere reserves at the North Sea coast are leading, possibly as they are subject to the trilateral agreement on the Wadden Sea, as the evaluation reports are fairly new, and they have better equipped management, being biosphere reserves and national parks at the same time. Important barriers of the implementation of the ecosystem services approach may arise from limited resources and from the administrative allocation of reserve management to environmental ministries, which is in conflict with the cross-sectoral character of the ecosystem services approach.
Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy
Authors: Lv Mengqi , Wang Chongyuan , Li Fudong , Peng Junhui , Wen Bin , Gong Qingguo , Shi Yunyu , Tang Yajun
Published: October 2016

Mitophagy is an essential intracellular process that eliminates dysfunctional mitochondria and maintains cellular homeostasis. Mitophagy is regulated by the post-translational modification of mitophagy receptors. Fun14 domain-containing protein 1 (FUNDC1) was reported to be a new receptor for hypoxia-induced mitophagy in mammalian cells and interact with microtubule-associated protein light chain 3 beta (LC3B) through its LC3 interaction region (LIR). Moreover, the phosphorylation modification of FUNDC1 affects its binding affinity for LC3B and regulates selective mitophagy. However, the structural basis of this regulation mechanism remains unclear. Here, we present the crystal structure of LC3B in complex with a FUNDC1 LIR peptide phosphorylated at Ser17 (pS17), demonstrating the key residues of LC3B for the specific recognition of the phosphorylated or dephosphorylated FUNDC1. Intriguingly, the side chain of LC3B Lys49 shifts remarkably and forms a hydrogen bond and electrostatic interaction with the phosphate group of FUNDC1 pS17. Alternatively, phosphorylated Tyr18 (pY18) and Ser13 (pS13) in FUNDC1 significantly obstruct their interaction with the hydrophobic pocket and Arg10 of LC3B, respectively. Structural observations are further validated by mutation and isothermal titration calorimetry (ITC) assays. Therefore, our structural and biochemical results reveal a working model for the specific recognition of FUNDC1 by LC3B and imply that the reversible phosphorylation modification of mitophagy receptors may be a switch for selective mitophagy.
Fathers’ Imprisonment and Mothers’ Multiple-Partner Fertility
Authors: Cancian Maria , Chung Yiyoon , Meyer Daniel R.
Published: October 2016

We consider the intersection between two striking U.S. trends: dramatic increases in the imprisonment of fathers and increases in the proportion of mothers who have children with more than one partner (multiple-partner fertility, or MPF). Using matched longitudinal administrative data that provide unusually comprehensive and accurate information about the occurrence and timing of imprisonment, fertility, and MPF for the population of the state of Wisconsin, we consider the relationship between paternal imprisonment and MPF among unwed mothers. Employing discrete-time event history analysis with multinomial logistic regression, we model the occurrence and timing of the mother’s second birth, distinguishing between a birth with the same father and a birth with a different father, and distinguishing between current imprisonment and a history of imprisonment. We find that current imprisonment is associated with an increased likelihood of MPF and a decreased likelihood of fertility with the same father (compared with no additional birth) and that a history of imprisonment is associated with increased MPF in some models but not in our preferred model. To control for unobserved heterogeneity among mothers and assess the evidence of a causal effect of fathers’ imprisonment, we also employ the case-time-control method, a fixed-effects method for the analysis of nonrepeated events. Results suggest that fathers’ current imprisonment may increase mothers’ MPF. Policy implications are discussed.
Ready, Willing, and Able? Impediments to the Onset of Marital Fertility Decline in the United States
Authors: Hacker J. David
Published: October 2016

This study relies on IPUMS samples of the 1850, 1860, 1870, and 1880 censuses, aggregate census data, and the timing of state laws criminalizing abortion to construct regional estimates of marital fertility in the United States and estimate correlates of marital fertility. The results show a significant lag between the onset of marital fertility decline in the nation’s northeastern census divisions and its onset in western and southern census divisions. Empirical models indicate the presence of cultural, economic, and legal impediments to the diffusion of marital fertility control and illustrate the need for more inclusive models of fertility decline.
How a teaching rotation in medical school affects graduates’ subsequent careers
Authors: Kloek Anne T. , Van Zijl Angela C.M. , Ten Cate Olle T.J.
Published: October 2016

Introduction Teaching opportunities and teacher courses for medical students are increasingly offered by medical schools but little has been investigated about their long-term effect. The aim of our study was to investigate the long-term career effect of an intensive elective teaching experience for final year medical students.

Methods We approached UMC Utrecht medical graduates who had taken a final year, 6‑week full time student teaching rotation (STR) elective, 6 to 9 years after graduation, with an online survey to ask about their educational activities and obtained teaching certificates, their current roles related to education, and their appreciation of the rotation, even if this was a long time ago. In addition, we surveyed control groups of students who had not taken the STR, divided into those who had expressed interest in the STR but had not been placed and those who had not expressed such interest.

Results We received responses from 50 STR graduates and 88 non-STR graduates (11 with interest and 77 without interest in the STR). STR graduates were more educationally active, had obtained more university teaching certificates and were more enthusiastic teachers. However, we could not exclude confounding, caused by a general interest in education even before the STR.

Conclusions Our findings indicate a high appreciation of the student teaching rotation and a likely but not proven long-term association between STR participation and building an educational career.
Geometry of minimizers for the interaction energy with mildly repulsive potentials
Authors: Carrillo J.A. , Figalli A. , Patacchini F.S.
Published: October 2016

We show that the support of any local minimizer of the interaction energy consists of isolated points whenever the interaction potential is of class

C^{2}

and mildly repulsive at the origin; moreover, if the minimizer is global, then its support is finite. In addition, for some class of potentials we prove the validity of a uniform upper bound on the cardinal of the support of a global minimizer. Finally, in the one-dimensional case, we give quantitative bounds.
Etanercept, an inhibitor of TNF‐a, prevents propofol‐induced neurotoxicity in the developing brain
Authors: Chen Bo , Deng Xiaoyuan , Wang Bin , Liu Hongliang
Published: October 2016

Propofol can induce acute neuronal apoptosis, neuronal loss or long‐term cognitive impairment when exposed in neonatal rodents, but the mechanisms by which propofol induces developmental neurotoxicity are unclear. Recent studies have demonstrated that propofol can increase the TNF‐α level in the developing brain, but there is a lack of direct evidence to show whether TNF‐α is partially or fully involved in propofol‐induced neurotoxicity. The present study shows that propofol exposure in neonatal rats induces an increase of TNF‐α in the cerebral spinal fluid, hippocampus and prefrontal cortex (PFC). Etanercept, a TNF‐α inhibitor, prevents propofol‐induced short‐ or long‐term neuronal apoptosis, neuronal loss, synaptic loss and long‐term cognitive impairment. Furthermore, mTNF‐α (precursor of TNF‐α) expression in microglia cells is increased after propofol anaesthesia in either the hippocampus or PFC, but mTNF‐α expression in neurons is only increased in the PFC. These findings suggest that TNF‐α may mediate propofol‐induced developmental neurotoxicity, and etanercept can provide neural protection. Microglia are the main cellular source of TNF‐α after propofol exposure, while the synthesis of TNF‐α in neurons is brain‐region selective.
Analysis of first and second trimester maternal serum analytes for the prediction of morbidly adherent placenta requiring hysterectomy
Authors: Oztas Efser , Ozler Sibel , Caglar Ali Turhan , Yucel Aykan
Published: October 2016

Morbidly adherent placenta (MAP) is a growing concern currently and is still a diagnostic challenge for obstetricians. As emergency hysterectomy due to unscheduled delivery in MAP carries significant risks, we aimed to evaluate whether first and second trimester serum analytes may be used in the prediction of MAP requiring hysterectomy. A retrospective chart review of all identified cases of placenta previa totalis with and without MAP was performed. A total of 316 pregnant women diagnosed as placenta previa totalis were identified and included in the analysis. Cases were examined in three groups (Group 1: 204 nonadherent placenta previa patients; Group 2: 61 MAP patients managed with endouterine hemostatic square sutures and/or Bakri balloon tamponade; and Group 3: 51 patients with MAP requiring hysterectomy). Among all first and second trimester screening analytes only maternal serum alphafetoprotein (MS‐AFP) levels were significantly higher in patients with MAP requiring hysterectomy (p < 0.001). According to the Receiver Operating Characteristic (ROC) analysis performed for the predictive value of MS‐AFP levels, the area under the curve (AUC) was 0.742 [95% confidence interval (CI): 0.505–0.979]. The best MS‐AFP cut‐off value was 1.25 multiple of the median (MoM) with 85.94% sensitivity and 71.43% specificity (p = 0.036). The best predictors which affect the increased risk of hysterectomy, was further evaluated by multivariate logistic regression analyses. Only elevated maternal serum alphafetoprotein (MS‐AFP) was found to be an independent predictor of MAP requiring hysterectomy [odds ratio (OR) = 25.329, 95% confidence interval (CI):1.487–43.143, p = 0.025]. In conclusion, increased second trimester MS‐AFP levels independently predict morbidly adherent placenta requiring hysterectomy among women with placenta previa totalis.
NGP 555, a γ‐secretase modulator, lowers the amyloid biomarker, Aβ42, in cerebrospinal fluid while preventing Alzheimer's disease cognitive decline in rodents
Authors: Kounnas Maria Z. , Lane‐Donovan Courtney , Nowakowski Dan W. , Herz Joachim , Comer William T.
Published: October 2016

Introduction

Alzheimer's disease (AD) is defined by the progressive accumulation of amyloid plaques and neurofibrillary tangles in the brain which precedes cognitive decline by years.

Methods

Using amyloid biomarkers, chemical modeling, mouse behavioral models, and drug development techniques, we investigate the properties of NGP 555, a clinical‐stage γ‐secretase modulator.

Results

NGP 555 shifts amyloid peptide production to the smaller, nonaggregating forms of amyloid. Our preclinical studies show beneficial effects on amyloid biomarkers, pathology, and cognition. NGP 555 has successfully completed chemistry, pharmacology, toxicity, metabolism, and safety studies.

Discussion

Abundant data support Aβ42 as a target for prophylactic or early‐stage intervention therapies in AD. The γ‐secretase modulator, NGP 555 is being actively developed in human clinical trials for the prevention of Alzheimer's disease with the overall aim to achieve an appropriate balance of potency/efficacy on reducing the toxic forms of amyloid versus safety.
African Americans are less likely to enroll in preclinical Alzheimer's disease clinical trials
Authors: Zhou Yan , Elashoff David , Kremen Sarah , Teng Edmond , Karlawish Jason , Grill Joshua D.
Published: October 2016

Introduction

Alzheimer's disease (AD) incidence is disproportionately high in African Americans, yet, recruitment of this community to AD clinical trials is challenging.

Methods

We compared 47 African Americans and 78 whites in their willingness to enroll in a hypothetical preclinical AD trial and examined barriers and facilitators in their decision making.

Results

African American race (OR = 0.45; 95% CI, 0.22–0.93) and score on the research attitude questionnaire (OR = 1.12; 95% CI, 1.04–1.22) were independently associated with willingness to participate. African Americans rated study risks, the requirement of a study partner, study procedures, the ratio of drug to placebo, and study location as more important factors in the decision whether to enroll than did whites.

Discussion

These results suggest that researchers will encounter challenges in recruiting African Americans to preclinical AD trials. Future research will be necessary to understand the optimal means to improve recruitment of underrepresented populations.
Recruitment of Immune Effector Cells against Glioblastoma-Multiforme by a MHC-Chlorotoxin Chimeric Protein
Authors: Cohen-Inbar O.
Published: October 2016

Glioblastoma Multiforme is the most common malignant primary brain tumor, having a mean overall survival <2 years. The lack of an efficient immune response against the tumor have been attributed to its immunosuppressive capabilities and an immunosuppressing local environment. Aim: We set out to design a chimeric molecule that recognizes and binds tissue inducible metalloproteinase known to be induced in GBM cells (MMP-2) on one end. Its other end, the effector domain, mobilizes and recruits cytotoxic T-cells to mount an effective anti-tumor reaction. Methods: The targeting moiety is the small 36-amino acids Chlorotoxin, derived from the venom of the Israeli Yellow scorpion. The effector end is a single chain HLA-A2 (Human leukocyte antigen subtype A2) covalently bound to phosphoprotein-65 derived from the cytomegalovirus, to which most of the human population has developed a specific immune response. Results: The molecular construct was cloned and expressed in E.coli. The protein product was isolated, purified, and then folded in vitro. Various activity assays employed demonstrated retained activity of each domain, including flow-cytometry, intracellular staining, fluorescence immunohistochemistry, radiolabeled toxicity assays etc. Initial in-vivo studies show great promise. Conclusions: We present a proof of concept study for a new immunotherapy approach to battle GBM. A molecular construct which contains a non-antibody compact and highly specific targeting domain, combined with the ability to recruit anti-CMV T-cell lymphocyte population. The recruitment of potent memory CTL’s to the tumor’s milieu may prove resistant to the previously described local immunosuppressive environment brought about by the tumor.
OS5 - 173 Inhibition of eEF2K as a Novel Therapeutic Strategy in Neuroblastoma and Medulloblastoma
Authors: Delaidelli A , Khan D , Leprivier G , Pfister SM , Taylor MD , Maris JM , Sorensen PH
Published: October 2016

Medulloblastoma and neuroblastoma are aggressive solid pediatric tumors, with 5 year survival rates lower than 50-60%. In addition, more than 80% of the survivors develop permanent neurological impairments. Hence, there is a dire need to identify and validate novel, more effective and less toxic therapeutic approaches. Tumors are continually exposed to acute changes in the micro-environment, including nutrient availability. We previously showed that eukaryotic Elongation Factor-2 Kinase (eEF2K) is a critical regulator of cellular adaptation to acute metabolic stress. Based on those findings, we hypothesize that eEF2K is a marker of outcome and mediates medulloblastoma and neuroblastoma adaptation to acute stress. METHODS – Proprietary gene expression datasets (for medulloblastoma) and the R2 genomic analysis platform (for neuroblastoma) were analyzed for links between eEF2K expression and outcome. Effects of eEF2K knockdown on cell survival were evaluated in BE(2)C neuroblastoma cells. Immunoblotting and immunohistochemistry were performed on neuroblastoma cell lines and tissue microarrays (TMAs) for key molecules in the pathway. Similar studies are underway in medulloblastoma cell lines and TMAs. RESULTS - Low eEF2K mRNA expression is predictive of improved survival in medulloblastoma and neuroblastoma. Low p-eEF2 protein expression, indicative of low eEF2K activity, improves survival in human neuroblastoma. Neuroblastoma cell lines with eEF2K knockdown are more sensitive than controls to nutrient deprivation. CONCLUSIONS - eEF2K may represent a critical mechanism for adaptation to acute metabolic stress in neuroblastoma and medulloblastoma, and is therefore a promising therapeutic target. We are currently exploring the pharmacological inhibition of eEF2K in xenograft tumor models.
OS12 - 137
The Geriatric Scoring System (GSS) for Risk Stratification in Meningioma Patients as a Predictor of Outcome in Patients Treated With Radiosurgery
Authors: Cohen-Inbar O.
Published: October 2016

Meningiomas are the most common primary benign brain tumor. Radiosurgery (primary or adjuvant) allows excellent local control. The Geriatric scoring system (GSS) for pre-operative risk stratification and outcome prediction of patients with meningiomas has been previously reported. The GSS incorporates eight tumor and patient parameters on admission. A GSS score higher than 16 was previously reported to be associated with a more favorable outcome. We assessed the validity of the GSS score and its influence on outcome in patients treated with gamma-knife radiosurgery (GKRS). Methods: Patients treated with single session GKRS for WHO-1 meningioma during 1989-2013 at the University of Virginia were reviewed. A cohort of 323 patients, 50.2% (n=162) males. Median age was 56 (29-84), and median follow-up was 53.6 (6-235) months. Median tumor volume was 4.5 cm3 (0.2-23). Median margin and maximal doses were 15 Gy (8-36) and 32.3 Gy (20-65), respectively. Results: Tumor volume control was achieved in 87% (n=281), and post-GKRS clinical neurological improvement reported in 66.3% (n=214). The median change in KPS was +10 (range -30 to +40). The most common complication was intermittent headaches (34.1%, n=110) and cranial nerve deficits (14.2%, n=46). The GSS (calculated and grouped as GSS>16 and GSS<=16) was found to correlate with different Post-GKRS functional status (p<0.0001) and tumor control (p=0.028). Conclusion: The GSS, used for risk stratification and outcome prediction in patients with meningiomas seems valid for patients undergoing single session GRKS. GSS score greater than 16 is associated with a better long-term functional status and tumor control.
PS1 - 140 The Effect of Timing of Stereotactic Radiosurgery Treatment of Melanoma Brain Metastases Treated with Ipilimumab
Authors: Cohen-Inbar O.
Published: October 2016

Melanoma represents the third most common cause of CNS metastases. Immunotherapy has evolved as a treatment option for patients with stage-IV melanoma. Stereotactic radiosurgery (SRS) also elicits an immune response within the brain and may interact with immunotherapy. We report a cohort of patients treated for brain metastasis with immunotherapy and evaluate the effect of SRS timing on the intracranial response. Methods: All consecutively treated melanoma patients receiving Ipilimumab and SRS for their brain metastasis were included in the retrospective analysis. 46 patients harboring 232 brain metastases were reviewed. The median clinical follow-up was 7.9 months (3-42.6). Median age was 63 years (24.3-83.6). 32 patients received SRS before or during ipilimumab cycles (Group-A) whereas 14 patients received SRS after the ipilimumab treatment (Group-B). Radiographic and clinical responses were assessed at approximately 3 months intervals after SRS. Results: The two cohorts were comparable in pertinent pre-treatment aspects with the exception of SRS timing relative to ipilimumab. Local recurrence free duration (LRFD) was significantly longer in Group-A patients (19.6 months, range 1.1-34.7 months) as compared to group-B patients (3 months, range 0.4-20.4 months), respectively (p=0.002). Post-SRS perilesional edema was more significant in Group-A. Conclusions: The effect of SRS and ipilimumab in attaining LRFD seems greater when SRS is performed before or during ipilimumab treatments. The timing of immunotherapy and SRS may effect LRFD and post-radiosurgical edema. The interactions between immunotherapy and SRS warrant further investigation so as to optimize the therapeutic benefits and mitigate the risks associated with multimodality, targeted therapy.
PS1 -125 Assessment of Function and Quality of Life in a Phase II Multi-Institutional Clinical Trial of Fractionated Simultaneous In-Field Boost Radiotherapy for Patients with 1-2 Brain Metastases
Authors: Bauman G , Yartsev S , Roberge D , MacRae R. , Roa W , Panet-Raymond V , Masucci L , Yaremko B , D’Souza D. , Palma D. , Sexton T. , Yu E. , Pantarotto J.R. , Ahmad B. , Fisher B. , Dar A.R. , Lambert C. , Pond G. , Stitt L. , Tay K.Y. , Rodrigues G.
Published: October 2016

We examined functional outcomes and quality of life of whole brain radiotherapy (WBRT) with integrated fractionated stereotactic radiotherapy boost (FSRT) for brain metastases treatment. Methods Eighty seven people with 1-3 brain metastases were enrolled on this Phase II trial of WBRT (30Gy/10)+simultaneous FSRT, (60Gy/10). Results Mean (Min-Max) baseline KPS, Mini Mental Status Exam (MMSE) and FACT-BR quality of life were 83 (70-100), 28 (21-30) and 143 (98-153). Lower baseline MMSE (but not KPS or FACT-Br) was associated with worse survival after adjusting for age, number of metastases, primary and extra-cranial disease status. Crude rates of deterioration (>10 points decrease from baseline for KPS and FACT-Br, MMSE fall to<27) ranged from 26-38% for KPS, 32-59% for FACT-Br and 0-16%for MMSE depending on the time-point assessed with higher rates generally noted at earlier time points (<6months post-treatment). Using a linear mixed models analysis, significant declines from baseline were noted for KPS and FACT-Br (largest effects at 6 weeks to 3 months) with no significant change in MMSE. Conclusions The effects on function and quality of life of this integrated treatment of WBRT+simultaneous FSRT were similar to other published series combining WBRT+SRS.
PS1 - 160 A Telephone Based Cognitive Assessment Tool for Brain Metastases Patients
Authors: Tsao M.N. , Edelstein K. , Bernstein L.J. , Wong J. , Laperriere N. , Perry J.R. , Sahgal A. , Menard C. , Soliman H. , Chow E. , Barnes T. , Danjoux C. , Millar B.A. , Wong R. , Wells W. , McIntyre R.S. , Mason W. , Chung C.
Published: October 2016

Improving neurocognitive outcomes following treatment for brain metastases have become increasingly important. We propose that a brief telephone-based neurocognitive assessment may improve follow-up cognitive assessments in this palliative population. Aim: To prospectively assess the feasibility and reliability of a telephone based brief neurocognitive assessment compared to the same tests delivered face-to-face. Methods: Brain metastases patients to be treated with whole brain radiotherapy (WBRT) were assessed using a brief validated neurocognitive battery at baseline, at 1 month and 3 months following WBRT (in person and over the phone). The primary outcome was feasibility and inter-procedural (in person versus telephone) reliability. The secondary objective was to evaluate the change in neurocognitive function before and after WBRT. Results: Out of 39 patients enrolled, 82% of patients completed the baseline in-person and telephone neurocognitive assessments. However, at 1 month, only 41% of enrolled patients completed the in-person and telephone cognitive assessments and at 3 months, only 10% of patients completed them. Results pertaining to reliability and change in neurocognitive function will be updated. Conclusion: The pre-defined definition of feasibility (at least 80% completion for face to face and telephone neurocognitive assessments) was met at baseline. However, a large proportion of participants did not complete either telephone or in person neurocognitive follow-up at 1 month and at 3 months post-WBRT. Attrition remained a challenge for neurocognitive testing in this population even when a telephone-based brief assessment was used.
PS1 - 176 Where Have All the Fat Cells Gone? A Comparative Analysis of Adiposity Patterns in Childhood Brain Tumor Survivors and Non-Cancer Controls
Authors: Wang K.W. , Kearsley E. , Falzone N. , Fleming A. , Burrow S. , de Souza R.J. , Thabane L. , Samaan M.C.
Published: October 2016

Brain tumors are the most common solid tumors in children in Canada. While technological advances have increased their survival rates, survivors of childhood brain tumors (SCBT) often develop obesity, which can reduce lifespan and quality of life. While adiposity is a known factor for cardiometabolic disorders in the general population, adiposity patterns in SCBT have not been determined. This study aims to investigate how adiposity patterns differ between SCBT and non-cancer controls, and how lifestyle and treatment factors may contribute to these patterns. Methods: Fifty-nine SCBT and 108 non-cancer controls were recruited from the clinics at McMaster Children’s Hospital. Sociodemographic and lifestyle details were collected using standardized tools to assess diet, physical activity, and sleep. Brain tumor type, location and treatment details were obtained from medical records. Total and visceral adiposity were determined by total fat mass (FM) as well as waist-to-hip (WHR) and waist-to-height ratio (WHTR). Results: SCBT have higher total and visceral adiposity, while BMI is similar to controls. Female SCBT who received radiotherapy and/or chemotherapy have higher adiposity. A dietary pattern of white bread and fried foods with low dark bread was positively associated with adiposity. Lower physical activity levels, but not sleep durations, were associated with higher adiposity. Conclusion: SCBT have higher visceral and total adiposity than non-cancer controls. Sex, chemoradiotherapy, high fat diet, and physical inactivity, can contribute to these adiposity patterns. These results provide multiple points of entry to design interventions that reduce adiposity, and may improve long-term outcomes in SCBT.
PS1 - 183 Recommendations for the Referral of Patients from Proton Beam Therapy, an Alberta Health Services Report: A Model for Canada?
Authors: Patel S. , Kostaras X. , Parliament M. , Olivotto I.A. , Nordal R. , Aronyk K. , Hagen N.
Published: October 2016

Proton beam therapy (PBT) offers compelling advantages in physical dose distribution compared to photon therapy. There are increasing numbers of gantry-based proton facilities worldwide but no such facilities exist in Canada. To access PBT, Canadian patients must travel abroad for treatment at high cost. In the face of limited access, this report seeks to provide recommendations for the selection of patients most likely to benefit from PBT and suggests an out-of-country referral process. METHODS: A systematic literature search for studies between January 1990 and May 2014 evaluating clinical outcomes after PBT. A draft report was developed through review of evidence, externally reviewed, and approved by the Alberta Health Services Cancer Care Proton Therapy Guidelines steering committee. RESULTS: Proton therapy is often used to treat tumours close to radiosensitive tissues, and children at risk of developing significant late effects of radiation therapy (RT). Local control rates with PBT appear similar to or, in some cases, higher than photon RT in uncontrolled and retrospective studies. Randomized trials comparing equivalent doses of PBT and photon RT are not available. SUMMARY: Referral for PBT is recommended for patients being treated with curative intent, with an expectation for long-term survival, and who are able and willing to travel abroad to a proton facility. Commonly accepted indications for referral include chordoma and chondrosarcoma, intraocular melanoma, and solid tumours in children and adolescents occurring in patients with greatest risk of long-term sequelae. Current data do not provide sufficient evidence to recommend routine referral of patients with most head and neck, breast, lung, gastrointestinal tract, and pelvic cancers including prostate cancer. It is recommended that all referrals be considered by a multidisciplinary team to select appropriate cases.
PS2 - 197 DICER Governs Characteristics of Glioma Stem Cells and the Resulting Tumors in Xenograft Mouse Models of GBM
Authors: Mansouri S. , Singh S. , Alamsahebpour A. , Burrell K. , Li M. , Karabork M. , Ekinci C. , Solaroglu I. , Chang J.T. , Aldape K. , Zadeh G.
Published: October 2016

The RNAse III endonuclease DICER is a key regulator of microRNA (miRNA) biogenesis and is frequently down-regulated in a variety of malignancies. We characterized the role of Dicer in glioblastoma (GB), specifically demonstrating its effects on the ability of glioma stem-like cells to form tumors in a mouse model of GB. DICER silencing in glioma stem-like cells (GSCs) reduced their stem cell characteristics, while tumors arising from these cells were more aggressive, larger in volume, and displayed a higher proliferation index and lineage differentiation. The resulting tumors, however, were more sensitive to radiation treatment. Our results demonstrate that DICER affects the tumorigenic potential of GSCs, providing a platform for analysis of specific relevant miRNAs and development of potentially novel therapies against GB.
PS2 - 217 Treatment of Glioblastoma Brain Tumor-Initiating Cells with Microglial and Macrophage-Derived Cytokines
Authors: Poon C.C. , Sarkar S. , Hughes M.L. , Yong V.W. , Kelly J.J.
Published: October 2016

The most common brain cancer, glioblastoma (GBM), also has the worst five-year survival rates of all cancers. This is due in part to cancer stem cells, known as brain tumor initiating cells (BTICs), which initiate GBM and are resistant to current therapies. Thus, it is important to study therapeutics targeting BTICs. Innate immune cells, microglia and macrophages (MMs), are also important GBM-associated cells. GBM influences MMs to promote tumor growth. However, my research group discovered that an old drug, amphotericin B, re-stimulates MMs to secrete cytokines that inhibit BTIC self-renewal (Nature Neurosci 17:46-55, 2014). Hence, I hypothesize these cytokines are potential GBM treatments. Methods: Twenty genetically diverse BTIC lines were exposed to interleukin-8 (IL8), monocyte chemoattractant protein-1 (MCP1), and tumor necrosis factor-alpha (TNF), the cytokines secreted most abundantly by amphotericin-stimulated MMs. Assays for proliferation, differentiation, apoptosis, and cell cycle arrest were performed. BTICs were then co-cultured with human GBM-derived MMs stimulated with TNF. Lastly, the relationship between TNF receptors (TNFR1/2) and presumed BTICs was determined in frozen human GBM sections by immunofluorescence. Results: TNF had the most potent inhibitory effect on BTIC proliferation. Also, TNF was able to increase BTIC differentiation, and induce apoptosis and G1 cell cycle arrest. In MM-BTIC co-culture, TNF stimulated MMs to decrease sphere formation. Interestingly, in human GBM tissue TNFR1 co-labeled with OLIG2, a major transcription factor expressed in presumed BTICs, implicating TNF as a BTIC-specific treatment. Conclusion: TNF is a promising candidate for the treatment of GBM.
PS2 - 205 Application of Computer-Assisted Diagnostics for Immunohistochemistry Analysis of Gliomas
Authors: Alamsahebpour A. , Zadeh G. , Aldape K.
Published: October 2016

In the current practice of pathology, the identification of cell markers and their respective distribution represents an indispensable dialogue for diagnostic, predictive, therapeutic, and research purposes. Early immunohistochemical protocols were limited to direct, fluorescent labeled antibodies, yielding quick results but lacking sensitivity. More recently, the use of indirect techniques –utilization of enzyme labels–and various detection systems have continued to advance the complexity of IHC, increasing both its specificity and sensitivity of detecting one or multiple antigen(s) (Ag) simultaneously. As such, IHC has become an affordable, powerful, and readily available means for the identification of candidate biomarkers (mostly lineage markers) in formalin-fixed, paraffin-embedded (FFPE) tissue samples. Pathologists are now asked to “quantify” expression levels of differential prognostic markers–at microscopic level–using this arguably “non-quantitative” technique. Conventionally, histological grading relies mainly on manual counting of positively immunostained cells, a labour intensive protocol that may be associated with subjectivity, intra- and inter- observer variation and reproducibility issues. The subjectivity and lack of reproducibility has prompted the use of computer-assisted or fully automated image analysis technologies. Digital image acquisition systems are becoming commonplace and as such, the demand for complex assessments of digital images of histological slides must be matched with quantitative platforms. In this study, we aim to introduce a computer-assisted image-computing platform that is both accurate and efficient in quantification of isolated and heterogeneous candidate biomarkers in glioblastoma.
PC3 - 164 Urban-Rural Residence and Brain Cancer Survival in Canada (1996-2008)
Authors: Ross J. , Shi Q. , Yuan Y. , Davis F.G.
Published: October 2016

Disparities in cancer survival rates have been identified for rural patients in Canada and are thought to be due to inequities in access to care. The objective was to perform the first examination of urban and rural brain cancer survival in Canada. Methods: A population-based retrospective cohort study was performed using Canadian Cancer Registry data for patients diagnosed with a primary brain cancer from 1996-2008. Seven major brain cancer histology groups used were glioblastoma, diffuse astrocytoma, glioma (not otherwise specified), oligodendroglioma, anaplastic astrocytoma, oligoastrocytic tumours, and anaplastic oligodendroglioma as categorized by the Central Brain Tumor Registry of the United States (CBTRUS). Kaplan-Meier (KM) survival estimates and Cox Proportional Hazards Regression were performed, adjusting for sex, histology, age group, region, and urban-rural residence. Rural residence was defined using Statistics Canada’s “Rural and Small Town” definition of living in a region with a population of less than 10,000 people. Results: No significant difference between urban and rural residence was identified in crude KM survival estimates. Though not significant, 5-year survival was generally better among rural residents than urban residents, except for rural residents with anaplastic astrocytoma. There remained no significant difference for Cox hazard ratios after adjustment for age, sex, or region. Conclusions: This is the first study to examine the effect of urban-rural residence on brain cancer survival. No significant differences for any histology were found, indicating equitable access to care for brain cancer patients in Canada, regardless of their location of residence.
PC3 - 191 Assessment of Preoperative Functional MRI Measurement of Language Lateralisation in Brain Tumour Patients
Authors: Kosteniuk E. , Lau J.C. , Megyesi J.F.
Published: October 2016

This study aims to evaluate reliability of clinical functional magnetic resonance imaging (fMRI) in identifying language lateralisation index (LI), verified with Edinburgh handedness inventory (EHI), in brain tumour patients. Methods In this retrospective study, 31 of a single surgeon’s brain tumour patients over a 12 year period have been selected. Lesion type varied, 12 (39 percent) were high grade gliomas, 10 (32 percent) low grade gliomas, 3 (10 percent) meningiomas, and 6 (19 percent) other types. Patients underwent language fMRI paradigms for preoperative assessment, and a neuroimaging analyst was able to identify an LI value for at least one Brodmann area (BA). For each paradigm, a neuroimaging analyst attempted to calculate LI for Wernicke’s area (BA 22) and Broca’s area (BA 44 and 45). Results Of 113 total LI values, 66 (58 percent) were concordant to EHI-predicted hemispheric dominance. Reliability of language LI appears dependent upon the type of language task performed. Verb generation correctly identified Broca’s area in 18 patients (64 percent) and Wernicke’s area in 11 patients (61 percent), sentence completion correctly identified Broca’s area in 18 patients (72 percent) and Wernicke’s area in 9 patients (60 percent), and naming correctly identified Broca’s area in 7 patients (47 percent) and Wernicke’s area in 3 patients (27 percent). Conclusions Results show limited correlation between language LI determined by fMRI and EHI. The main limitation of this study is that language LI is being compared to EHI, rather than gold standard measure of hemispheric dominance (e.g. Wada).
PC3 - 141
Long-Term Results of Stereotactic Radiosurgery for Skull Base Meningiomas
Authors: Cohen-Inbar O.
Published: October 2016

Gamma knife radiosurgery (GKRS) is well-established in the management of inaccessible, recurrent, or residual benign skull base meningiomas. Most series report clinical outcome parameters and complications in the short -intermediate period after radiosurgery. Reports of long-term tumor control and neurological status are still lacking. Objective: We report the presentation, treatment, and long-term outcome of skull base meningiomas after GKRS. Methods: From a prospectively collected IRB approved database, we selected patients with a WHO grade I skull base meningioma treated with a single-session GKRS and a minimum of 60 months follow up. 135 patients, 54.1% males (n=73) form the cohort. Median age was 54 years (19-80). Median tumor volume was 4.7 cm3 (0.5-23). Median margin dose was 15 Gy (7.5-36). Median follow up was 102.5 months (60.1-235.4). Patient and tumor characteristics were assessed to determine predictors of neurological function and tumor progression. Results: At last follow up, tumor volume control was achieved in 88.1% (n=119). Post-GKRS clinical improvement or stability was reported in 61.5%. The 5, 10, and 15 years actuarial progression free survival rates are 100%, 95.4%, and 68.8%, respectively. Favorable outcome (both tumor control and clinical preservation/improvement) was attained in 60.8% (n=79). Pre-GKRS performance status (KPS) was shown to influence tumor progression (p=0.0001) and post-GKRS clinical improvement / preservation (p=0.003). Conclusion: GKRS offers a highly durable rate of tumor control for WHO-I skull base meningiomas, with an acceptably low incidence of neurological deficits. KPS at the time of radiosurgery serves as a reliable long-term predictor of overall outcome.