bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of semi‐automated continuous solid‐phase extraction and gas chromatography–mass spectrometry for the determination of polycyclic aromatic hydrocarbons in alcoholic and non‐alcoholic drinks from Andalucía (Spain)
Authors: Rascón Andrés J , Azzouz Abdelmonaim , Ballesteros Evaristo
Published: July 2018

BACKGROUND

Polycyclic aromatic hydrocarbons (PAHs) are a large group of contaminants that can reach drinks in various ways. Their assessment in terms of food safety is needed as a priority. The present study developed a methodology to estimate their presence in several types of drinks.

RESULTS

In this work, a method was developed for detecting and quantifying PAHs in drinks using a semi‐automated, solid‐phase extraction closed system for clean up and isolation, and gas chromatography–mass spectrometry (GC–MS) for determination. The proposed method is accurate, precise, and sensitive, with low limits of detection (0.02–0.6 ng L−1), low relative standard deviations (< 6.5%), and high recoveries (90–103%). Its high flexibility allows application to a variety of drinks from (Spain) including distillates, beer, wine, cider, soft drinks, fruit juice, tea, and coffee.

CONCLUSION

This methodology allows the detection of this family of compounds at trace levels using low quantities of sample and solvents. Most of the samples studied contained two or more of the Environmental Protection Agency's (EPA's) 16 PAH priority pollutants, albeit at levels below the legally allowed limit. © 2018 Society of Chemical Industry
A Moderate Interleukin‐6 Reduction, Not a Moderate Weight Reduction, Improves the Serum Iron Status in Diet‐Induced Weight Loss with Fish Oil Supplementation
Authors: Huang Shih‐Yi , Sabrina Nindy , Chien Yi‐Wen , Chen Yi‐Chun , Lin Shyh‐Hsiang , Chang Jung‐Su
Published: July 2018

Background & Aims

Whether moderate weight loss or a reduction in IL‐6 improves the serum iron status in overweight (OW) and obese adults supplemented with or without fish oil is explored.

Methods and Results

In total, 93 OW/obese Taiwanese adults with ≥2 metabolic components are randomized to a 12‐week calorie‐restricted diet with meal replacement alone (CRMR, n = 45) or supplemented with fish oil (CRMRF, n = 48). Mean reductions in the %body weight and serum IL‐6 are 7.5% versus 5.9% and 21% versus 35% for the CRMR and CRMRF groups, respectively. In the CRMRF group, a moderate loss of IL‐6 (reduced ≥35%) also significantly improves the serum iron and transferrin saturation compared to those with loss of <35% in the mean serum IL‐6 or those of the CRMR group who has a moderate loss of IL‐6 (reduced ≥21%) (all p < 0.05). In contrast, modest weight loss does not improve the serum iron status.

Conclusions

Fish oil is ineffective as an adjunct for weight or fat loss but has beneficial effects on preserving the lean body mass. A significant improvement in the iron status is only observed in those with moderate loss of serum IL‐6 supplemented with fish oil.
Lithocholic Acid Improves the Survival of Drosophila Melanogaster
Authors: Staats Stefanie , Rimbach Gerald , Kuenstner Axel , Graspeuntner Simon , Rupp Jan , Busch Hauke , Sina Christian , Ipharraguerre Ignacio R. , Wagner Anika E.
Published: July 2018

Scope

Primary bile acids are produced in the liver, whereas secondary bile acids, such as lithocholic acid (LCA), are generated by gut bacteria from primary bile acids that escape the ileal absorption. Besides their well‐known function as detergents in lipid digestion, bile acids are important signaling molecules mediating effects on the host's metabolism.

Methods and results

Fruit flies (Drosophila melanogaster) are supplemented with 50 μmol L–1 LCA either for 30 days or throughout their lifetime. LCA supplementation results in a significant induction of the mean (+12 days), median (+10 days), and maximum lifespan (+ 11 days) in comparison to untreated control flies. This lifespan extension is accompanied by an induction of spargel (srl), the fly homolog of mammalian PPAR‐γ co‐activator 1α (PGC1α). In wild‐type flies, the administration of antibiotics abrogates both the LCA‐mediated lifespan induction as well as the upregulation of srl.

Conclusion

It is shown that the secondary bile acid LCA significantly induces the mean, the median, and the maximum survival in D. melanogaster. Our data suggest that besides an upregulation of the PGC1α‐homolog srl, unidentified alterations in the structure or metabolism of the gut microbiota contribute to the longevity effect mediated by LCA.
Technical Note: Acceleration of online adaptive replanning with automation and parallel operations
Authors: Zhang Jingqiao , Ahunbay Ergun , Li X. Allen
Published: July 2018

Purpose

Limited by various human interventions and manual operations, the routine practice of online adaptive replanning (OLAR) is time consuming and impractical with the current planning technology. To accelerate OLAR and to minimize human efforts, the methods and software tools are developed to automate OLAR workflow and to use parallel processing during OLAR.

Methods

Speedy online adaptive replanning SOLAR, a software tool, was developed to automate the OLAR workflow and to implement parallel operation in plan generation and contour editing. The SOLAR tool is designed to automate and monitor the operation of OLAR on multiple client workstations and to allow parallel manual contour editing and plan generation with multiple workstations. The performance of the SOLAR tool was tested on selected prostate and pancreatic cancer cases.

Results

The SOLAR system has been tested in the clinical environment. With the automation and parallel operations, the operation time for OLAR can be reduced by 70%, allowing OLAR to be completed within 10 min for the tested prostate cancer cases and within 15 min for the pancreatic cancer cases. The SOLAR system generated superior plans compared to the standard repositioning method.

Conclusion

SOLAR software was developed to accelerate online adaptive replanning workflow with automation and parallel operations. By reducing the time and human intervention, thus, reducing potential human error, the SOLAR solution would improve the practicality of OLAR.
Automated quality control assessment of clinical chest images
Authors: Willis Charles E. , Nishino Thomas K. , Wells Jered R. , Ai H. Asher , Wilson Joshua M. , Samei Ehsan
Published: July 2018

Purpose

The purpose of this study was to determine whether a proposed suite of objective image quality metrics for digital chest radiographs is useful for monitoring image quality in a clinical setting unique from the one where the metrics were developed.

Methods

Seventeen gridless AP chest radiographs from a GE Optima portable digital radiography (DR) unit (“sub‐standard” images; Group 2) and 17 digital PA chest radiographs (“standard‐of‐care” images; Group 1) and 15 gridless (non‐routine) PA chest radiographs (images with a gross technical error; Group 3) from a Discovery DR unit were chosen for analysis. Group 2 images were acquired with a lower kVp (100 vs 125) and shorter source‐to‐image distance (127 cm vs 183 cm) and were expected to have lower quality than Group 1 images. Group 3 images were expected to have degraded contrast vs Group 1 images. Images were anonymized and securely transferred to the Duke University Clinical Imaging Physics Group for analysis using software described and validated previously. Individual image quality was reported in terms of lung gray level, lung detail, lung noise, rib‐lung contrast, rib sharpness, mediastinum detail, mediastinum noise, mediastinum alignment, subdiaphragm‐lung contrast, and subdiaphragm area. Metrics were compared across groups. To improve precision of means and confidence intervals for routine exams, an additional 66 PA images were acquired, processed, and pooled with Group 1. Three observer studies were conducted to assess whether humans were able to identify images classified by the algorithm as abnormal.

Results

Metrics agreed with published Quality Consistency Ranges with three exceptions: higher lung gray level, lower rib‐lung contrast, and lower subdiaphragm‐lung contrast. Higher (stored) bit depth (14 vs 12) accounted for higher lung gray level values in our images. Values were most internally consistent for Group 1. The most sensitive metric for distinguishing between groups was mediastinum noise, followed closely by lung noise. The least sensitive metrics were mediastinum detail and rib‐lung contrast. The algorithm was more sensitive than human observers at detecting suboptimal diagnostic quality images.

Conclusions

The software appears promising for objectively and automatically identifying suboptimal images in a clinical imaging operation. The results can be used to establish local quality consistency ranges and action limits per facility preferences.
The correlation between the type of forceps application and the rate of levator ani muscle avulsion: A prospective cohort study
Authors: García Mejido José Antonio , Aquise Pino Adriana , Fernández Palacín Ana , de la Fuente Vaquero Paloma , Ramos Vega Zenaida , Sainz Bueno José Antonio
Published: July 2018

Objectives

The association between the use of forceps and levator ani muscle (LAM) avulsion seems to be clear‐cut. However, whether the lesion is due to the mechanical trauma yielded by the instrument or to the intrinsic complexity of this type of delivery, is yet to be determined. This study aims at determining the difference in LAM avulsion rate between Kielland rotational forceps and non‐rotational forceps.

Study Design

Prospective observational study with 94 nulliparous women with forceps‐assisted deliveries (FD) between July 2015 and January 2016. 3D‐TpUS was performed 6 months after every patient's delivery, during which LAM avulsion, and levator hiatus area and anteroposterior and transverse diameters were assessed.

Results

A total of 89 nulliparous were studied, comprising 27 rotational‐FD, and 62 non‐rotational‐FD. No differences in obstetric, intrapartum, or neonatal characteristics were observed between study groups. There were no statistically significant differences in the presence of avulsion between cases of rotational forceps (44.4% vs 35.5%, OR: 1.5 [0.6‐3.6]), correction of asinclitism of the fetal head (34.4% vs. 40.4% OR: 0.8 [0.3‐1.9]) or station (midforceps: 32.8% vs low forceps: 50.0% OR: 2.0 [0.8‐5.1]).

Conclusions

We have not observed differences in the LAM‐avulsion rate between rotational forceps and non‐rotational forceps performed by highly experienced personnel in instrumental deliveries.
Leader–member exchange and prohibitive voice in nonprofit organizations in China: The moderating roles of superior–subordinate tenure matching
Authors: Pei Zhijun , Pan Yingchun , Skitmore Martin , Feng Tao
Published: July 2018

The specific purpose of the present research contributes to addressing a gap in the organizational literature by examining how a superior–subordinate relationship may influence the use of prohibitive voice by employees in nonprofit organizations (NPOs). With data collected from 1,798 employees in 103 NPOs in southeastern China, the article investigates the influence of leader–member exchange (LMX) quality on prohibitive voice and explores the moderating effects of superior–subordinate tenure matching on the influence of LMX on prohibitive voice in NPOs. The results indicate that the quality of LMX relationships has a significant, positive influence on employee prohibitive voice behavior in NPOs, and this influence is moderated by superior–subordinate organizational tenure matching and LMX tenure matching. The study offers insights into the use of voice in NPOs as these organizations experience more difficult agency problems than for‐profit firms.
Redox control of iodotyrosine deiodinase
Authors: Hu Jimin , Su Qi , Schlessman Jamie L. , Rokita Steven E.
Published: July 2018

The redox chemistry of flavoproteins is often gated by substrate and iodotyrosine deiodinase (IYD) has the additional ability to switch between reaction modes based on the substrate. Association of fluorotyrosine (F‐Tyr), an inert substrate analog, stabilizes single electron transfer reactions of IYD that are not observed in the absence of this ligand. The co‐crystal of F‐Tyr and a T239A variant of human IYD have now been characterized to provide a structural basis for control of its flavin reactivity. Coordination of F‐Tyr in the active site of this IYD closely mimics that of iodotyrosine and only minor perturbations are observed after replacement of an active site Thr with Ala. However, loss of the side chain hydroxyl group removes a key hydrogen bond from flavin and suppresses the formation of its semiquinone intermediate. Even substitution of Thr with Ser decreases the midpoint potential of human IYD between its oxidized and semiquinone forms of flavin by almost 80 mV. This decrease does not adversely affect the kinetics of reductive dehalogenation although an analogous Ala variant exhibits a 6.7‐fold decrease in its kcat/Km. Active site ligands lacking the zwitterion of halotyrosine are not able to induce closure of the active site lid that is necessary for promoting single electron transfer and dehalogenation. Under these conditions, a basal two‐electron process dominates catalysis as indicated by preferential reduction of nitrophenol rather than deiodination of iodophenol.
FRETting about the affinity of bimolecular protein–protein interactions
Authors: Lin Tao , Scott Brandon L. , Hoppe Adam D. , Chakravarty Suvobrata
Published: July 2018

Fluorescence resonance energy transfer (FRET) is a powerful tool to study macromolecular interactions such as protein–protein interactions (PPIs). Fluorescent protein (FP) fusions enable FRET‐based PPI analysis of signaling pathways and molecular structure in living cells. Despite FRET's importance in PPI studies, FRET has seen limited use in quantifying the affinities of PPIs in living cells. Here, we have explored the relationship between FRET efficiency and PPI affinity over a wide range when expressed from a single plasmid system in Escherichia coli. Using live‐cell microscopy and a set of 20 pairs of small interacting proteins, belonging to different structural folds and interaction affinities, we demonstrate that FRET efficiency can reliably measure the dissociation constant (KD) over a range of mM to nM. A 10‐fold increase in the interaction affinity results in 0.05 unit increase in FRET efficiency, providing sufficient resolution to quantify large affinity differences (> 10‐fold) using live‐cell FRET. This approach provides a rapid and simple strategy for assessment of PPI affinities over a wide range and will have utility for high‐throughput analysis of protein interactions.
(E)‐β‐farnesene synthase gene affects aphid behavior in transgenic Medicago sativa
Authors: Wang Xuemin , Gao Yuhao , Chen Zhihong , Li Jindong , Huang Jianping , Cao Jiangbo , Cui Miaomiao , Ban Liping
Published: July 2018

BACKGROUND

Pea aphid (Acyrthosiphon pisum Harris) is one of the major pests in alfalfa crops, causing significant yield losses. (E)‐β‐farnesene (EβF), an alarm pheromone released by pea aphid, is generic to many species of aphids, and is used to minimize potential danger from predators and parasitoids by avoiding the source of the pheromone.

RESULTS

In this study, EβF synthase gene was constructed into a plant expression vector, and overexpressed in alfalfa (Medicago sativa L.), with expression among transgenic lines confirmed by qRT‐PCR. Subcellular localization analysis showed that EβF synthase gene was expressed in the plasma membrane and nucleus of the leaf. GC/MS of extraction from transgenic alfalfa indicated emission of EβF ranging from 5.92 to 13.09 ng day−1 g−1 fresh tissue. Behavior assays in Y‐olfactometers demonstrated that transgenic alfalfa expressing AaEβF gene could repel pea aphids, with aphids taking a significantly longer time to select a transgenic line compared with the control line (P < 0.01).

CONCLUSION

We have demonstrated a potentially valuable strategy of using EβF synthase genes for aphid control in alfalfa. © 2018 Society of Chemical Industry
A theoretical and experimental study on corrugated paperboard crushing under quasi‐static loadings
Authors: Li Xue , Wang Jun , Gao De , Lv Wei‐liang
Published: July 2018

This paper presents 2 mathematical models to predict the initial peak stress and the plateau stress of corrugated paperboard which is simplified and regarded as the orthotropic plate under longitudinal compression. The resultant stress‐strain curve exhibits initial stiffening stage and a long plateau stage, where the initial peak stress determining the edgewise crush resistance of the board and most impact energy will be absorbed by the long plateau stage. By analyzing the elastic buckling of the board wall, a model of predicting the initial peak stress was obtained, while the plateau stress model was developed based on the gradual process of compression for corrugated board and energy conservation principle. Moreover, experiments were carried out to corroborate the presented model by comparing the predicted value with that by experiments, showing overall good agreement. It can be concluded that the proposed models can be applied for design of corrugated containers and cushioning packaging by corrugated paperboard.
Phosphorylation and Octenylsuccinylation of Acid‐Thinned Starch for Enhancing Adhesion on Cotton/Polyester Blend Fibers at Varied Temperature Sizing
Authors: Bismark Sarkodie , Xun Zhang , Zhifeng Zhu , Charles Frimpong , William Badoe , Benjamin Asinyo , Ebenezer Howard K.
Published: July 2018

In this study, amphiphilic starch prepared by phosphorylation and octenylsuccinylation is surveyed to identify its effect on the adhesion of starch to cotton/polyester blend fibers at different temperature. Acid‐thinned cornstarch (ATS) is phosphorylated and octenylsuccinylated with pentasodium triphosphate and 2‐octenylsuccinic anhydride, respectively, to improve upon adhesion to cotton/polyester blend fibers. Two series of amphiphilic starch samples with different levels of the substitution (DS) are derived for determining desirable level of starch modification in sizing. Amphiphilic starch paste shows strong adhesion to cotton/polyester blend fibers than ATS paste. It is found that the modification reduces the crystallinity, changed the morphology, improves moisture regain, alleviates the adverse influence of starch retrogradation, and improves adhesion to fibers and desizing efficiency. The adhesion of amphiphilic starch paste to cotton/polyester blend fibers at 60 °C is statistically higher than adhesion of ATS at 95 °C. The amphiphilic starch with a total DS of 0.06 shows the highest potential use for strong cotton/polyester blend warp sizing due to its good sizing properties.
Twisted massive non-compact models
Authors: Li Songyuan , Troost Jan
Published: July 2018

Abstract

We study interacting massive N = (2, 2) supersymmetric field theories in two dimensions which arise from deforming conformal field theories with a continuous spectrum. Firstly, we deform N = 2 superconformal Liouville theory with relevant operators, and twist the theory into a topological quantum field theory. These theories can be thought of as twisted generalized Landau-Ginzburg models with negative power superpotential. We determine the structure constants of the chiral ring and therefore all correlators of these topological quantum field theories. We provide general formulas for the deformed operators of given charge as well as explicit solutions to the WDVV equations. Secondly, we analyze the topological anti-topological sector of the theory. We compute the metric at the conformal point through localization. Moreover, we show that the topological-anti-topological fusion differential equations on the metric in a family of non-compact theories takes the affine Toda form. The metric as a function of the family of theories is identical to the metric in certain deformed compact models. For a negative cubic power superpotential, for instance, it is governed by the Painlevé III differential equation.
Probing transverse-momentum dependent evolution with groomed jets
Authors: Makris Yiannis , Neill Duff , Vaidya Varun
Published: July 2018

Abstract

We propose an observable which involves measuring the properties (transverse momentum p

h⊥ and energy fraction z

h
) of an identified hadron inside a groomed jet. The jet is identified with an anti-kT/CA algorithm and is groomed by implementing the modified mass drop procedure with an energy cut-off parameter, z
cut. The transverse momentum of the hadron inside the jet is measured with respect to the groomed jet axis. We obtain a factorization theorem in the framework of Soft Collinear Effective Theory (SCET), to define a Transverse Momentum Dependent Fragmenting Jet Function (TMDFJF). The TMDFJF is factorized into collinear and collinear soft modes by matching onto SCET+. We resum large logarithms in E

J

/p

h⊥, where E

J
is the ungroomed jet energy, to NLL accuracy and apply this formalism for computing the shape of the p

h⊥ distribution of a pion produced in an e
+ + e
− collision. We observe that the introduction of grooming makes this observable insensitive to non-global logarithms and particularly sensitive to non-perturbative physics of the transverse momentum dependent evolution at low values of p

h⊥, which can be probed in the variation of the cut-off parameter, z
cut, of the groomer. We discuss how this observable can be used to distinguish between non-perturbative models that describe universal TMD evolution and provide a window into the three dimensional structure of hadrons.
Critical Driving Forces for Formation of Bainite
Authors: Leach Lindsay , Kolmskog Peter , Höglund Lars , Hillert Mats , Borgenstam Annika
Published: July 2018

An empirical equation for predicting bainite start temperatures of steels was recently derived by starting from binary Fe-C alloys and continuing with ternary Fe-C-M alloys. This result is now illustrated with a family of B
S lines in a T,C diagram for a series of constant Mn contents. The critical driving force for the formation of ferrite is calculated for diffusionless or diffusional processes, and these quantities are used as dependent variables with carbon content or temperature as independent variables. Negative critical driving forces are predicted for a diffusionless process in binary Fe-C alloys, showing that this process cannot apply to the formation of bainite. The critical driving force for a diffusional process increases strongly with decreasing temperature and increasing carbon content. Mn and Ni, contrary to Cr, Mo and Si, have remarkably small effects on this critical driving force. The results are discussed by imagining that the magnitude of the critical driving force is governed by the height of an energy barrier that must be surmounted during growth. It is modeled as completely determined by the alloy composition. It is represented with an equation evaluated by fitting to the recent empirical equation and describing the carbon dependence of the barrier.
Starting Points
Authors: Hinings Bob , Meyer Renate
Published: July 2018

This Element reviews the first 120 years of organization theory, examining its development from the sociology of organizations and management theory. It is initially organized around two streams of thought. The first is found in political economy and the sociology of organizations, with an emphasis on understanding the new organizations that arose in the late nineteenth and early twentieth centuries. The second derives from practitioner–scholars, whose aim was to provide theories and approaches to managing these new organizations. The Element then shows how each of the streams of understanding and managing came together to produce organization theory. In doing this, it also describes how the institutional frameworks in academic associations, academic centres and journals came out of these approaches and how they strengthened the development of organization theory.
06 Prognostic factors for survival and recurrence in adult medulloblastoma
Authors: Yusuf D. , Krauze A. , Easaw J. , Murtha A. , Amanie J. , Roa W. , Ghosh S. , Eisenstat D. , Patel S.
Published: July 2018

BACKGROUND: Adult medulloblastomas account for less than 1% of adult neoplasms. They are challenging to treat due to their rarity and the heterogeneity of treatment options, all of which have limited evidence. In this retrospective review, we examined cases of adult medulloblastoma diagnosed in Alberta during a 70-year period. METHODS: We reviewed the charts of patients diagnosed with medulloblastoma between 1944 and 2014. We performed Cox and logistic regression analysis to elucidate features that may influence recurrence risk and survival. RESULTS: We found 86 and analyzed 78 cases. The median age at diagnosis was 27 (range 16 to 71). Most were male (68%). Most had surgery (92%). By COG risk stratification, 54% were standard risk while 21% were poor risk. RT was administered to 85% of patients, and craniospinal irradiation (CSI) to 81%. Chemotherapy was administered to 48%. Median survival was 4.4 years from diagnosis (range 0 to 20). At last follow-up, 39% were alive and recurrence-free. Patients who had CSI and posterior fossa boost had longer survival (p=0.047 and<0.01, respectively) and were less likely to recur (p=0.041 and<0.01). Chemotherapy was also associated with decreased recurrence (p=0.025). CONCLUSIONS: Medulloblastomas carry a significant recurrence risk, especially for patients who had subtotal resection. CSI and posterior fossa boost were associated with fewer recurrences and improved survival. COG risk stratification, Chang staging, desmoplastic histology, vermian location, 4th ventricle involvement, tumor enhancement, presence of hydrocephalus and cerebrospinal fluid (CSF) involvement are not significantly prognostic.
08 Inhibition of autophagy by mevalonate pathway inhibitors, a new therapeutic approach to sensitize glioblastoma cells to temozolomide induced apoptosis
Authors: Shojaei S. , Alizadeh J. , Thliveris J. , Koleini N. , Kardami E. , Hatch G.M. , Xu Fr. , Hombach-Klonisch S. , Klonisch T. , Ghavami S.
Published: July 2018

Glioblastoma multiforme (GBM) is the deadliest brain tumor with an approximate 14 month survival rate after diagnosis and treatment. Temozolomide (TMZ), the chemotherapeutic drug of choice for GBM, is an alkylating agent that causes DNA damage. TMZ treatment results in the induction of apoptosis in GBM cells, however, it induces autophagy and consequently chemoresistance. Statins are mevalonate (MEV) cascade inhibitors with beneficial effects on the enhancement of the survival rate of patients with different types of cancer. Here, we determined the effect of simvastatin (Simva), a blood brain barrier permeable statin, on the sensitization of GBM cells to TMZ induced apoptosis through inhibition of autophagy flux. We pretreated two GMB cell lines, U251 and U87 cells, with low doses of Simva (1 and 2.5 M, respectively) with or without different intermediates of the mevalonate cascade and then treated cells with TMZ (100 M) for 48-96 hrs. A signficiantly reduced viability and increased in the population of apoptotic dead cells were observed in GBM cells treated with the Simva-TMZ compared to cells treated with TMZ alone. Addition of MEV, Farnesyl pyrophosphate, Geranylgeranyl pyrophosphate and cholesterol did not attenuate these effects significantly. Sima-TMZ treatment did not alter the total cholesterol pool in U87 and U251 cells compared to controls. Western blot analysis, immunocytochemistry and transmission electron microscopy revealed that Simva-TMZ inhibited autophagic flux. Overall, the results suggest that sensitization of GBM cells to TMZ-induced apoptosis by Simva is independent on the cholesterol biosynthetic pathway but may involve inhibition of autophagy.
12 The potential role of exercise in the supportive care of neurological cancer survivors: delivering effective and appropriate programming through the Alberta cancer exercise (ACE) study
Authors: Sellar C.M. , Spychka R.A. , Williamson T. , Culos-Reed S.N. , McNeely M.L.
Published: July 2018

BACKGROUND: Exercise has been shown to benefit health-related fitness, psychosocial health, and disease outcomes in cancer survivors. PURPOSE: To review the evidence on exercise for individuals diagnosed with Neurological Cancer (NC); present data on NC participants in the ACE pilot and ongoing implementation study; and propose a framework to incorporate exercise into the care of NC survivors in Alberta. METHODS: The ACE program is open to survivors with any cancer diagnosis at any stage of treatment. Exercise programming consists of two training sessions per week, with the pilot and implementation studies being 8 and 12 weeks in duration respectively. Outcomes are assessed at study baseline, post-exercise intervention, and 24-week follow-up, and include recruitment and follow-up rates, health-related fitness, psychosocial outcomes, and cancer symptoms. RESULTS: NC survivors represented 7 of 80 participants in the ACE pilot; however, only 3 of the 7 (43%) completed the study. Findings suggested a need for consideration of supervised exercise for some survivors with NC. To date, 14 NC survivors have enrolled in the ACE implementation study. Participants are screened and then referred to either supervised clinic-based or community-based exercise. Seven of 9 participants have completed the ACE intervention, and 5 of 5 have completed the 24-week follow-up. NC participants improved or maintained health-related physical fitness, and reported reduced symptom burden and fatigue. CONCLUSION: Preliminary results suggest exercise training is feasible and beneficial for NC survivors. To optimize recruitment and outcomes, efforts are needed to better identify, screen, and refer survivors to appropriate exercise programming.
16 Combining an oncolytic vaccinia virus with image-guided radiotherapy: a multi-modal therapeutic approach for treating glioma
Authors: Storozynsky Q. , Evans D. , Snyder N. , Potts K. , Agopsowicz K. , Godbout R. , Hitt M.
Published: July 2018

Malignant gliomas (MG) are highly invasive and aggressive brain tumors. Despite the current standard of care, the prognosis for patients with MG is abysmal– highlighting the need for novel, more effective treatment options to combat this aggressive disease. Oncolytic virus (OV) therapy is an advancing treatment option that harnesses tumor-selective viruses to kill cancer cells while simultaneously facilitating a systemic anti-tumor immune response. Many studies have noted synergistic effects when OV’s are combined with radiotherapy in preclinical cancer models, warranting further investigation of this multi-modal approach. Image-guided radiotherapy (IGRT) uses computer-modulated imaging techniques to precisely deliver ionizing radiation to treat cancer. Despite the precision IGRT offers, cancer cells can still be ‘missed’ due to tumor microextensions or radioresistant cell populations– such as glioma stem cells or therapy-induced senescent cancer cells –and may contribute to recurrence or progression. Here we propose to combine our mCherry-tagged mutant vaccinia virus (deltaF4L-deltaJ2R-mCherry), which exhibits tumor-selectivity due to mutations in key viral nucleotide biosynthesis genes, with IGRT executed using state-of-the-art Small Animal Radiation Research Platform (SARRP) technology. We hypothesize that combining deltaF4L-deltaJ2R-mCherry with IGRT will produce better tumor control than either modality alone, by generating additive or synergistic effects in which IGRT destroys the majority of the tumor mass while our OV seeks out and targets any remaining cancer cells that have been missed or are resistant to radiotherapy.
20 Disparities in survival for patients with glioblastoma multiforme
Authors: Fatehi Mostafa , Hunt Camille , Ma Roy , Toyota Brian
Published: July 2018

Background: Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer in adults. Recent efforts have elucidated genetic features of tumor cells and thus enhanced our knowledge of GBM pathophysiology. The most recent clinical trials report median overall survival between 14 and 20 months. However, real-world outcomes are quite variable and there is a paucity of data within the literature. Methods: Three hundred seventy two GBM patients were diagnosed in the province of British Columbia between January 2013 and January 2015. We have performed a retrospective review on the survival outcomes of the 278 patients who underwent surgical resection as part of the initial treatment. Results: Our results indicate a median age of 61.8y at time of diagnosis with a slight preponderance of males. The median overall survival was 10 months for patients who underwent surgery. As expected, patients over the age of 65 and those with worse initial Karnofsy Performance Status (KPS) scores had a poorer prognosis. Moreover, we have found extent of resection (EOR), treatment strategies and treatment location affect overall survival. Conclusion: The present study highlights factors which affect patient survival after surgery in British Columbia. Our outcomes are slightly worse than survival reported in the US. Variability in pathologic classification and in treatment strategy likely contribute to this difference. Further efforts should ensure access to the gold-standard of care.
23 Long-term survivors of brain metastases
Authors: Dasgupta Archya , Moraes Fabio Y , Co Jayson , Winter Jeff , Coolens Catherine , Millar Barbara-Ann , Laperriere Normand , Tsang Derek S. , Bernstein Mark , Kongkham Paul , Zadeh Gelareh , Conrad Tatiana , Berlin Alejandro , Shultz David B
Published: July 2018

Purpose: We identified key clinicopathologic features of brain metastasis (BM) patients who are long-term survivors (LTS). Methods: We screened a prospective database of 1892 patients (treated 2006-2017), identified 92 (5%) who lived > 3 years following BM diagnosis, and performed per patient analyses. Results: Median age at diagnosis of BM was 57 years (range 19-77), 77% were women. The most common tumors were lung (50%), breast (26%), thyroid (7%) and skin (5%). 42% had tumors with drug-targetable oncoproteins (e.g. EGFR mutant) and 15% expressed hormonal receptors. ECOG was <2 in 70%. 47% had stage IV disease at diagnosis (75% with brain as the first site). 55% had controlled extracranial disease at the time of BM diagnosis. Median BM diameter was 1.5 cm (range 0.2-7) and 62% had a single lesion. Treatment was with surgery, radiosurgery, whole brain radiation (WBRT), or systemic therapy alone in 38%, 62%, 52%, and 4%, respectively. 53% received targeted- or immuno-therapy. Median follow up was 63 months (range 36-113). 61% failed intracranially at a median 24 months (range 1-99). 5 and 10- year survival (from BM diagnosis) was 82%, and 34%, respectively. Neither upfront WBRT nor other variables tested correlated with improved survival. In patients who died, an MRI was available within 3 months from death in 57%; of those 55% had no active intracranial disease, suggesting that the majority of deaths were non-neurologic. Conclusion: In general, LTS of BM had a limited number of BM, inactive extracranial disease, and drug targetable mutations.
27 Characterization of the molecular consequences of CIC-knockout and neomorphic IDH1 R132H mutation on transcriptomic and epigenomic landscapes
Authors: Lee SD , Song J , Chan SY , Chittaranjan S , Marra MA
Published: July 2018

CIC, or Capicua, encodes a transcriptional repressor that is itself repressed by RAS/MAPK signalling. CIC is a recurrent target of somatic mutation in type 1 low grade gliomas (LGG), with at least half of the alterations predicted to be deleterious. Type 1 LGGs are a cohort of tumours that are molecularly defined by the loss of heterozygosity of chromosome arms 1p and 19q and the presence of neomorphic IDH1/2 mutations. Despite the high frequency of mutations in CIC within this tumour type, CIC’s putative tumour suppressive role remains to be elucidated. It is also unclear how CIC may cooperate with neomorphic IDH1/2 to promote gliomagenesis. To comprehensively characterize the molecular consequences of CIC loss, we performed RNA-seq, Whole Genome Bisulfite Sequencing, and ChIP-seq on 6 different histone modifications on isogenic CIC-wildtype (WT) and CIC-knockout (KO) normal human astrocytes. To also investigate the collective effects of CIC deficiency and neomorphic IDH1 on the transcriptome and epigenome, we generated the same dataset in isogenic CIC-WT and CIC-KO astrocytes possessing the IDH1 R132H mutation. Analysis of differentially expressed genes illustrates the enrichment of oncogenic pathways in specifically the CIC-KO, IDH1-R132H cells, supporting a synergistic relationship between CIC loss and IDH1-R132H in driving tumour progression. Integrative analyses are ongoing to unveil the epigenetic mechanisms underpinning the regulatory changes in these isogenic cell line models.
32 A population-based study of melanoma brain metastasis treatment: Has new progress in systemic therapy and new technology in radiotherapy improved patient outcomes?
Authors: Brastianos H , Nguyen P , Sahgal A , Eisenhauer E , Baetz T , Hanna TP.
Published: July 2018

Background: Outcomes for patients with melanoma brain metastases (MBM) have been poor. New radiotherapy technologies and systemic agents have improved outcomes. Outcomes have rarely been studied at the population-level. We undertook a population-based study investigating changes in management and outcome for patients with MBM in Ontario from 2007-2016. Methods: This was a retrospective population-based cohort study of patients treated for MBM in Ontario from 2007-2016. Melanoma was identified through the Ontario Cancer Registry. Treatments and outcome were described by era (2007-2009, 2010-2012, 2013-2016). Treatment with cranial radiotherapy and drugs were defined using Cancer Care Ontario data and supplemented by physician billing and drug reimbursement data. Neurosurgery was identified using CIHI hospital records. Time to event was investigated using Kaplan-Meier curves. Results: From January 2007-June 2016, 1096 patients with MBM were treated. Whole brain radiation therapy was the first brain-directed treatment in 75.5% of patients in 2007-2009, dropping to 52.0% for 2013-2016. Patients receiving stereotactic radiation or other conformal techniques as the first brain treatment increased from 3.4% in 2007-2009 to 21.3% 2013-2016. Use of BRAF/MEK inhibitors and immunotherapy increased: <2.0% in 2007-2009 to 40.9% 2013-2016. One-year and two-year overall survival (OS) following first brain-directed treatment was greater in 2013-2016: 21.8% at one year and 13.8% after two years (Wilcoxon p=0.001). This compared to 12.3% and 6.4% 2007-2009, and 10.7% and 5.5% 2010-2012. Conclusion: The advent of new radiation technologies and systemic treatments for MBM was associated with increased survival and greater avoidance of whole brain radiotherapy.
39 Lysosome disruptor’s siramesine and the kinase inhibitor lapatinib induce synergistic cell death through ferroptosis in glioma cells
Authors: Rodriguez Gloria Elisa Villalpando , Blankstein Anna , Henson Elizabeth S. , Gibson Spencer B.
Published: July 2018

Glioblastoma is inherently resistant to radiation and drug treatments. This is mediated by the most common forms of cell death are often actively inhibited. Identifying and exploiting alternative cell death pathways are essential to overcoming or bypassing drug resistance. Ferroptosis, a newly described, morphologically and biochemically distinct, cell death mechanism is characterized by iron-dependent cellular accumulation of reactive oxygen species. The combination of siramesine, a lysosome disruptor, and lapatinib, a dual tyrosine kinase inhibitor (TKI), synergistically induced death in glioma cancer cells. This cell death had characteristics of ferroptosis: it was blocked by the ferroptosis inhibitor ferrostatin-1 and the iron chelator deferoxamine. In addition, the amount of ROS and lipid peroxidation were increased in glioma cells. Iron transport protein remained unchanged but reactive iron levels increased. One target for kinase inhibitors is protein bisulfate isomerase (PDI). Knockdown of PDI in combination with siramesine increased cell death that was blocked by ferrostatin-1. Taken together, drug combinations that alter reactive iron and ROS levels might induce ferroptosis and overcome drug resistance in glioma cells.
45 Cognitive rehabilitation in neuro-oncology: Program development and evaluation
Authors: Richard NM , Mason WP , Shultz D , Laperriere N , Millar BA , Berlin A , Moraes F , Conrad T , Patel M , Maurice C , Bernstein M , Kongkham P , Zadeh G , Bernstein LJ , Edelstein K
Published: July 2018

Background: Brain tumors present unique challenges to patient and family quality of life (QOL). Cognitive dysfunction is common and functionally limiting, with no established treatments. These studies evaluate feasibility and preliminary efficacy of behavioral interventions developed for neuro-oncology patients. Study 1: A randomized controlled trial (N=25 primary brain tumor patients) compared an adapted version of Goal Management Training (GMT, a neuroscience-based integration of mindfulness and strategy training) and a newly-designed supportive psychoeducational intervention (Brain Health Program, BHP) to standard of care. Each intervention comprised 8 individual sessions and at-home practice between sessions. GMT patients’ executive functions improved immediately (p=.077, d=1.13), with maintenance at 4-month follow-up (p=.046, d=1.09). Both intervention groups reported improvements in everyday cognitive functioning immediately (p=.049; d’s GMT=0.43, BHP=0.79) and at follow-up (p=.001; d’s GMT=0.22, BHP=1.01). BHP patients also reported improved mood (p’s=.026 & .012, d’s=0.61 & 0.62). Study 2: Following a needs assessment about cognitive concerns and QOL in brain metastases patients (N=109) and caregivers (N=31), we developed a novel, brief (3 sessions + homework) Cognitive Support Program to provide education and strategy-training in key areas of concern: executive functions, memory, and communication. Options include caregiver co-training, and in-person or web-based delivery. Preliminary data from a pilot trial in progress demonstrate objective and subjective improvements. Conclusions: Cognitive rehabilitation may be a feasible and effective option for primary or metastatic brain tumor patients, addressing a need that is largely unmet in standard cancer care. Further development and larger trials appear warranted, with capacity for remote delivery recommended.
48 Phase 2 studies of dianhydrogalactitol (VAL-083) in patients with glioblastoma, MGMT-unmethylated
Authors: Bacha JA , Steino A , Schwartz R , Langlands J , Kanekal S , Lopez LM. , O'Brien BJ , Chen ZP , Penas-Prado M , Brown DM
Published: July 2018

Current standard-of-care for glioblastoma (GBM) includes surgery, radiation and temozolomide. Most tumors recur within a year from diagnosis and median survival for recurrent GBM (rGBM) is 3-9 months. Unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for temozolomide-resistance, exhibited by most GBM patients. VAL-083 is a DNA-targeting agent with a mechanism-of-action that is independent of MGMT. VAL-083 overcomes temozolomide-resistance in GBM cell-lines, cancer stem cells, and in vivo models. VAL-083 readily crosses the blood-brain barrier and accumulates in brain-tumor tissue. We recently completed a VAL-083 dose-escalation trial in temozolomide- and bevacizumab-refractory rGBM and determined that 40mg/m2/day given intravenously on days 1,2,3 of a 21-day cycle is generally well-tolerated. This dosing regimen was selected for subsequent GBM trials, including an ongoing single-arm, biomarker-driven Phase 2 trial (N=48) in temolozomide-refractory, bevacizumab-naïve rGBM , MGMT-unmethylated (Clinicaltrials.gov:NCT02717962). The primary objective of this study is to determine if VAL-083 improves OS compared to a historical control of 7.15 months for MGMT-unmethylated rGBM patients treated with lomustine (EORTC26101). In addition, another single-arm, biomarker-driven, Phase 2 study (N=25) of VAL-083 in combination with radiotherapy in newly diagnosed GBM, MGMT-unmethylated is ongoing (Clinicaltrials.gov:NCT03050736). This trial aims to determine a dose for further study of VAL-083 in combination with radiotherapy and explore if VAL-083 improves PFS and OS compared to historical results in newly diagnosed GBM. Enrollment and safety data updates will be provided at the meeting. The results of these studies, if successful, may support VAL-083 as part of a new chemotherapeutic treatment paradigm for GBM.
54 Genes preserving stem cell state in Group 3 MB BTICs contribute to therapy evasion and relapse
Authors: Bakhshinyan David , Vijayakumar Thusyanth , Venugopal Chitra , Adile Ashley A. , Singh Mohini , Qazi Maleeha , Mahendram Sujeivan , Manoranjan Branavan , McFarlane Nicole , Kameda-Smith Michelle , Singh Sheila
Published: July 2018

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naïve tumors, provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumors. By adapting the existing Children’s Oncology Group treatment protocol for children with newly diagnosed high-risk MB for treatment of mice intracranially engrafted with human MB cells, we have characterized the rare treatment-refractory cell population in Group 3 MBs. MB cell populations recovered separately from brains and spines during the course of tumor development and therapy were comprehensively profiled for gene expression analysis, stem cell and molecular features to generate a global, comparative profile of MB cells through therapy to relapse. One of the most intriguing observations from our gene expression data was consistent over-expression of proteins belonging to Inhibitor of DNA-binding/differentiation (ID) family and a longevity associated protein bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) in our refractory population. The persistent upregulation of genes preserving undifferentiated state and cellular longevity further strengthens the hypothesis of stem-cell like cells driving tumor relapse in MB. Targeting BPIFB4 using both knockdown (KD) and knockout (KO) strategies have resulted in decreased proliferation and self-renewal of both primary and recurrent MB cells, further highlighting its potential as a novel therapeutic target in MB. Our differential genomic and gene expression profiles of the “treatment-responsive” tumors against those that fail therapy have successfully contributed to discovery and characterization of novel therapeutic targets for the most aggressive subgroup of MB.