tbuckley/cabot-search huggingface dataset:
STEM-09. TREATMENT-RESISTANT SLOW-CYCLING CELLS SUPPORT METABOLIC HETEROGENEITY AND ADAPTABILITY IN GLIOBLASTOMA
Authors: Lan Hoang-Minh, Florian Siebzehnrubl, Changlin Yang, Kyle Dajac, Nicholas Andrews, Michael Schmoll, Krisha Amin, Alvin Vuong, Ana Jimenez-Pascual, Jianping Huang, Timothy Garrett, Elias Sayour, Duane Mitchell, Matthew Sarkisian, Brent A Reynolds, Loic P Deleyrolle
Journal: Neuro-Oncology (2017)

Bioenergetics has recently been garnering attention as a promising avenue for the development of anti-cancer therapies. Many cancers, including brain tumors, have long been thought to undergo widespread metabolic reprograming, with most tumor cells relying exclusively on glucose fermentation for rapid energy production. Recently, metabolic heterogeneity has been described in animal models of glioblastoma (GBM), suggesting that these tumors do not exclusively rely on aerobic glycolysis. However, the precise nature of the cellular compartments harboring those various metabolic specificities has not been established yet. We previously reported cellular diversity in GBM based on cell cycle kinetics and described the presence of fast-cycling cells (FCCs) and slow-cycling cells (SCCs). SCCs exhibit enhanced tumorigenicity and treatment resistance, thus representing attractive therapeutic targets. Actively proliferative cells depend on aerobic glycolysis but SCCs appear to mostly rely on oxidative phosphorylation. Our objective is to characterize the GBM metabolic landscape and explore tumor metabolism as a targetable vulnerability specific to FCCs and treatment-resistant SCCs. GBM patient-derived FCCs and SCCs, which were isolated by flow cytometry based on their dye-retention properties, were compared with respect to their metabolic properties and adaptabilities. Our study reveals the existence of a metabolic dichotomy between subsets of GBM cells. We found that SCCs are refractory to conventional treatment, drive tumor relapse, and do not rely on glucose fermentation, but rather exhibit functional mitochondrial oxidative activity that can be therapeutically targeted in vitro and in vivo. SCCs up-regulate lipid transport, storage, and metabolism, supporting their ability to survive and adapt to metabolic stresses such as glucose restriction. Our studies characterize specific cellular subtypes/states with distinct metabolic characteristics, supporting the concept of metabolic heterogeneity and adaptability in GBM. Our findings also identify lipid pathway components whose pharmacological inhibition can deplete cell subpopulations associated with tumor recurrence.
The Association of Severe Hypoglycemia With Incident Cardiovascular Events and Mortality in Adults With Type 2 Diabetes
Authors: Alexandra K. Lee, Bethany Warren, Clare J. Lee, John W. McEvoy, Kunihiro Matsushita, Elbert S. Huang, A. Richey Sharrett, Josef Coresh, Elizabeth Selvin
Journal: Diabetes Care (2017)

There is suggestive evidence linking hypoglycemia with cardiovascular disease, but few data have been collected in a community-based setting. Information is lacking on individual cardiovascular outcomes and cause-specific mortality.
CSIG-06. ENPP3 OVEREXPRESSION IN ASTROCYTOMAS
Authors: Marco Timmer, Jan Werner, Gabriele Röhn, Roland Goldbrunner
Journal: Neuro-Oncology (2017)

The ENPP (ectonucleotide pyrophosphatase/phosphodiesterase) ectoenzymes 1, 2 and 3 are type II transmembrane proteins with ATPase and ATP pyrophosphatase activities. ENPP3 (CD203c) is an activation marker for mast cells and basophils. In addition, it is regularly expressed in both uterus and prostate. First publications indicate a role of ENPP3 in glial tumors. The expression has been shown in both rat glial precursor cells and in human glioma cell lines. The exposure to N-ethyl-N-nitrosurea (EtNU) causes an overexpression of ENPP3 in neuroectodermal tumors originated from glial precursor cells in rats. A recent study demonstrated high ENPP3 expression in clear renal cell carcinoma and tumor growth inhibition was noticed via antibody-drug conjugates. Quantitative real-time PCR was performed with Cycler Rotor Gene Q and the Rotor-Gene SYBR Green using two primers with different target locations. SDHA was used as a housekeeping gene. Data analysis was performed with Graphpad Prism 7. Fresh frozen samples of 50 patients were used. Both primers detected a significantly higher level of ENPP3 in astrocytomas compared to control brain tissue (Primer A: 0.51 ± 0.09 vs. 0.15 ± 0.04, p=0.0045; Primer B: 1.13 ± 0.32 vs. 0.37 ± 0.14, p=0.0216), whereas primary GBM did not show elevation in comparison to control brain tissue (Primer A: 0.144 ± 0.016 vs. 0.15 ± 0.04; Primer B: 0.476 ± 0.104 vs. 0.37 ± 0.14). The expression levels of primary and secondary GBMs did not differ significantly. Immunostaining mainly showed positive staining in astrocytomas, while GBM exhibited little positive staining only. This is the ﬁrst study to prove ENPP3 expression on glioma patient-samples. Low-grade gliomas have significantly higher ENPP3 expression than control brain tissue. Unlike most cell surface molecules, ENPP3 shows stronger expression in low-grade glioma compared to glioblastoma. This finding could play a role for immunotargeting ENPP3 in gliomas.
Detection accuracy for epithelial dysplasia using an objective autofluorescence visualization method based on the luminance ratio
Authors: Nanami Yamamoto, Koji Kawaguchi, Hisako Fujihara, Mitsuhiko Hasebe, Yuta Kishi, Masaaki Yasukawa, Kenichi Kumagai, Yoshiki Hamada
Journal: International Journal of Oral Science (2017)

The autofluorescence visualization method (AVM) uses blue excitation light to assist in the diagnosis of epithelial dysplasia. It detects epithelial dysplasia as a black area, which is known as fluorescence visualization loss (FVL). In this study, we evaluated the detection accuracy for epithelial dysplasia of the tongue using the objective AVM and assessed its possible clinical utility. Seventy-nine tongue specimens clinically suspected to have leukoplakia or squamous cell carcinoma (SCC) were analyzed. First, the AVM was subjectively performed using the Visually Enhanced Lesion scope (VELscope), and the iodine-staining method was then performed. After biopsy, the histopathological results and the luminance ratio between the lesion and healthy tissue were compared, and a receiver operating characteristic curve was created. The cutoff value for the objective AVM was determined; the lesion was considered FVL-positive or -negative when the luminance ratio was higher or lower than the cutoff value, respectively. The histopathological diagnoses among the 79 specimens were SCC (n=30), leukoplakia with dysplasia (n=34), and leukoplakia without dysplasia (n=15). The cutoff value of the luminance ratio was 1.62, resulting in 66 FVL-positive and 13 FVL-negative specimens. The luminance ratio was significantly higher in the epithelial dysplasia-positive than -negative group (P<0.000 1). The objective AVM showed much higher consistency between histopathological results than did the two methods (kappa statistic=0.656). In conclusion, objective autofluorescence visualization has a potential as an auxiliary method for diagnosis of epithelial dysplasia.
EXTH-24. MGMT INHIBITION BY DISULFIRAM/COPPER COMPLEX RESTORES VELIPARIB ENHANCING TEMOZOLOMIDE EFFECT IN UNFAVORABLE GLIOBLASTOMA MULTIFORME
Authors: George Bobustuc, Deborah Donohoe, Dmitry Bosenko, Richard Rovin, Amin Kassam, Santhi Konduri
Journal: Neuro-Oncology (2017)

O6 methylguanine DNA methyltransferase (MGMT), a DNA repair enzyme, is over expressed in majority of glioblastoma multiforme (GBM) patients. MGMT overexpression causes temozolomide (TMZ) resistance. Poly (ADP – ribose) polymerase (PARP), another early DNA damage response system, like MGMT, has multiple other roles in maintaining genomic stability, coordinating cell cycle, apoptosis and inflammatory responses. Research and clinical evidence show that PARP inhibition in cancers harboring other DNA repair defects (most noticeable in BRCA mutated/defective cancers) limits cancer growth and enhances chemotherapy. Veliparib (ABT-888) is a potent PARP inhibitor. Disulfiram (DSF)/copper combination effectively inhibits MGMT and enhances Temozolomide effect in unfavorable (MGMT unmethylated) glioblastoma cell lines. Prior studies have suggested that Veliparib did not enhance Temozolomide activity in glioblastoma patients due to high MGMT expression levels. Here, we tested DSF/Cu combination in presence of Veliparib +/- Temozolomide in patient derived MGMT positive glioblastoma cell lines. Our results indicate that addition of Veliparib (to Temozolomide) did not significantly increase growth inhibition even at higher concentrations (up to 60µM) in both patient derived or established MGMT positive glioblastoma cells. Single agent treatment with DSF or copper, Temozolomide or Veliparib did not affect patient derived brain tumor cell growth. DSF/Cu complex significantly sensitized patient derived brain tumor cells to Veliparib alone (90%) and Veliparib + Temozolomide (95%) combination. In addition, Veliparib significantly increased apoptotic cell death when used in combination with DSF/Cu or DSF/Cu + Temozolomide. These treatment combinations also showed significant caspase 3/7 activation. Our findings suggest that MGMT inhibition via DSF/Cu complex restores Veliparib (Temozolomide enhancing) activity in patient derived glioblastoma cells.
Breast cancer secondary prevention: get fit to feel healthy
Authors: M. Pistelli, L. Bastianelli, A. Della Mora, M. Romeo, Z. Ballatore, V. Natalucci, M. Capecci, M.G. Ceravolo, R. Serrani, M. Ricci, D. Fumelli, M. Taus, A. Nicolai, R. Berardi
Journal: Annals of Oncology (2017)
Efficacy and safety of Nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer
Authors: V. Filipazzi, D. Dalu, L. Isabella, N. Tosca, S. Ferrario, A. Gambaro, L. Somma, C. Fasola, I. Pellegrini, G. Bombonati, R. Curcio, E. Damiani, M.T. Cattaneo
Journal: Annals of Oncology (2017)
CSIG-21. IDH3 PROMOTES GLIOBLASTOMA GROWTH THROUGH REGULATION OF ONE CARBON METABOLISM
Authors: Alexander Stegh
Journal: Neuro-Oncology (2017)

Neomorphic mutations in isocitrate dehydrogenase (IDH)1 and IDH2, but not in IDH3, have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma. In addition, as shown recently by our group, non-mutated wild-type IDH1 mRNA and protein are commonly overexpressed in primary GBM, and through enhanced production of cytoplasmic NADPH accelerate de novo lipid biosynthesis, regulate redox homeostasis, and enhance glioblastoma progression (Calvert et al., 2017; Cell Reports). While defined roles of mutated and wild-type IDH1 and IDH2 paralogs in cancer pathobiology emerged, little is known about IDH3, which catalyzes one of the rate-limiting, tightly controlled reactions of the TCA cycle. We demonstrate that IDH3a protein expression is elevated in Glioblastoma patient samples compared to normal brain tissue. In support of IDH3a pro-tumor effect, IDH3a over-expression (CRISPR/Cas9-mediated KO) enhanced (reduced) the tumorigenic potential of patient-derived xenografts, as demonstrated by accelerated (decreased) glioblastoma progression and decreased (increased) overall animal subject survival. On molecular levels, IDH3a binds serine hydroxymethyltransferase 1 (cSHMT1), a key regulator of one carbon metabolism. SHMT1 promotes the assembly of a multi-enzyme thymidylate synthesis complex at the nuclear lamina during S and G2/M phases, and appropriates folate metabolites between thymidylate synthesis and the methionine cycle. Through complex formation with SHTM1 at the nuclear lamina, IDH3a increases SHMT1 activity, and in so doing, increases the flux of folate metabolites through the thymidylate synthesis pathway, enhances nucleotide availability during DNA replication, promotes progression through the cell cycle, and decreases susceptibility to the anti-folate chemotherapeutic methotrexate, while shunting methionine cycle turnover and the methylation potential of cells. The identification of a nuclear IDH3-SHMT1 signaling axis point to the regulation of one carbon metabolism by cancer-associated IDH3a as a non-canonical mechanism of metabolic adaptation in glioblastoma, which promotes unabated tumor cell growth and resistance to anti-folate chemotherapy.
EXTH-32. REPEAT ADENOSINE RECEPTOR ACTIVATION IMPROVES GBM SURVIVAL IN MICE BY TRANSIENTLY MODULATING THE BLOOD-BRAIN BARRIER
Authors: Amelie Vezina, Matt McCord, Mark R Gilbert, Sadhana Jackson
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) has a poor prognosis partly due to inadequate chemotherapy delivery across the blood-brain barrier (BBB). Previous studies using an adenosine A2A receptor (A2AR) agonist, regadenoson, impacted tight/adherens junctions and multi-drug resistance (MDR) proteins after single dosing, transiently increasing BBB permeability. We hypothesized that repeated doses of regadenoson can further enhance BBB permeability by modulation of cell-cell junctions and MDR proteins expression to increase chemotherapy entry in the brain. Mouse brain endothelial cells (bEnd.3), were treated 3 times with 10μM regadenoson or vehicle during 8hrs and subsequently changed to fresh culture medium for 16hrs. Cells were collected at varied time points for immunoblotting, immunofluorescence and qRT-PCR expression studies of tight/adherens junctions: Claudin-5, ZO-1, VE-Cadherin, and MDR protein: ABCG2. Actin cytoskeletal changes were monitored by fluorescent staining. Cell-cell adhesion was monitored by electrical impedance. For in vivo studies, U87 GBM cells were implanted in SCID mice and survival was monitored following 3days of daily treatment with vehicle, temozolomide (TMZ), regadenoson or TMZ/regadenoson. Expression of Claudin-5, ZO-1, and VE-Cadherin was decreased approximately 4hrs after regadenoson treatment. Eight hours after treatment, ABCG2 expression decreased by 65%. We observed transient actin disorganization from 30mins, which started to resolve by 8hrs. Triple regadenoson dosing decreased cell impedance by 85% in comparison to control. Median survival of mice treated with TMZ/regadenoson was increased compared to TMZ alone (27 vs 18days). Our results demonstrate that cyclic A2AR activation by regadenoson causes short-lived in vitro cellular changes in endothelial junctions, MDR expression and cytoskeletal morphology. Additionally, repeat dosing of regadenoson with chemotherapy improved survival in an in vivo glioblastoma model. These results demonstrate that repeated activation of adenosine A2A receptors enhances drug delivery by transiently disrupting the BBB which could ultimately improve GBM survival rates.
PATH-02. USE OF RNAseq TO IDENTIFY TUMOR CELL AND MICROENVIRONMENT FACTORS ASSOCIATED WITH IMMUNE CYTOLYTIC ACTIVITY IN GLIOBLASTOMA
Authors: Stephen J Bagley, Donald M O’Rourke, Steven Brem, Gerald P Linette, Arati S Desai
Journal: Neuro-Oncology (2017)

Determinants of immune activation in glioblastoma (GBM) are poorly understood, providing little immunotherapeutic guidance. Using a validated gene expression signature of intratumoral immune cytolytic activity (CYT; Rooney et al, Cell 2015), we sought to determine which tumor-intrinsic and microenvironment factors are independently associated with T-cell effector function in GBM. GlioVis (http://gliovis.bioinfo.cnio.es) was accessed to obtain normalized RNAseq data from The Cancer Genome Atlas (TCGA). For all subjects with treatment-naïve, IDH-wild type GBM, we quantified mRNA expression of 17 pre-specified immune checkpoints, co-stimulatory receptors, and soluble immune inhibitory factors. We also calculated the CYT index (geometric mean of GZMA and PRF1 gene expression) for each subject. Linear regression was performed to determine the relationship between mRNA expression of each of the 17 factors and the CYT index (log-transformed) in univariate analyses. Variables associated with CYT in univariate analysis (p<0.01) were entered into a multivariate linear regression model. Backward selection (exit criterion p>0.05) yielded the final model, which we then validated in an independent cohort of newly diagnosed GBMs subjected to RNAseq (Bao et al, Genome Res 2014; GlioVis). 125 TCGA subjects were identified. The final multivariate linear regression model included the following variables, each positively associated with CYT except for VEGFA, which had a negative association: IL6 (p<0.001), IDO1 (p=0.027), TGFB1 (p=0.003), TNFRSF18 (GITR) (p=0.016), CTLA4 (p=0.001), and VEGFA (p<0.001). In the validation dataset (n=60), all variables remained significantly associated with CYT in multivariate analysis except for TNFRSF18 (GITR). We identified multiple immune checkpoints and soluble immune inhibitory factors independently associated with intratumoral CYT in untreated GBM. Further studies are warranted to determine whether each of these factors induces T-cell effector responses in GBM or, conversely, is upregulated as a means of tumor immune evasion. These results may inform rational combinations for immunotherapy in GBM.
Programmed death ligand 1 (PD-L1) expression status as prognostic factor in early stage non-small cell lung cancer (NSCLC)
Authors: M. D'Arcangelo, M. Puccetti, S. Bravaccini, A. D'Incecco, C. Ligorio, L. Terracciano, S. Damiani, C. Bennati, G. Minuti, S. Vecchiarelli, L. Landi, M. Incarbone, M. Milesi, S. Ravaioli, M.M. Tumedei, E. Rossi, F. Cappuzzo
Journal: Annals of Oncology (2017)
Infecciones por virus coxsackie en 2002 en Grecia: ¿epidemia verdadera o efecto mediático?
Authors: M Exindari, G Gioula, D Raptis, V Mavroidi, E Bouzia, V Kyriazopoulou
Journal: Eurosurveillance (2005)

El proposito de este estudio fue proporcionar pruebas acerca de la existencia de un brote de virus coxsackie B en 2002 en Grecia. Los datos sobre infecciones recientes confirmados por laboratorio entre 1998 y 2001 se compararon con los datos de 2002. Las infecciones se confirmaron serologicamente por deteccion de anticuerpos IgM para virus coxsackie B1-B6 mediante inmunofluorescencia indirecta. Se examinaron los sueros de 2.701 pacientes residentes en el norte de Grecia y sospechosos de sufrir infecciones por este virus: 2.056 pacientes entre 1998 y 2001, y 645 en 2002. La comparacion entre los resultados de los casos confirmados por laboratorio y los datos disponibles en el laboratorio entre los dos periodos mostro que: - El numero total de pacientes examinados por ano fue superior en 2002 (645 frente un promedio anual de 514 en 1998-2001). - La proporcion de infecciones recientes confirmadas por laboratorio fue inferior en 2002 (27,8 % frente a 32,7 %) y la incidencia estimada fue 0,66/10.000 en 2002 y 0,32-0,84/10.000 para 1998-2001. - La distribucion por edad fue diferente: la proporcion de casos en ninos frente a casos en adultos estaba invertida en 2002 comparada con 1998-2001, con una mayor proporcion de casos entre ninos en 2002. La diferencia entre los dos periodos fue estadisticamente significativa. El grupo de edad mas afectado en 2002 fue el de ninos entre 3 y 5 anos. - La distribucion estacional fue la misma para ambos periodos (con picos en primavera y otono). En 2002 hubo tres defunciones en Abril, mientras que en 1998-2001 no hubo defunciones. - Los sindromes clinicos implicados tambien fueron diferentes: los casos de infecciones respiratorias, principalmente neumonia, subieron de 5,75 % a 24,3 % en ninos en 2002, mientras que los casos de miopericarditis subieron en adultos de 13 % en 1998-2001 a 29,5 % en 2002. Este ultimo hallazgo, combinado con la implicacion de los medios (debido a los tres casos fatales), y el panico consiguiente generado en la poblacion, sugirieron la existencia de un brote, aunque los datos obtenidos en nuestro estudio no permiten confirmar esta hipotesis.
Association of air particulate pollution with bone loss over time and bone fracture risk: analysis of data from two independent studies
Authors: Diddier Prada, Jia Zhong, Elena Colicino, Antonella Zanobetti, Joel Schwartz, Nicholas Dagincourt, Shona C Fang, Itai Kloog, Joseph M Zmuda, Michael Holick, Luis A Herrera, Lifang Hou, Francesca Dominici, Benedetta Bartali, Andrea A Baccarelli
Journal: The Lancet Planetary Health (2017)

Air particulate matter (PM) is a ubiquitous environmental exposure associated with oxidation, inflammation, and age-related chronic disease. Whether PM is associated with loss of bone mineral density (BMD) and risk of bone fractures is undetermined.We conducted two complementary studies of: (i) long-term PM <2.5 μm (PM2.5) levels and osteoporosis-related fracture hospital admissions among 9.2 million Medicare enrollees of the Northeast/Mid-Atlantic United States between 2003-2010; (ii) long-term black carbon [BC] and PM2.5 levels, serum calcium homeostasis biomarkers (parathyroid hormone, calcium, and 25-hydroxyvitamin D), and annualized BMD reduction over a 8-year follow-up of 692 middle-aged (46.7±12.3 yrs), low-income BACH/Bone cohort participants.In the Medicare analysis, risk of bone fracture admissions at osteoporosis-related sites was greater in areas with higher PM2.5 levels (Risk ratio [RR] 1.041, 95% Confidence Interval [CI], 1.030, 1.051). This risk was particularly high among low-income communities (RR 1.076; 95% CI, 1.052, 1.100). In the longitudinal BACH/Bone study, baseline BC and PM2.5 levels were associated with lower serum PTH (Estimate for baseline one interquartile increase in 1-year average BC= -1.16, 95% CI -1.93, -0.38; Estimate for baseline one interquartile increase in 1-year average PM2.5= -7.39; 95%CI -14.17, -0.61). BC level was associated with higher BMD loss over time at multiple anatomical sites, including femoral neck (-0.08%/year per one interquartile increase; 95% CI -0.14, -0.02%/year) and ultradistal radius (-0.06%/year per one interquartile increase; 95% CI -0.12, -0.01%/year).Our results suggest that poor air quality is a modifiable risk factor for bone fractures and osteoporosis, especially in low-income communities.
NIMG-66. A METHOD FOR RAPIDLY CREATING HEAD MODELS OF GLIOBLASTOMA PATIENTS FOR STUDYING THE DELIVERY OF TTFIELDS TO THE BRAIN
Authors: Noa Urman, Avital Frenkel, Shay Levi, Manzur Doron, Ariel Naveh, Hadas Sara Hershkovich, Uri Weinberg, Cornelia Wenger, Eilon D Kirson, Ze’ev Bomzon
Journal: Neuro-Oncology (2017)

Computational studies simulating the delivery of TTFields to realistic head models are a standard method for investigating TTFields distribution in the brain. These studies are useful as they allow estimation of field distributions without the need for invasive physical measurements. Creating realistic head models of patients is labor-intensive because it requires accurate segmentation of patient’s MRI data-sets. This limits the usefulness of standard methods for creating head models in studies that require a large number of realistic head models, such as studies investigating connections between field intensity distributions and disease progression. Here we present a method for creating realistic models of Glioblastoma Multiforme (GBM) patients that overcomes this limitation. A prerequisite for our method is the creation of a highly detailed healthy head model which serves as a deformable template from which patient models can be created. When creating patient models, the tumor in the patient’s MRI is first segmented. Next, non-rigid registration algorithms are used to register the healthy regions of the patient head MRI images on to a 3D image representing the deformable template. This yields a non-rigid mapping of the patient’s head in to the template space, as well as the inverse transformation that maps the template in to the patient space. The inverse transformation is applied to the 3D deformable template and an approximation of the patient head in the absence of a tumor is found. Finally, the segmented tumor is planted back into the deformed template to yield a full patient model. Comparison of the models to patient MRIs reveals good representation of the patient anatomy within the model. This method enables rigorous investigation of important clinical questions related to the connection between TTFields distribution with the brain and disease progression.