tbuckley/cabot-search huggingface dataset:
DRES-19. SEX-BASED DIFFERENCES IN TUMOR RESPONSE TO (TARGETED) THERAPEUTICS: NUANCED SIGNALING MEDIATORS REVEAL TREATMENT OPPORTUNITIES
Authors: Gil Speyer, Jasmin Sponagel, Peter McDonald, Anu Roy, Scott Weir, Quinn Ostrom, Justin Lathia, Joshua Rubin, Jill Barnholtz-Sloan, Michael Berens
Journal: Neuro-Oncology (2017)

Despite the fundamental genetic and molecular differences present between male and females, the majority of cancer therapies do not take them into account. To identify compounds with sex-specific efficacy for the advancement of precision medicine, we mined drug dose responses from The Cancer Therapeutics Response Portal (945 cell lines, 545 compounds) and the Sanger Institute’s Genomics of Drug Sensitivity in Cancer (1,028 cell lines, 265 compounds). Analysis of RNAseq data uncovered pathway-enriched transcriptomic differences between sensitive and resistant, and groupings by sex. Across several PI3 kinase (PI3K) inhibitors, comparison between sensitive and resistant male cell lines highlighted significant rewiring (connectivity of nodes and edges) in the PI3K pathway. In contrast, concordant findings between sensitive and resistant female cell lines did not emerge. Male cell lines also uniquely rewired AKT1 in the downregulation of ERBB2/3 pathway, comparing sensitive and resistant responses to gefitinib, an inhibitor of AKT1 and EGFR. In addition, we performed an independent screen of the FDA Approved Drugs and Bioactives library (5,504 compounds) using a murine model of glioblastoma. Twenty-four compounds exhibited sex-specific effects and five of these targeted the PI3K pathway, providing cross-species validation of sex-specific response to PI3K inhibition. To ascertain whether this reflected sexual dimorphism in the PI3K pathway, we treated male and female murine GBM cells with insulin or IGF-1 and measured the dose and time dependence of activation of multiple downstream effectors of PI3K. We found significant sex differences in phosphorylation of Akt, mTOR and S6 kinase. Together, these results illustrate a workflow for evaluating sex differences in cancer biology and drug response. Moreover, within glioma specifically, these data suggest that sex-based vulnerability to drugs targeting PI3K pathway ascend to an exploitable feature in treatment planning warranting assessment in clinical trials.
Um surto de intoxicação alimentar por Salmonella enteritidis com origem em queijo produzido para comércio
Authors: M. G. Panico, F Primiano, F Nappi, F Attena
Journal: Eurosurveillance (1999)

Entre 30 de Junho e 2 de Julho de 1998, tres hospitais notificaram nove casos suspeitos de intoxicacao alimentar ao servico de epidemiologia e prevencao (Servizio di Epidemiologia e Prevenzione - SEP) da autoridade de saude local no distrito de Napoles (Azienda Sanitaria Locale, ASL NA 4). O SEP iniciou imediatamente a investigacao do surto.
MNGI-11. TREATMENT OF MENINGIOMA WITH TH-302 IN A PDX MOUSE MODEL AND CELL LINE
Authors: Vaibhav Patel, Asif Maknojia, Michael Garcia, David Cavazos, Aleksandra Gruslova, Bosse Courtney, Niko Papanikolaou, Dawit Kidane, Andrew Brenner, John Floyd
Journal: Neuro-Oncology (2017)

Meningioma account for 36% of intracranial tumors and 4.7-7.2% demonstrate aggressive clinical behavior. Current treatments are limited to surgery and radiation. We investigated hypoxia activated prodrugTH302 in patient-derived xenograft model of malignant meningioma. Female athymic nude mice were implanted subcutaneously with human meningioma tissue obtained intraoperatively. After 80 days of tumors growth animals were randomized into four groups 1) Control(n=1), 2) XRT (n=4), 3) TH302(n=5), and 4) XRT+TH302(n=4). Mice were either focally radiated using LINAC system in five fractions of 3Gy given daily to a total of 15 Gy, treated with TH302 at 50mg/kg started on day 3 of radiation for 9 doses every other day or combination of both. Tumor volume was measured by a digital caliper until endpoint of 4000 mm3 was reached. H&E, IHC and western blot analysis were performed to further elucidate mechanism of action in meningioma. Additionally, CH157MN meningioma cell line is being used for drug concentration screening (0.1uM - 500uM) to determine IC50 under normaxia and hypoxia conditions using MTT assay. Tumor growth in 1)Control: 1199 mm3 to 4371 mm3 in 35 days, 2)XRT: 890 mm3 to 4220 mm3 in 91 days, 3)TH302: 660 mm3 to 4894 mm3 in 130 days and 4)XRT+TH302: 890 mm3 to 4266 mm3 in 155 days. FFPE H&E and CA9 stained sections show increase in necrotic regions while decrease in hypoxia in XRT/TH302 vs XRT. Western blot showed increase in Chk1, Rad51, and Polβ in XRT+TH302. Our in vivo study shows that mice treated with XRT+TH302 compared to XRT alone have prolonged survival with p<0.0206 with decreased rate of tumor growth likely from TH302-dependent DNA damage of hypoxic cells resulting in cell death.
Evolution récente des infections à méningocoque en Europe
Authors: B Hubert, D A Caugant
Journal: Eurosurveillance (1997)

Peu d'infections provoquent autant d'emotion que l'apparition d'infections a meningocoque dans une communaute. La capacite de Neisseria meningitidis a tuer un enfant en bonne sante en quelques heures est une des raisons de cette angoisse. Il est egalement vrai que les moyens de prevention contre cette maladie sont actuellement limites et qu'ils reposent principalement sur le traitement precoce des malades et sur la prevention des cas secondaires.
P2.02-061 Two Novel Protein-Based Prognostic Signatures Improve Risk Stratification of Early Lung ADC and SCC Patients
Authors: E. Martinez-Terroba, C. Behrens, F. De Miguel, J. Agorreta, E. Monsó, L. Millares, M. Mesa-Guzman, J.L. Perez-Gracia, M. Lozano, J. Zulueta, R. Pio, I. Wistuba, M. Pajares, L. Montuenga
Journal: Journal of Thoracic Oncology (2017)
Vigilancia del paludismo en Italia: análisis de 1997 y datos provisionales de 1998
Authors: R Romi, D Boccolini, G Majori
Journal: Eurosurveillance (1999)

El paludismo es la mas frecuente de las enfermedades infecciosas importadas en Italia. Hasta su erradicacion, hace unos 50 anos, el paludismo era endemico en gran parte del pais. Desde entonces, se establecio un sistema de vigilancia del paludismo para detectar casos adquiridos localmente que podrian indicar una transmision autoctona.
P3.16-053 Genomic Challenges for Lung Cancers with Multiple Pulmonary Sites of Involvement
Authors: X. Kang, H. Zhou, T. Xuan, W. Yan, Y. Gong, L. Dai, Y. Guan, Y. Yang, H. Yang, H. Fu, M. Fan, Y. Lin, Z. Liang, H. Xiong, L. Yang, X. Yi, K. Chen
Journal: Journal of Thoracic Oncology (2017)
CMET-44. HER2 AND TRIPLE NEGATIVE BREAST CANCER PATIENTS DEMONSTRATE AN EARLIER TIME TO DEVELOPMENT OF BRAIN METASTASES
Authors: Toni Cao, Cesar Santa-Maria, Priya Kumthekar
Journal: Neuro-Oncology (2017)

Breast cancer represents the second most common cancer associated with brain metastases in the United States. Previous independent studies have identified the HER2 and triple negative hormone subtypes to be associated with a higher risk of CNS relapse. It has been previously demonstrated that HER2 patients have an increased risk of earlier brain metastases. Triple negative patients with brain metastases also have the shortest survival time compared to all other subtypes. Although the increased risk of brain metastases is well established in both of these patient groups, there is currently there is no accepted standard of care for routine brain metastases screening in this patient population. The purpose of this study was to determine if specific patient and tumor characteristics, including HER2 and triple negative diagnosis, affects the time to development of brain metastases. We analyzed our retrospective database of 385 breast cancer patients with brain metastases from 2003–2015. Patients were subsequently excluded for incomplete data as well as for having other aggressive primary malignancies, leaving a total of 305 patients to be included in the final analysis. Both HER2 and triple negative patients demonstrated a shorter time to CNS recurrence compared to luminal patients. HER2, triple negative, and luminal patients had a time to brain metastases of 22.5, 27.1, and 38.5 months, respectively (p < 0.025). In this single-institutional case series study, we confirm prior data showing that HER2 patients have a shorter time to brain metastases as compared to other breast cancer patients. We also demonstrate that triple negative breast cancer patients have a shorter time to brain metastases compared to luminal patients. This data suggests the utility of prospective studies to confirm if earlier screening can modify quality of life and survival time in both of these patient populations.
P3.02-035 Mutational Signatures and Their Association with Clinicopathological Features in Lung Adenocarcinoma of Smokers
Authors: T. Honda, K. Shiraishi, H. Sakashita, K. Masai, M. Kobayashi, S. Mimaki, N. Motoi, K. Tsuchihara, K. Tsuta, K. Okubo, N. Inase, S. Watanabe, T. Kohno
Journal: Journal of Thoracic Oncology (2017)
STEM-04. MECHANISM OF DYSREGULATION AND EFFICACY OF PHARMACOLOGICALLY TARGETING THE APC/C IN GLIOBLASTOMA
Authors: Kuntal De, Amanda Deighen, Treg Grubb, Matthew Summers, Monica Venere
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is the most lethal type of primary brain tumor with the common length of survival after diagnosis at only 12 to 15 months. One of the causes of poor patient outcomes is the cellular heterogeneity whereby GBM cancer stem cells (CSCs) drive therapeutic resistance. Hence, there is an urgent need to identify novel therapeutics against GBM that inclusively target the CSCs. Critical for tumor progression and treatment resistance is abnormal regulation of the cell cycle that is permissive for the background of inherent genomic instability present in most cancer cells and shown by our group to be elevated in CSCs. One key component of this tolerant proliferation state is the Anaphase-Promoting Complex (also called the cyclosome or APC/C), an E3 ubiquitin ligase that degrades cell cycle proteins via proteasomal-mediated degradation. The APC/C targets are differentially regulated throughout the cell cycle by two mutually exclusive activator proteins, CDC20 and CDH1. We previously published that the activity of APC/CCdh1 is attenuated in GBM CSCs. We now demonstrate that targeting APC/C activity via small molecule inhibition tips the balance of genomic instability in the CSCs to an unviable state. We also identified that protein levels of multiple regulators of the APC/C are altered in CSCs and likely contribute to decreased APC/CCdh1 activity. Small molecule inhibitors that increases chromosomal missegragation in CSCs offers a new therapeutic strategy to eliminate CSCs from tumors by forcing cells past a threshold of tolerance to genomic instability.
Les politiques d’immunisation contre les infections à pneumocoque en Europe
Authors: R G Pebody, T Leino, H Nohynek, W Hellenbrand, S Salmaso, P Ruutu
Journal: Eurosurveillance (2005)

L’infection a Streptococcus pneumoniae (Pneumococcus) (Pnc) est une cause frequente de manifestations cliniques invasives telles que les meningites, la septicemie et la pneumonie, en particulier chez les jeunes enfants et les personnes âgees. Un vaccin polysaccharide anti-Pnc a 23-valence (PPV) est disponible depuis de nombreuses annees et, depuis 2001, un vaccin conjugue heptavalent est commercialise en Europe. En 2003, dans le cadre du Pnc-EURO, projet sur les infections a pneumocoques finance par l’union Europeenne, un questionnaire a ete envoye aux 15 Etats membres de l’Union Europeenne, plus la Suisse, la Norvege et les 10 pays candidats, afin de faire le point sur la politique d’immunisation antipneumococcique. Vingt trois des 27 pays interroges representant l’actuelle Union Europeenne plus la Norvege et la Suisse, ont repondu au questionnaire. En 2003, la PPV etait commercialisee dans 22 des 23 repondants et figurait sur les recommandations officielles de 21 d’entre eux. Parmi ces derniers et pour les 20 pays ou l’information etait disponible, la vaccination etait ciblee sur des groupes a risque. Le nombre de groupes a risque variait de un a 12 selon les pays. Au moins 17 pays recommandent la vaccination par PPV chez les sujets de plus de 65 ans (dans trois pays, aux plus de 60 ans).
En 2003, treize pays avaient emis des recommandations nationales pour le VPC. A cette periode, aucun pays ne recommandait l’immunisation de masse des nouveaux-nes, preferant cibler les groupes a risque specifiques (entre un an et 11 ans), en particulier les enfants atteints d’asplenie (n=13) et d’infections a VIH (n=12). Dans sept pays, l’utilisation du VPC etait limitee aux enfants de moins de deux ans, et dans quatre pays aux enfants de moins de cinq ans. 
Les prochaines decisions sur l’utilisation de vaccins antipneumococciques en Europe tiendront compte de plusieurs facteurs: l’importance locale de la maladie, l’estimation de impact d’un programme universel, en particulier l’importance du serotype de remplacement et de l’immunite de groupe (protection indirecte envers la population non vaccinee); l’efficacite de calendriers vaccinaux a nombre de doses reduites et le cout du vaccin. Un pays au moins, en l’occurrence le Luxembourg, a mis en place une politique d’immunisation globale des nourrissons par le VPC depuis cette enquete.
SCDT-16. ENHANCING THE EFFICACY OF CHEMOTHERAPY BY FOCUSED ULTRASOUND MEDIATED SONOCHEMICAL INTERNALIZATION (SCI)
Authors: Henry Hirschberg, Steen Madsen
Journal: Neuro-Oncology (2017)

Systemically administered chemotherapeutic agents are, firstly limited by their inability to penetrate across the blood brain barrier (BBB). Site-specific disruption of the BBB using focused ultrasound (FUS) has been demonstrated in experimental animal glioma models and in a small number of patients. Secondly, many highly effective chemotherapeutic agents are large and water soluble and are actively transported into tumor cells by endocytosis. Their poor ability to escape from the resulting intracellular endosomes leads to their inactivation via lysosome-endosome fusion. Activation of sonosensitizers via focused ultrasound (FUS), i.e. sonodynamic therapy (SDT) has been proposed as an extension to light activated photodynamic therapy for the treatment of brain as well as other tumors. The use of focused FUS, as opposed to light, allows treatment to tumor sites buried deep within tissues as well as through the intact skull. We have examined ultrasonic activation of sonosensitizers to enhance the efficacy of the anti-cancer agent bleomycin (BLM). The combination of sonosensitizers drug and FUS is termed sonochemical internalization (SCI), as an extension of light based photochemical internalization (PCI). SCI is a technique which utilizes FUS for the enhanced delivery of endo-lysosomal trapped macromolecules into the cell cytoplasm. The released agent can therefore exert its full biological activity, in contrast to being degraded by lysosomal hydrolases. Our results indicate that, compared to drug or FUS treatment alone, FUS activation of the sonosensitizer AlPcS2a together with BLM significantly inhibits glioma growth. SCI is a promising new technology that, like PCI, may potentiate the efficacy of a wide variety of therapeutic compounds. However, unlike PCI, SCI is not limited by the poor tissue penetration inherent to light-based approaches and, as such, this ultrasound-based technology is ideally suited for the treatment of deep seated or intracranial lesions like gliomas.
L’exhaustivité de la déclaration du paludisme aux Pays-Bas entre 1995 et 2003 évaluée par la méthode de capture-recapture
Authors: S Klein, A Bosman
Journal: Eurosurveillance (2005)

En 1999 aux Pays-Bas, du fait de la nouvelle la loi sur les maladies infectieuses, l’obligation de declarer le paludisme a ete transferee des medecins aux laboratoires. Afin de mesurer l’impact de ce changement, une evaluation de l’exhaustivite de la notification du paludisme aux Pays-Bas entre 1995 et 2003 a ete realisee. Elle a ete calculee par rapport aux donnees des laboratoires sentinelle et des hospitalisations. Le nombre total de cas a ete estime par la methode de capture-recapture (CRM), afin d’evaluer l’exhaustivite par rapport a cette valeur. 
L’exhaustivite de la declaration par rapport aux donnees sentinelle etait de 18,2 % (95% IC de 15,7-20,7) de 1995-1998 et de 56,4 % (95% IC de 47,0-65,8) pour 2000-2003. Elle etait de 35,1% pour la periode 1995-2003 comparee aux donnees de declaration hospitaliere. Le nombre de cas estime de malaria entre 1995 et 1998 etait de 3123 (95% IC de 2796-3449) et s’elevait a 5043 (95% IC de 4343-5742) entre 2000 et 2003. Par rapport a ces chiffres, l’exhaustivite de la declaration est passee de 35,5 % (95% IC de 32,1-39,7) en 1995-1998 a 36,1 % (95% IC de 31,7-41,9) pour la periode 2000-2003. 
Avec le systeme de notification base sur les laboratoires, le nombre absolu de declarations de paludisme a augmente de facon significative, alors que l’exhaustivite restait stable par rapport aux donnees d’hospitalisations. L’augmentation des cas estimes de paludisme peut etre biaisee car les conditions requises pour la methode de capture-recapture n’ont pas ete suffisamment respectees pendant la periode de l’etude.
Early changes in plasma levels of mutant KRAS DNA as a sensitive marker of response to chemotherapy in pancreatic cancer
Authors: M. Del Re, C. Vivaldi, E. Rofi, E. Vasile, M. Miccoli, C. Caparello, P. d'Arienzo, L. Fornaro, A. Falcone, R. Danesi
Journal: Annals of Oncology (2017)
Cas groupés de grippe et syndrome grippal dans les écoles en Angleterre et au Pays de Galles, 2005/06
Authors: H Zhao, C A Joseph, N Phin
Journal: Eurosurveillance (2007)

En Angleterre et au Pays de Galles, les rapports cliniques en provenance des etablissements de soins primaires ont demontre que l’activite grippale pour la saison 2005/06 n’avait depasse le niveau de reference que pendant quatre semaines en fevrier 2006.
P2.14-016 Pulmonary Resection After Curative Intent Chemoradiation for NSCLC
Authors: G. Cetinkaya, H. Melek, B. Özkan, E. Özer, S. Sarıhan, E. Yentürk, T. Sevinç, A. Bayram, A. Toker, C. Gebitekin
Journal: Journal of Thoracic Oncology (2017)
ACTR-85. THE EFFECT OF REGADENOSON ON TEMOZOLOMIDE NEUROPHARMACOKINETICS IN GLIOBLASTOMA PATIENTS MEASURED BY INTRACEREBRAL MICRODIALYSIS
Authors: Sadhana Jackson, Jon Weingart, Edjah Nduom, Matthias Holdhoff, Jashri Blakeley, Anna F Piotrowski, Thura Abd, Richard George, Dorothea McAreavey, Xiaobu Ye, Nicole Anders, Cody Peer, Julie Barnes, William Figg, Michelle Rudek, Mark Gilbert, Stuart A Grossman
Journal: Neuro-Oncology (2017)

The blood-brain barrier (BBB) prevents effective delivery of systemic therapy to the brain. Activation of A2A adenosine receptor by regadenoson has demonstrated transient BBB disruption in animals, allowing dextran (70kD) brain entry and increased temozolomide delivery. Temozolomide is the standard treatment for glioblastoma yet brain:plasma concentrations are approximately 20%. This study evaluated the neuropharmacokinetics of temozolomide in brain interstitium (BI) with and without regadenoson. Patients with recurrent high grade glioma had intracerebral microdialysis (ICMD) catheter(s) placed in peritumoral tissue at the time of surgical resection. Computerized tomography confirmed catheter(s) placement. Patients received oral doses of temozolomide (150mg/m2) on postoperative day one and two. On postoperative day 2, they were given intravenous regadenoson (0.4mg) 60 minutes after temozolomide. Serial blood and ICMD samples were collected over 48 hours and concentrations were determined by tandem mass spectrometry. Five patients were enrolled with dialysate and plasma samples collected from each. The mean area-under-the-concentration-curve (AUC) in plasma and non-contrast BI was 18.7 ± 4.6 and 3.2 ± 1.6µg/ml x hr vs. 18.1 ± 2.8 and 3.1 ± 1.2µg/ml x hr for temozolomide alone vs. temozolomide/regadenoson respectively. The mean brain:plasma AUC was 17.7 % and 16.9% for temozolomide alone and temozolomide/regadenoson respectively. In two patients, the mean brain:plasma AUC increased by 55% with the administration of regadenoson. Peak concentration and Tmax in brain for each group was not statistically different. These results demonstrate that co-administration of regadenoson with temozolomide is safe, feasible and does not impact TMZ plasma concentrations. These preliminary results suggest that regadenoson may slightly raise brain interstitial temozolomide levels in select patients. Yet, at the current dose/schedule regadenoson does not provide a significant increase in temozolomide brain delivery. Further investigations to identify optimal regadenoson dosing, responsive patients and continued use of ICMD to identify other BBB modulators is warranted.
PATH-29. MOLECULAR DETERMINANTS ASSOCIATED WITH RESPONSE AND RESISTANCE TO DEPATUXIZUMAB MAFODOTIN (ABT-414) IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Andrew Lassman, Lisa Roberts-Rapp, Lei He, Xin Lu, Martin van den Bent, Kyriakos Papadopoulos, Ryan Merrell, Priya Kumthekar, David Reardon, Erica Gomez, JuDee Fischer, Fang Jiang, Zheng Zha, Anahita Bhathena, Kyle Holen, Peter Ansell, Hui K Gan, Andrew Scott
Journal: Neuro-Oncology (2017)

BACKGROUNDDepatuxizumab mafodotin (depatux-m, formerly ABT-414), is an EGFR-targeted antibody conjugated to the antimicrotubule agent monomethylauristatin F (MMAF). In an ongoing Phase I study, response in recurrent glioblastoma (rGBM) correlated with EGFR amplification in pre-treatment, archival tumor tissue. However, the correlation with efficacy is imperfect, prompting a search for other biomarkers that predict benefit or resistance, including attention to mutations that could impact sensitivity to the microtubule inhibitor of the depatux-m molecule.
GENE-12. EMERGING PRINCIPLES OF SYNTHETIC LETHALITY IN GLIOBLASTOMA
Authors: Pia Hoellerbauer, Sonali Arora, Heather Feldman, Lucas Carter, Emily J Girard, Philip Corrin, James M Olson, Patrick Paddison
Journal: Neuro-Oncology (2017)

Synthetic lethality occurs when mutations in two otherwise non-essential genes are combined to cause lethality. Because cancer is a disease of genetic alteration, synthetic lethality has been heralded as a method to identity candidate therapeutic targets, e.g., where a target gene could be “synthetic lethal” with a cancer driver mutation. To define synthetic lethal relationships in glioblastoma (GBM), we have performed multiple focused set and genome-wide CRISPR-Cas9 and RNAi lethality screens in patient-derived GBM stem-like cells (GSCs) and non-transformed human neural progenitor cells. Because GSCs isolates likely represent a sub-clone of the original tumor and we can determine GSCs’ genetic and epigenetic make up, it is possible to address the concept of synthetic lethality for GBM. To this end, we recently performed comprehensive CRISPR-Cas9 retests of all scoring GBM lethal genes (>900) from screens in three patient isolates with different and overlapping genetic drivers. We then performed secondary retests of high priority gene targets in 13 GSC harboring various alterations commonly found in GBMs, e.g., EGFRamp, NF1mut, PIK3CAmut, PTENloss/mut, TP53mut, etc. The results were surprising, first in what we did not find. We failed to find synthetic lethal targets for RB1mut, TERT expression, or TP53loss/mut, suggesting that synthetic lethal relationships for these alterations may not exist for GBM. Second, NF1mut interactors defined a broader class of synthetic lethal targets with over activity of the RTK/Ras pathway, which can arise from various activating lesions. Third, candidate “clean” synthetic lethal relationships can be observed, but, so far, only with EGFRamp, MYC/MYCNamp, and, possibly, PTEN/PIK3CA alterations. Thus, in general, our results suggest that the majority of synthetic lethal relationships in GBM arise from oncogenic activation of the RTK/Ras and PI-3 kinase pathway or amplification of MYC/MYCN. (Synthetic lethal targets will be revealed and discussed at the meeting.)