tbuckley/cabot-search huggingface dataset:
EXTH-39. EFFICACY OF THE ANTIBODY-DRUG CONJUGATE ABT-414 IN BRAIN TUMOR MODELS
Authors: Leslie Muldoon, Heather McConnell, Cymon Kersch, Edward Neuwelt
Journal: Neuro-Oncology (2017)

Brain tumor treatment is limited by a lack of effective therapies and inadequate drug delivery across the blood-brain barrier (BBB). The antibody-drug conjugate (ADC) ABT-414 (AbbVie Pharmaceuticals) couples the toxin monomethyl auristatin F to a humanized monoclonal antibody targeting overexpressed and mutant epidermal growth factor receptor (EGFR). ABT-414 inhibits tumor growth in multiple preclinical subcutaneous tumor models, but its efficacy in brain tumors may be reduced by inadequate delivery of the ADC across the BBB after intravenous administration. We have shown that intra-arterial infusion of hypertonic mannitol transiently disrupts the BBB to safely increase delivery of chemotherapy, antibodies and nanoparticles to the brain. We hypothesized that BBB disruption (BBBD) would improve ABT-414 efficacy in rat models of human brain tumors. Using intracerebral xenografts of U87MG human glioma cells expressing EGFRvIII (U87-EGFRv3), we found that ABT-414 is highly effective when delivered with BBBD as a single dose at concentrations as low as 1 mg/kg. One week after treatment, the tumor volume of treated animals was 0.47 ± 0.27mm3 (n=3) relative to controls 31.1 ± 8.3mm3 (n=10) (P<0.0001). Immunohistochemistry demonstrated apparent residual tumor consisting of a glial scar along the inoculation track with ~1–3 tumor cells present per section. Using ferumoxytol-enhanced magnetic resonance imaging to detect treatment-induced inflammatory responses, we observed strong signal dropout at tumor sites that co-localized with ferumoxytol uptake in activated macrophage/microglia within and around the residual lesion. Finally, we found that ABT-414 was partially effective in an intracerebral xenograft model using wildtype EGFR human non-small cell lung cancer cells. We conclude that BBBD delivery of ABT-414 is safe in rat brain and the immunoconjugate is highly effective in the treatment of rat brain tumor models.
GENE-58. EPIGENETIC REPROGRAMMING IN MUTANT IDH1 GLIOMA IMPACTS MEDIAN SURVIVAL, ENHANCES DNA DAMAGE RESPONSE AND CONFERS RADIO-RESISTANCE
Authors: Felipe J Nunez, Flor M Mendez, Padma Kadiyala, Masha Savelieff, Carl Koschmann, Stephen Carney, Rohin Patel, Shaan Manawar, Neha Kamran, Meghna Saxena, Mats Ljungman, Tingting Qin, Sator Maureen, Marta Dzaman, Sriram Vennneti, Shawn Hervey-Jumper, Maria E Figueroa, Pedro R Lowenstein, Maria G Castro
Journal: Neuro-Oncology (2017)

A distinctive glioma sub-type harbors mutations in Isocitrate Dehydrogenase 1 (IDH1-R132H: mIDH1), ATRX and p53. IDH1-R132H generates 2-hydroxglutarate (2HG), which gives rise to histone and DNA hypermethylation. Mutant IDH1 has been associated with better patients’ prognosis. We hypothesize that this is mediated by the impact of epigenetic changes on DNA-repair and DNA damage response (DDR) pathways. To test this, we developed a genetically engineered mouse glioma model harboring mIDH1, TP53 knockdown and ATRX knockdown using the Sleeping Beauty Transposase system. We also generated mouse tumor neurospheres (NS) and human glioma cells expressing mIDH1, with or without ATRX loss. Our results show that mIDH1 expression enhances median survival (MS > 160 DPI) when compared with wild type (wt) IDH1 (MS = 72 DPI). Mutant IDH1 tumors exhibit inhibition of cell differentiation; and enhanced histone 3 methylation. Analysis of ChIP-seq, RNA-seq and Bru-seq data indicates that genes involved in DNA-repair and DDR, including homologous recombination DNA-repair, were upregulated in the mIDH1 mouse model. Functional assessment of DNA repair activity was performed after ionizing radiation (IR), i.e., H2AX phosphorylation, GFP-reporter DNA repair assay, and comet assay. Our results demonstrate that mIDH1 mouse NS and human glioma cells exhibited increased DNA-repair and DDR activity and enhanced genomic stability. This phenotype is correlated with the response to IR where cells and mice harboring mIDH1 tumors were more resistant compared with wt-IDH1 tumors. The combination of IR with inhibitors of DDR reverts radio-resistance in mIDH1 tumor bearing mice. In conclusion, genetically engineered mice harboring glioma encoding mIDH1, ATRX and TP53 knockdown displayed increased MS in absence of treatment. This could be attributed to increased DNA-repair, DDR and genomic stability, which in turn hampers radiation efficacy. Our findings thus reveal a potential therapeutic approach targeting DDR for enhancing therapeutic efficacy of radiation in mIDH1 glioma patients
P2.01-055 Examining Metabolomics as a Prognostic Marker in Metastatic Non–Small Cell Lung Cancer Patients Undergoing First-Line Chemotherapy
Authors: D. Hao, A. Sengupta, K. Ding, N. Leighl, F. Shepherd, L. Seymour, A. Weljie
Journal: Journal of Thoracic Oncology (2017)
Semiquantitative Analysis of Dopamine Transporter Scans in Patients With Parkinson Disease
Authors: Sule Tinaz, Christopher Chow, Phillip H. Kuo, Elizabeth A. Krupinski, Hal Blumenfeld, Elan D. Louis, George Zubal
Journal: Clinical Nuclear Medicine (2017)

Purpose Dopamine transporter (DaT) imaging is an adjunct diagnostic tool in parkinsonian disorders. Interpretation of DaT scans is based on visual reads. SBRquant is an automated method that measures the striatal binding ratio (SBR) in DaT scans, but has yet to be optimized. We aimed to (1) optimize SBRquant parameters to distinguish between patients with Parkinson disease (PD) and healthy controls using the Parkinson's Progression Markers Initiative (PPMI) database and (2) test the validity of these parameters in an outpatient cohort. Methods For optimization, 336 DaT scans (215 PD patients and 121 healthy controls) from the PPMI database were used. Striatal binding ratio was calculated varying the number of summed transverse slices (N) and positions of the striatal regions of interest ( d ). The resulting SBRs were evaluated using area under the receiver operating characteristic curve. The optimized parameters were then applied to 77 test patients (35 PD and 42 non-PD patients). Striatal binding ratios were also correlated with clinical measures in the PPMI-PD group. Results The optimal parameters discriminated the training groups in the PPMI cohort with 95.8% sensitivity and 98.3% specificity (lowest putamen SBR threshold, 1.037). The same parameters discriminated the groups in the test cohort with 97.1% sensitivity and 100% specificity (lowest putamen SBR threshold, 0.875). A significant negative correlation (r = −0.24, P = 0.0004) was found between putamen SBRs and motor severity in the PPMI-PD group. Conclusions SBRquant discriminates DaT scans with high sensitivity and specificity. It has a high potential for use as a quantitative diagnostic aid in clinical and research settings.
Nicotinic acetylcholine receptor α7 subunit improves energy homeostasis and inhibits inflammation in nonalcoholic fatty liver disease
Authors: Dong-Jie Li, Jian Liu, Xia Hua, Hui Fu, Fang Huang, Yi-Bo Fei, Wen-Jie Lu, Fu-Ming Shen, Pei Wang
Journal: Metabolism (2017)
ACTR-89. KARNOFSKY PERFORMANCE STATUS AND STEROID USE IN PHASE II TRIAL OF BEVACIZUMAB AND TEMOZOLOMIDE FOR UPFRONT TREATMENT OF ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Hye Hyun Bahng, Stacey Green, Albert Lai, Jethro Hu, Richard Green, Fabio Iwamoto, Andrew B Lassman, Timothy Cloughesy, Phioanh Nghiemphu
Journal: Neuro-Oncology (2017)

We report the functional status and steroid dosing changes in a phase II clinical trial of bevacizumab and temozolomide for upfront treatment of patients with GBM and age ≥70. Evaluation of steroid use and functional status changes are important aspects of determining treatment success in improving or maintaining quality of life for patients with GBM. 50 GBM patients with age ≥70, KPS ≥60, were enrolled in this trial. Patients received treatments 4–6 weeks after surgery with bevacizumab and temozolomide until tumor progression. The maximal change in Karnofsky Performance Status (KPS) and dexamethasone dose from the start of treatment to date of progression is evaluated. Of the 46 patients with KPS data, the median KPS was 80 at the start of treatment. 27 (58.7%) patients had stable KPS throughout the study, with a median KPS of 80. 11 (23.9%) had KPS improvement, with a median score of 90. 8 patients (17.4%) had a decline in KPS, 6 of which were stable throughout treatment and presented a lower KPS only at disease progression. The median KPS score was 65 for these 8 patients. Of the 45 patients with dexamethasone data, 15 (33.3%) patients were not on dexamethasone at any point during treatment. 18 (60% of those on dexamethasone) were able to come off steroids completely by the end of their treatment. 12 (40%) patients remained on dexamethasone throughout the study, but 5 patients were able to reduce dosages, all by half or more. 2 patients who remained on steroids had to increase dexamethasone dose, one from 8mg total daily dosing to 12mg daily, and the other patient 2mg daily to 8mg daily. Our data suggests that upfront treatment with temozolomide and bevacizumab for elderly GBM patients can positively impact quality of life.
Nab-paclitaxel (Nab-P) in HER2-ve advanced breast cancer (ABC) patients (pts): focus on luminal cancers. Results from GIM13 - AMBRA study
Authors: G. Mustacchi, M. Cazzaniga, M. Giordano, O. Garrone, M. Donadio, L. Del Mastro, L. Livi, C. Natoli, A. Michelotti, A. Turletti, F. Riccardi, P. Marchetti, F. Montemurro, E. Romagnoli, S. De Placido, L. Biganzoli, G. Bisagni, E. Bria
Journal: Annals of Oncology (2017)
Association of vitamin E intake at early childhood with alanine aminotransferase levels at mid‐childhood
Authors: Jennifer A. Woo Baidal, Erika R. Cheng, Sheryl L. Rifas‐Shiman, Emily Oken, Matthew W. Gillman, Elsie M. Taveras
Journal: Hepatology (2017)

The extent to which vitamin E (alpha‐tocopherol) intake early in childhood is associated with alanine aminotransferase (ALT) level later in childhood is unknown. The objective of this research is to test the hypothesis that higher alpha‐tocopherol intake during early childhood is associated with lower odds of elevated ALT levels during mid‐childhood and to examine how body mass index (BMI) influences these relationships. We studied 528 children in Project Viva. Mothers reported child dietary intake at early childhood visits (median 3.1 years) using a validated food frequency questionnaire. At mid‐childhood (median 7.6 years), we collected child blood and anthropometric data. The main outcome was elevated sex‐specific mid‐childhood ALT level (≥22.1 U/L for female children and ≥25.8 U/L for male children). In multivariable logistic regression models, we assessed the association of energy‐adjusted alpha‐tocopherol intake with ALT levels, adjusting for child age, sex, race/ethnicity, diet, and age‐adjusted sex‐specific BMI z‐score at mid‐childhood. Among children in this study, 48% were female, 63% were non‐Hispanic white, 19% were non‐Hispanic black, and 4% were Hispanic/Latino. Mean alpha‐tocopherol intake was 3.7 ± 1.0 mg/day (range, 1.4‐9.2) at early childhood. At mid‐childhood, mean BMI z‐score was 0.41 ± 1.0 units and 22% had an elevated ALT level. In multivariable‐adjusted logistic regression models, children with higher early childhood vitamin E intake had lower odds of elevated mid‐childhood ALT (adjusted odds ratio [AOR], 0.62; 95% confidence interval [CI], 0.39, 0.99) for quartiles 2‐4 compared with the lowest quartile of intake. Findings persisted after accounting for early childhood diet (AOR, 0.62; 95% CI, 0.36, 1.08) and were strengthened after additionally accounting for mid‐childhood BMI z‐score (AOR, 0.56; 95% CI, 0.32, 0.99). Conclusion: In this cohort, higher early childhood intake of alpha‐tocopherol was associated with lower odds of elevated mid‐childhood ALT level. (Hepatology 2018;67:1339‐1347).
EXTH-09. TDP1/TOP1 RATIO AS A PREDICTIVE INDICATOR FOR THE RESPONSE OF GLIOBLASTOMA CANCER CELLS TO IRINOTECAN TREATMENT
Authors: Wenjie Wang, Monica Rodriguez Silva, Jeremy Chambers, Yuk-Ching Tse-Dinh
Journal: Neuro-Oncology (2017)

In order to make cancer chemotherapy more specific for individual patients, it would be valuable to find the predictive indicators which provide the information on cancer cell response to specific chemotherapeutic drug treatments. Topoisomerase I (TOP1) is an essential enzyme that modulates the topological structure of the chromosome during replication and transcription by cleaving and resealing the DNA. The anti-cancer drug Irinotecan (IRT) works as a topoisomerase I inhibitor, targeting topoisomerase and DNA by forming irreversible TOP1 cleavage complexes (TOP1cc), which result in an accumulation of DNA breaks. This may finally induce cell apoptosis. IRT has already been demonstrated to be effective against glioblastoma multiforme (GBM), which is the most aggressive primary brain tumor, with an extremely low median survival of around twelve months. Although TOP1 is overexpressed in most of the GBM cell lines compared with human astrocytes, TOP1 level does not correlate with IRT efficacy according to our study. Tyrosyl-DNA phosphodiesterase 1 (TDP1), a crucial repair enzyme, can rescue TOP1cc and decrease the efficacy of IRT. It has been reported that the TDP1/TOP1 ratio acts as a promising indicator for the response of small cell lung cancer to the topoisomerase I inhibitor topotecan treatment. In our study, we demonstrated that the TDP1/TOP1 activity ratio in GBM cell lines has the strongest correlation with the TOP1cc level as well as IC50 level for IRT treatment in comparison with TDP1 and TOP1 levels alone. The Pearson correlation coefficient (R) for TOP1cc level and IRT IC50 can reach 0.93 and 0.88, respectively. According to our results, the TDP1/TOP1 ratio might be a potential predictive indicator for the response of GBM cancer cells to IRT treatment and may further help to optimize the chemotherapeutic treatment protocols for individual patients.
Heart Disease and Stroke Statistics—2009 Update
Authors: Donald Lloyd-Jones, Robert Adams, Mercedes Carnethon, Giovanni De Simone, T. Bruce Ferguson, Katherine Flegal, Earl Ford, Karen Furie, Alan Go, Kurt Greenlund, Nancy Haase, Susan Hailpern, Michael Ho, Virginia Howard, Brett Kissela, Steven Kittner, Daniel Lackland, Lynda Lisabeth, Ariane Marelli, Mary McDermott, James Meigs, Dariush Mozaffarian, Graham Nichol, Christopher O'Donnell, Veronique Roger, Wayne Rosamond, Ralph Sacco, Paul Sorlie, Randall Stafford, Julia Steinberger, Thomas Thom, Sylvia Wasserthiel-Smoller, Nathan Wong, Judith Wylie-Rosett, Yuling Hong
Journal: Circulation (2008)
El refuerzo de la alerta precoz en la vigilancia en la Republica de Serbia: un año de experiencia
Authors: M Valenciano, I Bergeri, D Jankovic, N Milic, M Parlic, D Coulombier
Journal: Eurosurveillance (2004)

La Republica de Serbia, con el apoyo de la OMS, ha implantado un sistema de alerta (ALERT) para las enfermedades transmisibles prioritarias, como complemento al sistema de vigilancia de rutina que notifica los casos confirmados individuales. Este articulo describe los resultados de la evaluacion hecha un ano despues del inicio del programa. ALERT se basa en la notificacion de 11 sindromes por los centros de atencion primarios. Los datos son analizados una vez por semana en cada region y transmitidos a los epidemiologos nacionales. ALERT se percibe como una herramienta simple y flexible, con mejor aceptacion al nivel nacional que regional. Ciertas regiones perciben ALERT como un sistema paralelo insuficientemente ligado a las medidas de control. La sensibilidad del sistema para la deteccion de los casos de meningitis fue de un 93%, y para los casos de hepatitis del 37%. El analisis retrospectivo de los datos de ALERT permitio identificar nueve brotes, cinco de los cuales habian sido identificados por los epidemiologos. ALERT fue el sistema mas rapido para detectar cuatro brotes epidemicos identificados por los dos sistemas. El programa ALERT permitio iniciar una investigacion rapida y controlar brotes de hantavirus y salmonelosis y detectar el principio de la temporada gripal. Sin embargo, ALERT no consiguio detectar brotes de brucelosis y de tularemia identificados por un sindrome de fiebre inexplicado. Esta evaluacion demostro la necesidad de hacer una revision global de las actividades de vigilancia antes de crear un sistema como ALERT. 
Aunque las medidas de control basadas en la declaracion de casos confirmados individuales sean bien entendidas y establecidas, el proceso de investigacion y verificacion que deberia resultar del aumento de los sindromes de ALERT no parece ser totalmente comprendido. Los programas de formacion en epidemiologia de campo como EPIET son los mas adaptados para este cambio de perspectiva.
Third trimester placental grading by ultrasonography as a test of fetal wellbeing:: Authors' reply
Authors: J. Proud, A. Grant
Journal: BMJ (1987)

HIV testing: changing trends SIR,-Dr E J Beck and colleagues (18 July, p 191) drew attention to steep increases in the number of requests from patients in London for tests for antibody to the human immunodeficiency virus (HIV) in October and November 1986 and March 1987, which coincided with the publicity campaigns associated with the government's edu- cational programme about the acquired immune deficiency syndrome (AIDS).In Liverpool a similar trend was observed at the Public Health Laboratory, where these tests are performed on specimens submitted mainly from clinics for sexually transmitted diseases but also from hospital departments, drug dependency clinics, and general practitioners.The table shows the numbers of specimens for this test received monthly in the laboratory between May 1986 and June 1987, together with the number that were positive for antibody to HIV and the number of these that were from new patients.Sharp increases occurred in Liverpool at about the same time as in London, and, although, as in London, there was a pronounced fall in numbers from the peak in March 1987, the level maintained since then is much higher than that in the corresponding period in 1986.Though the proportion of patients who were found to be positive was much lower in Liverpool than in London, we also found that as the number of tests increased so the proportion that yielded positive results tended to decrease.Number of specimens for tests for antibody to HIV
P3.01-020 Clinical Features of Patients with Non-Small Cell Lung Cancer (NSCLC) Harboring Epidermal Growth Factor Receptor (EGFR) Mutations in Brunei
Authors: S.K. Lu, C.H. Leong, S. Binti Hj Mohd Diah, R. Patnaik, B. Sukumaran
Journal: Journal of Thoracic Oncology (2017)
Vigilância da resistência aos antibióticos na Dinamarca
Authors: D. L. Monnet, H. D. Hemborg, S. R Andersen, C Schöller, T. L. Sørensen, F Bager
Journal: Eurosurveillance (2000)

Dados recentes, obtidos pelo Programa Integrado de Monitorizacao e Investigacao da Resistencia aos Antibioticos Dinamarques (DANMAP), demonstraram que, na Dinamarca, os niveis de resistencia da Salmonella enterica sao moderados e que a resistencia observada nos isolamentos de Escherichia coli, que provocam doenca em animais, deve ser encarada como um reservatorio de resistencia e nao como uma ameaca a saude publica. Alem disso, as tendencias da resistencia nos isolamentos clinicos de E. coli, efectuados na Dinamarca, foram consistentes com os padroes dinamarqueses de utilizacao de antibioticos. A resistencia do Staphylococcus aureus e Streptococcus pneumoniae continua a ser rara. No entanto, o recente aparecimento de S. pneumoniae resistente a penicilina e a eritromicina e preocupante. Finalmente, a monitorizacao da resistencia em bacterias comensais, colhidas em animais para consumo humano e em alimentos, demonstra o impacto positivo sobre a resistencia exercido por intervencoes, tais como a proibicao de antibioticos promotores de crescimento em exploracoes de animais.
Abstract 20984: Transfer of Functional Properties From the Two-Domain Apolipoprotein E3 to a Single Domain 5-Helix Bundle Apolipoprotein
Authors: James V Horn, Leesa M Kakutani, Robert S Kiss, Vasanthy Narayanaswami, Paul M Weers
Journal: Circulation (2017)

Apolipoprotein E3 (apoE3) is a 34 kDa exchangeable apolipoprotein critical for lipid transport and associates with chylomicrons, VLDL, and a subclass of HDL. The protein contains two independently folded domains: a 22 kDa N-terminal domain and a 10 kDa C-terminal domain. The N-terminal domain contains LDL receptor binding sites and is tightly folded into a 4-helix bundle. The smaller C-terminal (CT) domain contains helical segments that: (i) promote protein-protein interaction and apoE3 self-association, (ii) bear high lipid binding affinity, and, (iii) facilitate cholesterol efflux from macrophages. In contrast, insect apolipophorin III (apoLp-III) is a one-domain protein bearing a 5-helix bundle, does not self-associate and binds to diacylglycerol enriched lipoproteins. To better understand the domain organization of apolipoproteins, a chimeric protein was constructed of apoLp-III and the CT domain of apoE3 (residues 201-299). The structure and function of the 28 kDa apoLp-III/CT-apoE3 chimera was determined and compared to that of parent proteins apoLp-III and apoE3. The novel chimeric construct was expressed in E. coli and purified using an N-terminal poly-histidine tag. Electrophoresis and Western blot analysis showed that the apoLp-III/CT-apoE3 chimera was of the expected size and reacted with apoE3 specific antibodies. Circular dichroism demonstrated that the chimera was α-helical, similar to both parent proteins. While apoLp-III was monomeric, the chimera formed tetramers similar to apoE3. Probing for hydrophobic pockets on the protein surface with anilinonaphthalene-8-sulfonic acid demonstrated that the CT domain provided increased binding sites for the probe. Addition of the CT domain to apoLp-III conferred an increased ability to promote cholesterol efflux from J774 macrophages, comparable to that of parent apoE3. Thus, the fold of apoLp-III/CT-apoE3 chimera was similar to that of apoE3, promoted self-association and cholesterol efflux. This demonstrated that functional characteristics of CT domain of apoE3 can be transferred independently to another apolipoprotein, allowing us to further increase our understanding of apolipoprotein domains.
Préparation en vue d'une pandémie grippale en Italie : ressources et procédures dans les services de pédiatrie
Authors: V Giacomet, L Tarallo, G De Marco, A Giannattasio, A Barbarino, A Guarino
Journal: Eurosurveillance (2007)

L’Organisation mondiale de la Sante (OMS) a fait savoir que, pour gerer efficacement une pandemie grippale majeure, la preparation doit inclure la formation des medecins a la prise en charge des maladies contagieuses et la mise a niveau des ressources et des procedures hospitalieres.