tbuckley/cabot-search huggingface dataset:
Tissue distribution, metabolism, and excretion of the antibody-drug conjugate Herceptin-monomethyl auristatin E in rats
Authors: Cinthia V. Pastuskovas, Ellen M. Maruoka, Ben Q. Shen, Harmut Koeppen, Svetlana O. Doronina, Peter D. Senter, Thomas F. Zioncheck
Journal: Cancer Research (2005)

5063  Antibody-drug conjugates (ADC) are a relatively new and evolving approach to improve the potency and selectivity of anti-tumor agents. Key questions exist regarding the in vivo disposition of the drug conjugate (i.e. the cytotoxic moiety) as it relates to optimizing dosing and understanding safety. In this study, Herceptin, a humanized monoclonal antibody directed against the Her2 receptor, was conjugated to the cytotoxic drug monomethyl auristatin E (MMAE) through a highly stable protease-cleavable dipeptide linker. The linker is selectively cleaved by lysosomal enzymes after internalization and free MMAE is capable of binding tubulin and blocking cell proliferation. Initial studies in mouse xenograft tumor models have demonstrated enhanced tumor-specific cell killing relative to unconjugated Herceptin. The objective of this study was to characterize the tissue distribution, metabolism and route of elimination of Herceptin-Val-Cit-[14C]MMAE following an IV bolus dose of (11 mg/kg, 100uCi/kg) of the radiolabeled ADC in Sprague-Dawley rats. Tissue distribution was assessed by quantitative whole body autoradiography (QWBA) 1, 4, 7, and 14 days following dosing. The results from QWBA indicated the presence of radioactivity in highly perfused organs (lungs>liver>heart>kidney) on day 1 post-dose, with evidence for hepatic elimination of the drug via the bile/gastro-intestinal tract (GI) on day 4. Radioactivity decreased in most organs with a similar pharmacokinetic profile as blood radioactivity. Persistence of radioactivity was observed in tissues with rapidly dividing cells such as the GI epithelia, bone marrow, spleen and thymus on days 4 and 7. These data are consistent with target organs of toxicity identified in previous toxicology studies. Excretion studies indicated that MMAE was primarily eliminated intact in feces (∼80%) and urine (∼ 6%) within 7 days following dosing. Characterization of radioactivity in rat plasma showed evidence for a time-dependent biotransformation of Herceptin-Val-Cit-[14C]MMAE including the liberation of low levels of free drug. In conclusion, Herceptin-Val-Cit-[14C]MMAE distributes to highly perfused organs. The majority of blood radioactivity represented radiolabeled ADC, however, low levels of free drug were detected. The cytotoxic moiety, MMAE, was primarily eliminated intact in the feces with greater than 86% of drug being excreted 7 days post dose.
Le huitième colloque international du Groupe de travail européen sur la diphtérie et du Réseau européen de surveillance de la diphtérie - juin 2004 : des progrès à faire pour le contrôle de la diphtérie dans la région Europe
Authors: A De Zoysa, A Efstratiou
Journal: Eurosurveillance (2004)

Le huitieme colloque international du Groupe de travail europeen sur la diphterie (ELWGD) et du Reseau europeen de surveillance de la diphterie DIPNET a ete co-organise en juin 2004 avec le bureau regional pour l'Europe de l'OMS, a Copenhague, Danemark. L'article suivant presente une mise a jour internationale des progres aussi bien cliniques qu'epidemiologiques ou microbiologiques de la diphterie en Europe, tels que presentes lors du colloque. L'ensemble de ces donnees souligne le besoin d'une amelioration de la couverture vaccinale, de la surveillance et des etudes epidemiologiques pour maintenir un controle de la diphterie dans la region Europe.
CSIG-02. MOLECULAR PROFILING IDENTIFIES INCREASED TRANSGELIN-2 EXPRESSION IN LOW(ER) GRADE GLIOMAS WITH WILD-TYPE IDH1/2 VS. MUTANT IDH1/2
Authors: Sasha Beyer, Erica H Bell, Joseph P McElroy, Oliver Oehkke, Jessica Fleming, Aline Paixao Becker, Tiantian Cui, Ori Staszewski, Marco Prinz, Anca-Ligia Grosu, S Jaharul Haque, Arnab Chakravarti
Journal: Neuro-Oncology (2017)

Low(er) grade gliomas (LGGs) exhibit variable prognoses and responses to chemotherapy and radiation. While gliomas were traditionally categorized by histopathological features, the World Health Organization revised the classification system by integrating prognostic molecular biomarkers, including isocitrate dehydrogenase (IDH)1/2 mutations. LGGs with mutant (MT)-IDH have improved prognosis compared to wild-type (WT) LGGs. Therefore, we aimed to elucidate signaling mechanisms governing differences in clinical response by mRNA profiling. The Affymetrix ClariomD array and LIMMA analysis identified genes differentially expressed in Mut-IDH vs. WT-IDH in grade II (n=19) and grade III (n=38) gliomas from our cohort and data were compared with the TCGA. In vitro functional studies confirmed roles in invasion and proliferation. Our analysis identified 343 probesets with significant differential gene expression in Mut-IDH vs. WT-IDH gliomas (FDR p-value<0.1). Among these genes, we identified transgelin-2, an actin-polymerizing gene, associated with poor prognosis and increased tumor growth and invasion in cancer. However, its role in gliomas has not yet been reported. Transgelin-2 mRNA (FDR p-value<0.1) and protein (FDR p-value<0.05) were heightened in WT vs. Mut-IDH in our LGG cohort. Transgelin-2 mRNA was also significantly higher in WT-IDH gliomas in the TCGA cohort (FDR<0.05). Interestingly, there was significantly greater transgelin-2 promoter methylation in LGGs with Mut- vs. WT-IDH (FDR p<0.05) in both cohorts. Transgelin-2 was also associated with poor prognosis in both the TCGA (HR 2.6, p=3.1x10-5) and our (HR 3.74, p=0.079) cohorts. Our in vitro studies confirmed that knock-down of transgelin-2 decreased proliferation and invasion of glioma cells. Our study suggests that transgelin-2 may contribute to proliferation and invasion and may serve as a potential prognostic biomarker in WT-IDH1/2 LGGs. Future studies will evaluate transgelin-2 as a novel therapeutic target and predictive biomarker contributing to chemoradiation resistance in gliomas. FUNDING: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01, BTFC, OSU-CCC (all to AC).
IMMU-37. METABOLIC REPROGRAMMING OF THE GLIOMA MICROENVIRONMENT INHIBITS TUMOR IMMUNOSUPPRESSION
Authors: Jason Miska, Megan Muroski, Aida Rashidi, Alan Chang, Peng Zhang, Yu Han, Maciej S Lesniak
Journal: Neuro-Oncology (2017)

Anti-tumor immunity in murine models of glioblastoma is potently suppressed by regulatory T-cell (Treg) accumulation within the tumor. Recent studies have highlighted that both glioma and immunosuppressive cellular subsets utilize fatty acid metabolism for survival. Inhibition of fatty acid oxidation (FAO) prolongs survival in glioma bearing mice, however, the immunity of tumor microenvironment (TME) upon inhibition of this pathway is not known. In this study we looked at the immunological effects of etomoxir, an inhibitor of mitochondrial import of fatty acids (FA) on an intracranial model of glioma. We tested both intracranial and systemic administration of this inhibitor to understand effects on systemic immunity as well as specifically within the TME. Glioma bearing mice had significantly increased free fatty acids within the interstitial fluid of the tumor, suggesting this may be an abundant energy source within this environment. We measured the effect of etomoxir on the GL261 murine tumor line, and found minimal effects on glioma cultures, with cytostatic effects occurring only at very high concentrations. Through the use of a novel nanoparticle-FA sensor, we observed that Tregs uptake significantly more FA compared to effector T-cells in tumor bearing mice and may be the target of FAO inhibition. We demonstrate a significant increase in survival with intracranial etomoxir treatment (p<0.01, **), which does not occur in immunodeficient animals. Both intracranial and systemic Etomoxir treatment caused a significant decrease in total number of Tregs within the glioma tissue, with a concomitant increase in CD8 T-cell functionality. Our data suggests that that FA metabolism contributes to the immunosuppressive TME, and may be a metabolic target to enhance immunotherapy against glioma.
OA 10.03 Liquid Biopsy in the Lung Cancer Clinic: A Prospective Study of Plasma DNA next Generation Sequencing to Guide Matched Therapy
Authors: J. Sabari, D. Stephens, A. Ni, A. Lee, N. Pavlakis, S. Clarke, C. Diakos, M. Offin, S. Datta, N. Tandon, M. Duboff, J. Simpronio, A. Martinez, J. Isbell, V. Rusch, D. Jones, A. Rimner, S. Henderson, C. Raymond, L. Lim, M. Li, G. Riely, C. Rudin, B. Li
Journal: Journal of Thoracic Oncology (2017)
A tuberculose pulmonar em dois centros de prisão preventiva em São Petersburgo, Russia
Authors: T Lobacheva, V Sazhin, E Vdovichenko, J Giesecke
Journal: Eurosurveillance (2005)

A situacao da tuberculose (TB) no sistema penitenciario russo foi descrita muitas vezes. 
Foi realizado um estudo epidemiologico descritivo da TB em dois centros de prisao preventiva (SIZO) de Sao Petersburgo. Foram buscados nas bases de dados medicos destes dois centros os casos de TB diagnosticados entre o 1 de janeiro 2000 e o 31 dezembro 2002. O metodo de diagnostico mais frequente foi a radiologia pulmonar. 
Em total, 876 casos de TB foram notificados nestes centros durante este periodo de tres anos. Em 432 deles, o diagnostico foi feito ao entrar na prisao e em 444 casos, a doenca foi declarada durante o encarceramento, aumentando a proporcao de casos diagnosticados duranto o encarceramento com o tempo. A maioria dos casos tinham menos de 30 anos. 
A incidencia da TB nos centros de detencao preventiva na Russia ainda e muito alta e necessita uma vigilância estrita.
SURG-26. AWAKE CRANIOTOMY WITH 5-ALA IN HIGH GRADE GLIOMAS GIVES SIMULTANEOUS GUIDANCE OF TUMOR AND FUNCTIONAL BORDER
Authors: Jane Skjøth-Rasmussen, Christina Malling Engelmann, Jannick Brennum
Journal: Neuro-Oncology (2017)

In high-grade gliomas (HGG) the use of 5-ALA as surgical assistance is proven not only to increase the number of patients with gross-total resection (GTR) but also improve overall survival (OS). Not all patients may have the benefit of GTR due to closeness to eloquent areas risking neurological deficits. In low grade gliomas awake mapping craniotomy is becoming standard of care in many centres. In HGG patients this procedure is frequently used but combining these two methods may help the surgeon achieving the best possible resection maintaining the onco-functional balance for the individual patient and maintaining a good outcome. 19 patients aged 35 to 70, median age 54 (9 females) was operated for suspected HGG with the combined method of 5-ALA assisted surgery and awake mapping craniotomy with a median surgical time of 148 minutes. Retrospectively the hospital records were reviewed for information on neuropsychological assistance, histological report, postoperative MRI and neurological status. The procedure was the 1st operation for 11 of 19 patients, for 5 patients it was the second operation and for 4 patients it was the 3rd or more procedure. Complete or near complete tumor removal was obtained in 10 of 19 cases and in 12 cases more than 90 % of the tumor volume was resected judged by volume measurements. In cases of first time surgery in GBM 6 (67%) of 9 patients had GTR. Despite close relationship with eloquent structures the combined procedure of 5-ALA and awake mapping led us to an overall satisfactory tumor removal without exacerbating the condition postsurgical. Keywords: Brain tumor, surgery, 5-ALA, Awake mapping craniotomy, high grade gliomas
Synergistic induction of differentiation by COX inhibitors and 1, 25-dihydroxyvitamin D3 in human leukemia cells involves Raf1 but not ERK 1/2 signaling.
Authors: Farnaz Jamshidi
Journal: Cancer Research (2008)

LB-277   Differentiation therapy of cancer is being explored as a potential modality for treatment of myeloid leukemia, and derivatives of vitamin D are gaining prominence as agents for this form of therapy. Cyclooxygenase (COX) inhibitors have been reported to enhance  1,25-dihydroxyvitamin D 3  (1,25D)-induced monocytic differentiation of promyeloblastic HL60 cells, but the mechanisms of this effect are not fully elucidated , and whether this potentiation can occur in other types of myeloid leukemia it not known. We found that combination treatment with 1,25D and non-specific COX inhibitors acetyl salicylic acid (ASA) or indomethacin can robustly potentiate differentiation of other types of human leukemia cells, i.e. U937, THP-1, and ASA +/- 1,25D is effective in primary AML cultures. Increased cell differentiation is paralleled by arrest of the cells in the G1 phase of the cell cycle, and by increased phosphorylation of Raf1 and p90RSK1 proteins. However, there was no evidence that this increase in phosphorylation of Raf1 was transmitted to the MEK/ERK module of the MAPK signaling cascade. Transfection of small interfering (si) RNA to Raf1 decreased differentiation of U937 cells induced by a combination of ASA or indomethacin with 1,25D. However, phosphorylation levels of MEK1 and ERK1/2, though not of p90RSK, were increased when P-Raf1 levels were decreased by the siRNA, suggesting that in this system the MEK/ERK module is under a negative control of Raf-1 and does not function in the conventional manner. Identification of the strong antiproliferative activity of ASA/1,25D combinations associated with monocytic differentiation has implications for cancer chemoprevention in individuals who have predisposition to myeloid leukemia.
P3.01-026 Analysis of Long-Term Response to First-Line Afatinib in the LUX-Lung 3, 6 and 7 Trials in Advanced EGFRm+ NSCLC
Authors: M. Schuler, J.C. Yang, L. Sequist, Y. Wu, C. Zhou, S. Geater, T. Mok, E. Tan, C. Hu, N. Yamamoto, J. Feng, K. O’Byrne, S. Lu, V. Hirsh, Y. Huang, S. Ellis, C. Samuelsen, A. Märten, J. Fan, K. Park, L. Paz-Ares
Journal: Journal of Thoracic Oncology (2017)
Abstract 12535: Interaction Between Gene Polymorphism of Alpha Adducin (ADD1) and Alcohol Habit on the Risk of Essential Hypertension in A Japanese Population
Authors: Masahiko Eto, Masanobu Okayama, Taro Takeshima, Maki Kumada, Takanori Aonuma, Yoshikazu Nakamura, Eiji Kajii
Journal: Circulation (2015)

Objectives: To evaluate the interactions between single nucleotide polymorphism (SNP) of alpha adducin gene(ADD1) and alcohol habits on the risk of hypertension (HT) in Japanese. Methods: We analyzed 19284 Japanese subjects enrolled in the genome banking project at Jichi Medical University, including 8711 HT cases and 10573 non-HT controls.Diagnosis of HT was based on BP≥140/90mmHg or anti-HT medications. We divided the subjects into four groups according to gender and age (≤49 or ≥50) and performed statistical analyses in each group. SNP rs4961(GG/GT/TT, Gly460Trp) of ADD1 was genotyped by TaqMan method. Alcohol habits were categorized to never, sometimes, and daily drinker for frequency of drinking. To assess the contribution of genotypes, alcohol habits, and the combinations of both to HT risk, we compared the frequencies of them between cases and controls by chi-squared test. The strength of the associations was estimated by odds ratios(ORs) and 95% confidence intervals(CI) by using logistic regression analysis. For the interaction, we assessed the joint ORs, which were calculated for each of nine combined categories created by cross-classification. Non-risk reference was never drinker carrying GG. Results: (1)Although genotype distributions did not significantly differ between cases and controls in all groups, the frequencies of alcohol habits and the combinations of both significantly differed in all groups.(2)Compared to GG, the ORs (95%CI) of TT were 1.11(0.83-1.49) in M≤49, 1.00(0.86-1.17) in M≥50, 0.83(0.58-1.17) in F≤49, and 0.99(0.85-1.15) in F≥50. Compared to never drinker, the ORs (95%CI) of daily drinker were 1.77(1.32-2.37, p&lt;0.001) in M≤49, 1.64(1.44-1.87, p&lt;0.001) in M≥50, 1.26(0.88-1.80) in F≤49, and 1.13(0.90-1.43) in F≥50. Compared to never drinker with GG, the ORs (95%CI) of daily drinker with TT were 3.43(1.74-6.73, p&lt;0.001) in M≤49, 1.83(1.41-2.39, p=0.001) in M≥50, 0.77(0.37-1.59) in F≤49, and 1.41(0.92-2.17) in F≥50. Conclusions: The interactions between ADD1 rs4961 and alcohol habits had significant effects on HT risk in Japanese males≤49 years. The interactions between ADD1 genotypes and alcohol habits may contribute to young-onset hypertension in Japanese males.
P3.15-004 Distinct Role of FAK Kinase and C-Terminal Domains on Small-Cell Lung Cancer Proliferation
Authors: F. Aboubakar Nana, M. Lecocq, M.Z. Ladjemi, B. Detry, S. Dupasquier, P. Massion, Y. Sibille, Y. Sibille, C. Pilette, C. Pilette, S. Ocak, S. Ocak
Journal: Journal of Thoracic Oncology (2017)
Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation
Authors: Lu-Chen Weng, Sarah R. Preis, Olivia L. Hulme, Martin G. Larson, Seung Hoan Choi, Biqi Wang, Ludovic Trinquart, David D. McManus, Laila Staerk, Honghuang Lin, Kathryn L. Lunetta, Patrick T. Ellinor, Emelia J. Benjamin, Steven A. Lubitz
Journal: Circulation (2017)

Background: The long-term probability of developing atrial fibrillation (AF) considering genetic predisposition and clinical risk factor burden is unknown. Methods: We estimated the lifetime risk of AF in individuals from the community-based Framingham Heart Study. Polygenic risk for AF was derived using a score of ≈1000 AF-associated single-nucleotide polymorphisms. Clinical risk factor burden was calculated for each individual using a validated risk score for incident AF comprised of height, weight, systolic and diastolic blood pressure, current smoking status, antihypertensive medication use, diabetes mellitus, history of myocardial infarction, and history of heart failure. We estimated the lifetime risk of AF within tertiles of polygenic and clinical risk. Results: Among 4606 participants without AF at 55 years of age, 580 developed incident AF (median follow-up, 9.4 years; 25th–75th percentile, 4.4–14.3 years). The lifetime risk of AF &gt;55 years of age was 37.1% and was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of AF at 55 years of age, those in low-polygenic and clinical risk tertiles had a lifetime risk of AF of 22.3% (95% confidence interval, 15.4−9.1), whereas those in high-risk tertiles had a risk of 48.2% (95% confidence interval, 41.3−55.1). A lower clinical risk factor burden was associated with later AF onset after adjusting for genetic predisposition ( P &lt;0.001). Conclusions: In our community-based cohort, the lifetime risk of AF was 37%. Estimation of polygenic AF risk is feasible and together with clinical risk factor burden explains a substantial gradient in long-term AF risk.
P1.07-039 Blood Biomarkers Correlate with Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Anti PD-1 Antibodies
Authors: A. Soyano, B. Dholaria, J. Marin, N. Diehl, D. Hodge, Y. Luo, L. Yang, A. Adjei, K. Knutson, Y. Lou
Journal: Journal of Thoracic Oncology (2017)
P2.01-035 Phase II Study: Weekly Docetaxel as First Line Chemotherapy for Elderly Patients with Squamous-Cell Non-Small-Cell Lung Cancer
Authors: S.Y. Lee, J.H. Choi, S.M. Chung, J.Y. Oh, Y.S. Lee, K.H. Min, G.Y. Hur, J.J. Shim, K.H. Kang, H.K. Lee
Journal: Journal of Thoracic Oncology (2017)
SURG-33. GLIOBLASTOMA IN THE ELDERLY: THE IMPACT OF EXTENT OF RESECTION ON SURVIVAL
Authors: Ahmed Alaqeel, Magalie Cadieux, Michael Opoku-Darko, Chelsea Demler, John Kelly
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) occurs commonly in individuals above 65 years of age. Most clinical trials that guide recommendations for treatment of GBM tend to exclude patients above the age of 65 years. In this study, we evaluated a cohort of elderly patients treated at a single institution in order to identify factors that impact overall survival. A retrospective review was performed of elderly patients (≥ 65 years old) with newly diagnosed GBM treated between 2013 and 2016. Tumor volumetric analysis was performed using the Osirix software. Various characteristics were evaluated in univariate and multivariate stepwise models to examine their effects on overall survival. 63 patients were included in the study with a median age of 72 years. Tumors most frequently involved the temporal lobe (36.5%), followed by the frontal lobe (34.9 %), parietal (30.1%), and occipital (6.3%) lobes. Pre-operative tumor volume was 30.6 cm3. Four patients (6.3%) underwent biopsy only and the remaining 93.7% of patients underwent resection with many (55%) having gross-total resection (GTR). The majority (95.2%) of the patients received postoperative radiotherapy or radiotherapy and concurrent temozolomide. The mean survival for all patients was 12 months; three patients experienced long-term (≥ 2-year) survival. Extent of resection was seen to significantly impact overall survival; patients who underwent GTR had a median survival of 15.8 months, whereas those who underwent subtotal resection had survival of 9.8 months (p<0.05). This study demonstrates that extent of resection positively influences overall survival in elderly patients with GBM, suggesting that safe maximal resection should be considered. Furthermore, administration of the postoperative chemoradiotherapy can improve survival and quality of life for this elderly patient population.
Epidémiologie des infections associées à Streptococcus pyogenes en Europe
Authors: T L Lamagni, A Efstratiou, J Vuopio-Varkila, A Jasir, C Schalén
Journal: Eurosurveillance (2005)

A la fin des annees 1980, plusieurs pays d’Europe ont rapporte des epidemies dues a Streptococcus pyogenes. Comparee aux decennies precedentes ou de telles epidemies etaient tres rares, ce changement marque le debut d’une nouvelle periode. Il fait partie d’un phenomene global dont les raisons restent encore inconnues. Le bilan de la surveillance des infections a S. pyogenes en Europe au cours des quinze dernieres annees a permis d’identifier des augmentations de ces infections dans plusieurs pays. Cependant, les comparaisons entre pays restent difficiles du fait des differences dans les methodes de surveillance entre les pays, ce qui montre la necessite d’une strategie de surveillance unifiee pour l’ensemble de l’Europe. C’est pour repondre a ce besoin que le programme Strep-EURO a ete mis en place en 2002.
Infecciones por Salmonella enterica del serotipo Oranienburg asociadas al consumo de un queso de producción local en el Tirol
Authors: F Allerberger, P Kreidl, M P Dierich, E Klingsbichel, D Jenewein, C Mader, D Khaschabi, M Schönbauer, C Berghold
Journal: Eurosurveillance (2000)

Entre el 10 de agosto y el 29 de septiembre de 1999, se detectaron dieciseis casos de infeccion por Salmonella enterica del serotipo Oranienburg en Tirol (Austria). Diez de ellos presentaban diarrea con sangre y seis eran portadores asintomaticos. Las entrevistas realizadas a 11 de los 16 casos permitieron relacionar el brote con una granja alpina y con el consumo de queso de leche de vaca producido localmente. Los analisis microbiologicos revelaron presencia de S. Oranienburg en el queso y en el corral de aves de la granja. Las aves habian circulado por la zona de elaboracion del queso y tenian libre acceso a la misma.