tbuckley/cabot-search huggingface dataset:
Phase I/II study of arterial infusion with 5-fluorouracil combined with systemic gemcitabine for unresectable pancreatic cancer.
Authors: T. Tanaka, H. Nishiofuku, M. Sho, H. Anai, S. Sueyoshi, K. Yamamoto, Y. Inaba, H. Sakaguchi, Y. Nakajima, K. Kichikawa
Journal: Journal of Clinical Oncology (2011)

307 Background: Unresectable pancreatic cancer is poorly responsive to conventional therapies. We conducted a phase I/II study to ascertain the recommended dose (RD) of 5-fluorouracil (5-FU) in arterial infusion chemotherapy combined with systemic gemcitabine in unresectable pancreatic cancer and to evaluate the safety and efficacy. Methods: 5-FU was administered through the pancreatic and hepatic arteries via the port system as a 5-hour infusion on days 1, 8, and 15 every 4 weeks for 5 cycles. Gemcitabine was administered in 30-minute intravenous infusion at the same days. In phase I, escalating 5-FU doses for level 1 and 2 was set at 750mg and 1,000mg/m 2 , respectively. Dose of coadministered gemcitabine (1,000 mg/m 2 ) was fixed. Using a 3+3 study design, dose-limiting toxicity (DLT) was assessed, and RD was estimated in the first cycle. In phase II, more RD patients were added to assess tumor response, toxicity, overall survival and progression-free survival. Results: During the phase I, 7 patients were enrolled. DLT was not observed. One patient dropped out of this study because of insufficient drug distribution via the port system. Assuming RD at 1,000mg/m 2 of 5-FU, the phase II enrolled a total of 16 patients (metastatic, 14; local advanced, 2). The tumor response rate was 68.8% (CR 0, PR 11, SD 2, PD 3). The grade 3 toxicities of neutropenia (6%) and thrombocytopenia (6%) were observed. Median overall and progression-survival times (all patients) were 9.8 and 6.2 months, respectively. Conclusions: Arterial infusion 5-FU 1,000mg/m 2 combined with full-dose systemic gemcitabine was tolerable and can produce a high response rate with encouraging survival duration for unresectable pancreatic cancer. No significant financial relationships to disclose.
Extracorporeal Photopheresis (ECP) for Acute Graft-Versus Host Disease (GvHD) after Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)
Authors: Sandra Eder, Marie-Thérèse Rubio, Ramdane Belhocine, Myriam Labopin, Eolia Brissot, Anne-Claire Mamez, Federica Giannotti, Giorgia Battipaglia, Annalisa Ruggeri, Arnon Nagler, Mohamad Mohty
Journal: Blood (2015)
Abstract P330: Comparative Effectiveness of Atenolol and Metoprolol for Prevention of CVD Events in Hypertensive Patients
Authors: Emily D Parker, Karen L Margolis, Nicole K Schneider, David J Magid, Heather M Tavel, Susan M Shetterly, P. Michael Ho, Joe V Selby, Bix E Swain, Julie A Schmittdiel, Patrick J O'Conner
Journal: Circulation (2012)

OBJECTIVE: Randomized controlled trials have demonstrated the efficacy of selected beta blockers for preventing cardiovascular (CV) events in patients following myocardial infarction (MI) or with heart failure (HF). However, the effectiveness of atenolol for preventing CV in patients with hypertension (HTN) has been questioned recently. METHODS: Using data from Cardiovascular Research Network HTN registry, we compared incident MI, HF, and stroke in 21,960 patients who were new beta blocker users between 2000-2009. Patients had no prior history of CV disease and had not previously filled a prescription for either atenolol or metoprolol tartrate. Exposure to either atenolol or metoprolol tartrate was ascertained from pharmacy data. In order to control for confounding by indication, patients were matched 1:1 based on the propensity to have metoprolol dispensed. The propensity score model included age, sex, race/ethnicity, year of beta blocker initiation, number of visits in the previous year, insurance payer, systolic blood pressure at baseline, and prevalence of lipid disorders, diabetes, chronic kidney disease, and whether the patient was on additional anti-HTN medication at baseline. Incident CV events, patient and provider characteristics were determined from electronic heath record , health plan enrollment and claims data. Cox proportional hazards regression was used to examine the associations of different beta blockers with incident CV events. RESULTS: The propensity-matched 10,980 new metoprolol tartrate users were similar to the 10,980 new atenolol users with regard to demographic and clinical characteristics. During follow-up (median 3.9 years), there were 743 incident MI, 806 incident HF, and 749 incident stroke events. Hazard rate ratios for MI, HF and stroke were 1.00 (95% confidence interval 0.96-1.02), 0.98 (95% CI 0.96-1.02), and 0.99 (95% CI 0.96-1.02), respectively. The results from multivariate models adjusted for the variables in the propensity model were similar. CONCLUSIONS: There were no statistically significant differences in incident MI, HF, stroke between atenolol and metoprolol tartrate users. These results do not support recent concerns that atenolol may not be as safe as other beta-blockers for preventing CV morbidity in patients with HTN. Large registries similar to the one used in this analysis may be useful for addressing comparative effectiveness questions that are unlikely to be resolved by randomized trials.
Triterpenoid Methyl-CDDO Is a Potent Inducer of Apoptosis in CD34+ AML Progenitor Cells Via Activation of SAPK Pathways and Inhibition of MAPK Cascades.
Authors: Marina Konopleva, Peter Ruvolo, Rooha Contractor, Svitlana Kurinna, Yue-Xi Shi, Teresa McQueen, Michele Milella, Michael Andreeff
Journal: Blood (2004)
474. A New cGMP Facility To Produce Clinical Grade Batches of Lentiviral Vectors and CAR-T Cell in Europe
Authors: Abdel Zemmar, Guillaume Deplaine, Amel Hadri, Julien Deroyer, Cecile Bauche
Journal: Molecular Therapy (2015)

THERAVECTYS is a Paris-based, privately-owned, fully integrated discovery & clinical development biotech company. We are developping lentiviral vectors for human and veterinary vaccination and immunotherapy applications. We have have proudly achieved the first-ever human vaccination clinical trial conducted with lentiviral vectors with our anti-HIV vaccine candidate. We are now pursuing our clinical development of further therapeutic innovative vaccine candidates, both in oncology & infection diseases. Particularly, our first oncology clinical trial, which targets Adult T-cell Leukemia/Lymphoma virally-induced by HTLV-1, is programmed before Q3 2015. In addition, we are developing our own T-cell therapy programs (CAR and TCR) based on its proprietary new lentiviral-based system allowing a real switch of the production of the CAR or of the TCR by the modified T-cells To control costs, respect timelines and maintain the high quality and diversity of all ongoing and future clinical development programs, THERAVECTYS has decided to internalize the bio-production of its lentiviral vectors and the associated quality controls. To achieve this goal, THERAVECTYS has built a GMP facility in compliance with the requirements of regulatory agencies (EMA and FDA). The 340m2 plant is equipped with state-of-the-art bioreactors (from 20 to 1000L), semi-automated downstream skids and a fill-and-finish system to conform to our fully integrated single use process. This process implies a 16day-USP step corresponding to the expansion and transfection of HEK293SF cells, and a 2day-DSP step comprising 3 purifications. This GMP facility will allow us to produce batches from a minimum of 300 up to 5 000 vials complying with up to phase III clinical trial requirements. Additionally, our GMP facility which is composed of defined distinct independent rooms will allow us to develop our current validated technics, lentiviral vector production and CAR T cells engineering, without any cross-contamination. Our Quality Control unit was architecturally designed to house a vast array of analytical equipment. With more than 30 different analytical methods including environmental monitoring of the GMP facility, contaminants evaluation and RCL testing, THERAVECTYS has gained full independence by keeping all analytical and microbiology testing in house. This cutting-edge GMP facility (production and QC unit) had been built in 9 months, and should be operational in Q1 2015 (the certification process is currently underway). It will allow THERAVECTYS to protect its unique and advanced know-how in the manufacturing of lentiviral vectors and CAR-T cells.
Abstract 3377: Co-spheroid analysis reveals attenuating effect of HS27A stroma cells on DLD1 colon carcinoma susceptibility to MEK kinase inhibitor trametinib
Authors: Claudia Hoffmann, Daniel Feger, Oliver Siedentopf, Holger Weber, Sarah Umber, Jan E. Ehlert
Journal: Cancer Research (2015)

Abstract In cancer treatment, stroma-derived microenvironmental cues are suspected to exert an adversary impact on anti-cancer drug efficacy. In order to take such influences into account in cellular drug screening campaigns, we have set up a high-throughput-compatible co-spheroid model, enabling the analysis of various combinations of cancer and stroma cell lines. This assay system allows for cell analysis in a three-dimensional (3D) close-to-physiological environment with simultaneous detection of cancer and stroma cell viability based on differential luciferase cell-labelling. Our data revealed that growth characteristics strongly depend on the specific cell types combined. Stroma cells in contrast to tumor cells usually ceased to proliferate or even showed dramatic loss of viability possibly due to metabolic hijacking. We report on the optimization of the cellular test systems to ensure significant viable stroma cell counts during the drug testing phase. In such an optimized co-spheroid model of Firefly-luciferase labelled DLD-1 colon cancer cells with Renilla-luciferase labelled HS27A stroma cells, we identified the MEK kinase inhibitor Trametinib as a compound showing a 10-30fold attenuated potency as compared to the DLD-1 mono-spheroid model. Based on these results we suggest integrating optimized co-spheroid studies into early drug development to focus on compounds that remain active under microenvironmental conditions. Citation Format: Claudia Hoffmann, Daniel Feger, Oliver Siedentopf, Holger Weber, Sarah Umber, Jan E. Ehlert. Co-spheroid analysis reveals attenuating effect of HS27A stroma cells on DLD1 colon carcinoma susceptibility to MEK kinase inhibitor trametinib. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3377. doi:10.1158/1538-7445.AM2015-3377
PTU-064 The use of non-heart-beating donor grafts increases perioperative resource utilisation in liver transplantation: Abstract PTU-064
Authors: R Broomhead, S Patel, A K Burroughs, B S Fernando, S Mallet, J P O'Beirne
Journal: Gut (2010)

<h3>Introduction</h3> The use of NHBD donor grafts for liver transplantation (LT) is increasing. Large series suggest that patient outcomes are equivalent to heart beating donor (HBD) graft recipients but there is currently scarce literature on the impact on the increasing use of NHBD on perioperative resource utilisation. <h3>Methods</h3> We analysed patients undergoing NHDB LT in our centre over a 2-year period and compared perioperative variables to a similar number of HBD recipients (matched for age, disease severity and indication) to determine if the use of NHBD donor livers increased resource utilisation. <h3>Results</h3> 16 NHBD recipients were matched to 16 patients undergoing HBD LT. There were no differences in indication, MELD, age or sex between the groups. NHBD LT was associated with more frequent post reperfusion hypotension and clinically significant lysis requiring tranexamic acid. Post operative stay on ITU was longer and there was a more frequent need for vasopressors, ventilation and renal replacement therapy in NHBD recipients (Abstract 064). 2 patients (both from the NHBD group) had primary non-function and underwent emergency regrafting. 90-day survival was 100% in both groups. <h3>Conclusion</h3> The use of NHBD grafts in LT results in acceptable patient and graft survival however there appears to be increased severity of reperfusion syndrome and more requirement for post operative organ support. These data suggest that though patient outcomes may not be significantly affected, increasing use of NHBD grafts may lead to significantly impact on the resources and costs associated with liver transplantation.
Abstract LB-025: Survivin is trafficked into cancer cell-derived exosomes via a microtubule-dependent mechanism
Authors: Bridget T. Kreger, Marc Antonyak, Richard Cerione
Journal: Cancer Research (2015)

Abstract Cell-cell communication plays important roles in promoting tumor growth and metastasis, and these events are frequently targeted by therapies. The generation of extracellular vesicles (EVs), including exosomes and microvesicles (MVs), are beginning to be appreciated as one such form of communication that has important consequences in cancer. MVs are small vesicular structures (0.1-2 μm) that are derived from plasma membranes and are shed into the cell's surroundings; exosomes (30-100 nm) are rerouted endosomes that are released by the fusion of multi-vesicular bodies with the plasma membrane. Both types of EVs influence the behavior of recipient cells through the transfer of their cargo, which includes oncogenic factors, signaling proteins, RNA transcripts, and cytoskeletal components. However, the mechanism through which cargo is selectively trafficked to EVs has not yet been elucidated. We have discovered that disrupting microtubule dynamics in the MDAMB231 breast cancer cell line using the microtubule inhibitor nocodazole has the intriguing effect of significantly increasing the amount of the anti-apoptotic factor survivin that is contained within the EVs shed by these cells. This finding has been replicated in several additional human cancer cell lines and also when using the chemotherapy agent Paclitaxel (Taxol), which also inhibits microtubule dynamics. When MVs were separated from exosomes using procedures that were developed to resolve these two classes of EVs from MDAMB231 cell conditioned medium, survivin was found to be a specific cargo of exosomes and was absent from MVs. Moreover, the exosomes containing survivin enhanced the survival of recipient cells exposed to serum-starvation. Overall, these results show how a specific protein (e.g. survivin) can be selectively packaged into exosomes, as well as shed light on a novel mechanism that underlies Paclitaxel resistance. Citation Format: Bridget T. Kreger, Marc Antonyak, Richard Cerione. Survivin is trafficked into cancer cell-derived exosomes via a microtubule-dependent mechanism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-025. doi:10.1158/1538-7445.AM2015-LB-025
Abstract 462: Cytotoxic CD8+ T cells and immunosuppressive T regulatory cells are associated with aggressive breast cancer subtypes
Authors: Galina F. Khramtsova, Rita Nanda, Ekaterina A. Khramtsova, Lise Sveen, Sope Olugbile, Olufunmilayo I. Olopade
Journal: Cancer Research (2015)

Abstract Background: An increase in tumor infiltrating lymphocytes (TILs) indicates an immune response to tumor antigens. CD8+ TILs play a vital role in cancer progression, and may have tumor suppressive effects. FoxP3+ T regulatory cells (Tregs), however, suppress a variety of immune cells - including CD4+ TILs, CD8+ TILs, dendritic cells, B cells, and macrophages - and thus may inhibit the beneficial effect these cells have on tumor suppression. Specifically, CD8+ TILs - which are a critical component of tumor-specific adaptive immunity - are a major target of Tregs. This study was aimed at understanding how these TILs correlate with breast cancer molecular subtypes in diverse population of breast cancer patients. Methods: Tissue Microarrays (TMAs) of breast cancer cases from 1992-2010 were obtained from the University of Chicago breast cancer biospecimen bank under IRB approved protocols. Molecular subtype was assigned based on immunohistochemical (IHC) staining into the following groups: luminal A (ER+ and/or PR+, HER2-), luminal B (ER+ and/or PR+, HER2+), HER2-like (ER/PR-, HER2+) and basal-like (ER/PR/HER2-, EGFR+ and/or CK5/6+). IHC for CD8 and FoxP3 was performed on TMAs using DAKO, cat # M7103 antibody, and Abcam antibody cat #ab20034. The amount of CD8+ and FoxP3+ cells presents within the neoplastic tissue were counted manually in two high-powered fields (x400) by two independent pathologists, and recalculated for 1 mm2. The ratio of FoxP3+/CD8+ was calculated and correlated with molecular subtype. Results: Of the 292 cores evaluated, 268 were evaluable representing 134 individual cases. There were 28 basal-like (20.9%), 14 HER2 (10.4%), 78 luminal A (58.3%), and 14 luminal B (10.4%). Basal-like tumors showed the highest infiltration of both Tregs and CD8+ TILs when compared to other breast cancer subtypes, and the ratio of FoxP3+: CD8+ TILs in basal-like tumors were 1.7, 2.5, and 4.5-fold higher than in HER2, Luminal A, and Luminal B tumors respectively (p&amp;lt;0.05 for all correlations). Summary: FoxP3+ and CD8+ TIL infiltration density were significantly different among molecular subtypes of breast cancer. Future studies will examine the genomic determinants and prognostic significance of TILs in aggressive breast cancer subtypes, especially basal-like breast cancers. Citation Format: Galina F. Khramtsova, Rita Nanda, Ekaterina A. Khramtsova, Lise Sveen, Sope Olugbile, Olufunmilayo I. Olopade. Cytotoxic CD8+ T cells and immunosuppressive T regulatory cells are associated with aggressive breast cancer subtypes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 462. doi:10.1158/1538-7445.AM2015-462
Abstract SY16-02: Clinical whole exome interpretation for precision cancer medicine
Authors: Eliezer M. Van Allen
Journal: Cancer Research (2015)

Abstract Translating whole exome sequencing (WES) for prospective clinical use may impact the care of cancer patients. However, since this approach greatly expands the quantity of genomic data generated for an individual patient, multiple innovations are necessary for clinical implementation. These include clinical analysis and interpretation of large scale WES data, effective representation of WES data in a clinical environment for physician consumption, and development of knowledge-sharing platforms to ensure effective curation of clinically relevant variants. Here, we describe heuristic methods for the clinical interpretation of WES data. We also discuss approaches that may facilitate physician understanding of WES data in a clinical setting. Finally, we review existing knowledge bases and emerging mechanisms for crowdsourcing variant curation that may enable prospective WES-scale genomic profiling. Overall, this methodology may inform the widespread implementation of precision cancer medicine. Citation Format: Eliezer M. Van Allen. Clinical whole exome interpretation for precision cancer medicine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY16-02. doi:10.1158/1538-7445.AM2015-SY16-02
Abstract 5518: Development of bio-affinity nanoparticles: Applications for cancer imaging and therapeutics
Authors: Idit Dotan, Philip J.R. Roche, Elliot Mitmaker, Mark A. Trifiro, Miltiadis Paliouras
Journal: Cancer Research (2015)

Abstract Treatment of advanced cancer, is an extremely challenging proposition. Surgery is curative at early stages, but with substantial complications. Molecular treatments in early disease are of questionable benefit, coupled with the lack of therapeutic options in advanced disease, make treatment extremely challenging. Early cancers evolve through many somatic mutations involving many selective processes, induced in part by classical drug therapies themselves initiating drug resistance. Genetic cancers studies show extensive single missense mutations, copy number variations, splicing variants, genetic rearrangements and short DNA alterations in a large number of genes. However, physical agent therapies are immune to genetic alterations, a targeting the cancer cell and adjacent cells. By investigating cell surface markers that are correlated with disease progression, we have coupled bio-affinity agents (antibody, ligand, aptamer) to functionalized carbon nanoparticles and developed a platform of delivering highly-localized “energy” in the immediate proximity to the cells causing significant cellular damage. Similarly, these agents can be simultaneously used as imaging agents, creates a theranostic treatment agent. We have used papillary thyroid (PTC) and prostate cancer (CaP) cancer cells and selectively targeted THSR and PSMA, respectively in our models. Using a 2W laser light for 30 seconds, we are able to achieve near 100% cell killing of targeted cells, whereas receptor-null cells remain unharmed. Electron microscopy was used as a direct analysis to answer the mechanistic question of cell necrosis and cell death that cannot be approached via light microscopy. Altogether these results suggest that significant and specific cell killing can be achieved with small amounts of power over short periods of time. In conclusion, whereas in the past, simultaneous multiple drugs therapies have been limited by systemic toxicities, this approach represents a single delivery platform that can carry several small molecule drugs, in conjunction with new genetic modalities, in a targeted fashion with the added benefit of self-imaging so as to document successful targeting. Citation Format: Idit Dotan, Philip J.R. Roche, Elliot Mitmaker, Mark A. Trifiro, Miltiadis Paliouras. Development of bio-affinity nanoparticles: Applications for cancer imaging and therapeutics. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5518. doi:10.1158/1538-7445.AM2015-5518