tbuckley/cabot-search huggingface dataset:
Abstract 2157: PI3K/AKT-induced stabilization of FUSE binding proteins (FBPs) in liver cancer cells
Authors: Jana Samarin, Ilan Stein, Elad Horwitz, Xin Chen, Mona Malz, Eli Pikarsky, Diego Calvisi, Peter Schirmacher, Kai Breuhahn
Journal: Cancer Research (2015)

Abstract Far upstream element-binding proteins (FBPs) represent a family of transcription factors, which are highly overexpressed in the majority human liver cancer (hepatocellular carcinoma; HCC). Nuclear accumulation of FBP-1, -2, and -3 in HCC cells support cell proliferation and migration. However, the mode of FBP dysregulation in HCC cells has not been defined so far. Genomic alterations of the fubp (FBP-1; chr. 1p31.1), khsrp (FBP-2; chr. 19.p13.3), and fubp3 (FBP-3; 9p34.11) gene loci in primary human HCCs were determined by matrix-comparative genomic hybridization (CGH). In order to identify specific stimuli of FBP enrichment, different human HCC cell lines were cultured under different cell density and hypoxic conditions or treated with growth factors (e.g., TGFß, IGF-II), chemical inhibitors (e.g., AG1478, SB203580, MEK1/2, sorafenib, and PI3K inhibitors), and gene-specific siRNAs (e.g., Akt1-3, rictor, raptor). The in vivo relevance of the findings was confirmed using HCC mouse models (e.g., Mdr2-/- animals) and human HCC tissue specimens (immunohistochemistry and western blotting). Only few genomic gains were found for all FBP family members in human HCC samples (e.g., 6% for fubp). In vitro, inhibition of EGFR (by AG1478) or administration of the multi-kinase inhibitor sorafenib reduced FBP protein levels. Furthermore, inhibition of the PI3K/Akt/mTOR pathway revealed strong effects on FBP protein half-live without significant impact on FBP transcription. Other pathways or stimuli only caused minor effects on FBP expression (e.g., p38 or Raf1 inhibition). These findings were confirmed in mouse HCC models with high-level expression of FBPs, where injection of sorafenib or rapamycin significantly diminished FBP amounts. Reduction of FBP concentrations after inhibition of the PI3K/Akt/mTOR pathway was rescued after inhibition of caspase-3/-7 activity. Lastly, a significant correlation between pAkt and nuclear FBP expression was detected in human HCC tissues. These results demonstrate that activation of the PI3K/Akt/mTOR signalling axis is responsible for increased stabilisation of FBPs in human HCC cells. Elevated FBP half-live is at least partly mediated through crosstalk between the PI3K/Akt/mTOR pathway and caspase activity. These data are important for a deeper understanding of how druggable upstream regulators may affect FBP bioavailability in hepatocarcinogenesis. Citation Format: Jana Samarin, Ilan Stein, Elad Horwitz, Xin Chen, Mona Malz, Eli Pikarsky, Diego Calvisi, Peter Schirmacher, Kai Breuhahn. PI3K/AKT-induced stabilization of FUSE binding proteins (FBPs) in liver cancer cells. [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 2157. doi:10.1158/1538-7445.AM2015-2157
Comparison of Concurrent Use of Thoracic Radiation With Either Carboplatin-Paclitaxel or Cisplatin-Etoposide for Patients With Stage III Non–Small-Cell Lung Cancer
Authors: Conor E. Steuer, Madhusmita Behera, Vinicius Ernani, Kristin A. Higgins, Nabil F. Saba, Dong M. Shin, Suchita Pakkala, Rathi N. Pillai, Taofeek K. Owonikoko, Walter J. Curran, Chandra P. Belani, Fadlo R. Khuri, Suresh S. Ramalingam
Journal: JAMA Oncology (2016)

<h3>Importance</h3> The 2 most common chemotherapy regimens used concurrently with thoracic radiation for patients with unresectable IIIA and IIIB non–small-cell lung cancer (NSCLC) are carboplatin-paclitaxel and cisplatin-etoposide. There are no prospective comparisons of these 2 regimens in this setting. <h3>Objective</h3> To conduct a systematic review of published trials to compare outcomes and toxic effects between cisplatin-etoposide and carboplatin-paclitaxel in patients with non–small-cell lung cancer receiving thoracic radiation. <h3>Evidence Review</h3> Studies that enrolled patients with stage III disease receiving radiotherapy (RT) with carboplatin-paclitaxel or cisplatin-etoposide were identified using electronic databases (MEDLINE, EMBASE, and Cochrane library) and meeting abstracts. Trials were excluded if they were phase 1, enrolled less than 10 patients, or included surgical resection. A systematic analysis of extracted data was performed with software using random and fixed effect models. Clinical outcomes were compared using point estimates for weighted values of median overall survival, progression-free survival, response rate, and toxic effects. A 2-tailed<i>t</i>test with a significance level of .05 was used for all comparisons. <h3>Findings</h3> Overall, 3090 patients were included from 31 studies in the cisplatin-etoposide groups (median age, 61 years; 65% male; 40% squamous histology; median radiation dose, 63.0 Gy), and 3728 patients from 48 studies in carboplatin-paclitaxel groups (median age, 63 years; 65% male; 40% squamous histology; median radiation dose, 64.6 Gy). There was no significant difference in response rates between cisplatin-etoposide and carboplatin-paclitaxel (58% vs 56%;<i>P</i> = .26), respectively. For cisplatin-etoposide vs carboplatin-paclitaxel, there was no significant difference in median progression free survival (12 months vs 9.3 months;<i>P</i> = .20), overall survival (19.6 months vs 18.4 months;<i>P</i> = .40), or 3-year survival rate (31% vs 25%;<i>P</i> = .50). Cisplatin-etoposide was associated with higher grade 3 to 4 hematological toxic effects compared with carboplatin-paclitaxel (eg, neutropenia [54% vs 23%;<i>P</i> &lt; .001] and grade 3/4 nausea/vomiting [20% vs 11%;<i>P</i> = .03]), while rates of grade 3 to 4 pneumonitis (12% vs 9%;<i>P</i> = .12) and esophagitis (23% vs 21%;<i>P</i> = .27) were similar. <h3>Conclusions and Relevance</h3> Cisplatin-etoposide and carboplatin-paclitaxel regimens were associated with comparable efficacy when used with concurrent definitive radiotherapy for patients with stage III unresectable NSCLC. The toxic effect profiles favored the carboplatin-paclitaxel regimen.
Oral Vinorelbine as single agent in the treatment of poor Performance Status (pPS) metastatic Non Small Cell Lung Cancer (NSCLC): a single institution experience
Authors: G.P. Spinelli, V. Stati, A. Papa, L. Rossi, M. Minozzi, M. Verrico, D. Caruso, E. Zaccarelli, F. Zoratto, M. Strudel, E. Giordani, G. Magaro, S. Rosati, G. Angius, B. Rossi, S. Tomao
Journal: Annals of Oncology (2015)
A multicenter prospective randomized study testing non-inferiority of thalidomide 100 mg/day as compared with 400 mg/day in patients with refractory/relapsed multiple myeloma: Results of the final analysis of the IFM 01–02 study
Authors: I. Yakoub-Agha, C. Doyen, C. Hulin, G. Marit, L. Voillat, B. Grosbois, J. Harousseau, C. Duguet, R. Zerbib, T. Facon, J. Mary
Journal: Journal of Clinical Oncology (2006)

7520 Background: Thalidomide (THAL) is effective in pts with relapsed or refractory multiple myeloma (RRMM). A study by Yakoub-Agha et al of 83 patients (Hematol J, 2002) supported this effectiveness but showed a high incidence of THAL toxicity ≥ grade II, related to either THAL cumulative dose or dose-intensity. Themean daily dose of THAL in the first 90-day treatment period, however, did not influence response, overall survival (OS), or event-free survival. Given the dose-related toxicities and an unknown minimally effective THAL dose, the IFM conducted a prospective randomized study to compare the efficacy of THAL 100 mg/d with 400 mg/d in pts with RRMM after ≥2 lines of prior therapy. Methods: The study design was approved by the ethics committee at Lille University Hospital, and all pts gave written informed consent. Given the improved response seen with THAL plus dexamethasone (DEX), this combination was specified per protocol in both study arms for treatment failure (TF) defined as progression at any time or stable disease after 3 months of THAL treatment. THAL dose reduction for toxicity was permitted, but no increase over the initial dose was allowed. All pts received pamidronate routinely. The primary end point was 1-year OS. Secondary endpoints were response rate, EFS, and safety. Results: All results are based on intent-to-treat analyses. In all, 400 pts were enrolled (400 mg, n = 195; 100 mg, n = 205). The 2 groups were comparable in terms of patient characteristics, disease features including Ch13 deletion and prior therapy. Pts in the THAL 100 mg arm received DEX more frequently for TF than those in the 400 mg group, but this difference did not influence 1-year OS: 73 ± 3% vs 69 ± 3% in the 400 mg and 100 mg groups, respectively. The hypothesis of inferiority of 100 mg was rejected. Also, THAL 100 mg was better tolerated than 400 mg with less high-grade somnolence, constipation, and peripheral neuropathy (p &lt; .001, p = .01 et p = .05, respectively). There was no difference regarding deep vein thrombosis. Conclusion: THAL 100 mg/d is comparable in terms of survival with 400 mg/d (with DEX as salvage therapy in case of TF in both arms) in pts with RRMM and better tolerated. [Table: see text]
Fever after cancer chemotherapy is affected by drug fever on post-treatment days 3-4
Authors: Daiki Ogawara, Minoru Fukuda, Shiro Ueno, Mikio Oka, Akira Kondo, Shinya Tomari, Katsumi Nakatomi, Yoichi Nakamura, Kazuto Ashizawa, Shigeru Kohno
Journal: Annals of Oncology (2015)
Abstract 4794: Identification of FOXM1 driven gene network as a prognostic marker in breast cancer
Authors: In-Sun Chu, Seon-Kyu Kim, Yun-Gil Roh, Sun-Hee Leem
Journal: Cancer Research (2015)

Abstract A transcription factor FOXM1 is known to play a key role in cell cycle progression where endogenous FOXM1 expression peaks at S and G2/M phases. It was previously reported that expression level of FOXM1 in breast cancer was strongly correlated with patient survival, since FOXM1 influenced endocrine therapy and chemo-response effect. The aim of this study is to estimate prognostic value of FOXM1 gene and to identify novel markers interconnected with FOXM1 to predict heterogeneous breast cancer behaviors. Microarray gene expression profiling was performed using gene expression data obtained from 317 Korean patients with breast cancer to identify a signature associated with FOXM1. Various statistical methods, including the leave-one-out cross validation, were applied to identify a gene expression signature able to predict breast cancer outcome. The predictive value of the signature was verified in the two larger independent cohorts obtained from a public database. Unsupervised cluster analysis of gene expression data from the Korean cohort showed highly concordant subtypes of Caucasian cohort. Significant differences in overall and disease specific survival between the subgroups divided by the expression signature of FOXM1-associated genes were observed (log-rank test, each P &amp;lt;0.001, respectively). Multivariate Cox regression analysis revealed that the expression signature of FOXM1-associated genes was a strong predictor of breast cancer outcomes. Our findings were verified in the two independent patient cohorts and confirmed that the signature produced consistent prediction patterns. Finally, gene network analyses in the signature revealed that, FOXO1, CCNK, MYC, BRD4 and EIF4G1 could be important mediators interconnected with FOXM1 in the breast cancer behavior. The expression signature of FOXM1 and its associated genes represents a promising diagnostic tool for the identification of breast cancer patients that have a high risk of poor clinical behavior. Note: This abstract was not presented at the meeting. Citation Format: In-Sun Chu, Seon-Kyu Kim, Yun-Gil Roh, Sun-Hee Leem. Identification of FOXM1 driven gene network as a prognostic marker in breast cancer. [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 4794. doi:10.1158/1538-7445.AM2015-4794
175. Double-Layered Cell Sheets Transplantation That Achieves Durable Factor VIII Delivery in the Mouse Model of Hemophilia A
Authors: Hideto Matsui, Masahi Noda, Rie Utoh, Midori Shima, Teruo Okano, Mitsuhiko Sugimoto
Journal: Molecular Therapy (2015)

Hemophilia A is an inherited bleeding disorder caused by a deficiency of the procoagulant cofactor VIII (FVIII). Currently, the patients with hemophilia A are being treated through repeated intravenous injection of FVIII concentrates. Since FVIII is a secreted protein and the tight regulation of its expression is not necessary, ex vivo gene therapy strategies for hemophilia A might be good for the therapeutic alternative. We previously demonstrated that therapeutic levels of plasma FVIII were documented from hemophilia A mice over 300 days, in which lentivirally-engineered blood outgrowth endothelial cells (BOECs) sheet were implanted subcutaneously (Tatsumi K et.al. PLoS One 2013 8(12):e83280). To enhance the viability of the implanted BOECs which boost the FVIII expression, double-layered cell sheets transplantation was performed by placing the recovered BOECs sheet onto the fibroblast sheet directly. FVIII transduced BOECs and non-transduced fibroblasts were cultured on temperature-responsive culture dish independently. Both cells were recovered as a contiguous cell sheet. Subcutaneous co-transplantation studies of BOEC and fibroblast sheet indicated that all hemophilia A mice treated with cyclophosphamide expressed between 40-50 mU/mL levels of FVIII without developing anti-FVIII inhibitory antibodies over 200 days. In contrast, the hemophilia A mice without any prior immuno-suppressive treatment developed neutralizing anti-FVIII antibodies between 5-10 Bethesda units. These therapeutic FVIII levels were two times higher than the group of hemophilia A mice that were transplanted BOECs sheet alone. Histological examination in the part of the mice revealed that the combination of BOEC and fibroblast sheet was structured as flat clusters without any cells infiltration. In conclusion, tissue engineering approach using double-layered cell sheets are viable for persistent tissue survival and providing therapeutic values. This novel ex vivo gene transfer strategy can provide the safe and efficacious delivery of FVIII in hemophilia A and merits further assessment.
Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting
Authors: Clare Y. Slaney, Bianca von Scheidt, Alexander J. Davenport, Paul A. Beavis, Jennifer A. Westwood, Sherly Mardiana, David C. Tscharke, Sarah Ellis, H. Miles Prince, Joseph A. Trapani, Ricky W. Johnstone, Mark J. Smyth, Michele W. Teng, Aesha Ali, Zhiya Yu, Steven A. Rosenberg, Nicholas P. Restifo, Paul Neeson, Phillip K. Darcy, Michael H. Kershaw
Journal: Clinical Cancer Research (2016)

Purpose: While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model.Experimental Design: In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100). We used a regimen of adoptive cell transfer incorporating vaccination (ACTIV), with recombinant vaccinia virus expressing gp100, to treat a range of tumors including orthotopic breast tumors and large liver tumors.Results: ACTIV therapy induced durable complete remission of a variety of Her2+ tumors, some in excess of 150 mm2, in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Vaccinia virus induced extensive proliferation of T cells, leading to massive infiltration of T cells into tumors. Durable tumor responses required the chemokine receptor CXCR3 and exogenous IL2, but were independent of IFNγ. Mice were resistant to tumor rechallenge, indicating immune memory involving epitope spreading. Evidence of limited neurologic toxicity was observed, associated with infiltration of cerebellum by T cells, but was only transient.Conclusions: This study supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues. Clin Cancer Res; 23(10); 2478-90. ©2016 AACR.
Pharmacokinetic aspects of retinal drug delivery
Authors: Eva M. del Amo, Anna-Kaisa Rimpelä, Emma Heikkinen, Otto K. Kari, Eva Ramsay, Tatu Lajunen, Mechthild Schmitt, Laura Pelkonen, Madhushree Bhattacharya, Dominique Richardson, Astrid Subrizi, Tiina Turunen, Mika Reinisalo, Jaakko Itkonen, Elisa Toropainen, Marco Casteleijn, Heidi Kidron, Maxim Antopolsky, Kati-Sisko Vellonen, Marika Ruponen, Arto Urtti
Journal: Progress in Retinal and Eye Research (2016)

Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory.
700. Stable Correction of Severe Metabolic Liver Disease Phenotypes in the Growing Murine Liver Using a Hybrid rAAV/piggyBac Transposon Gene Delivery System
Authors: Sharon C. Cunningham, Susan M. Siew, Claus V. Hallwirth, Christine Bolitho, Natsuki Sasaki, Gagan Garg, Iacovos P. Michael, Nicola A. Hetherington, Gustavo de Alencastro, Andras Nagy, Ian E. Alexander
Journal: Molecular Therapy (2015)

Liver-targeted gene therapy using adeno-associated virus-based vectors (rAAV) shows therapeutic promise in animal models and adult-focused clinical trials. This promise, however, is not directly translatable to the growing liver where rapid clearance of rAAV episomal genomes occurs in concert with hepatocellular proliferation. This phenomenon has been shown to underpin progressive loss of therapeutic efficacy, initially achieved in the neonatal period, in mouse models of early-onset urea cycle defects (UCDs). We have developed a hybrid rAAV/piggyBac transposon vector system combining the highly efficient liver-targeting properties of rAAV with stable piggyBac-mediated transposition of the transgene into the hepatocyte genome. Transposition efficiency was first tested using an EGFP expression cassette following delivery to newborn wild-type mice, with a 20-fold increase in stably gene-modified hepatocytes observed 4 weeks post-treatment compared to traditional rAAV gene delivery. We then modeled the therapeutic potential of the system in the context of severe early onset UCDs. A single treatment in the perinatal period was sufficient to confer robust and stable phenotype correction in the ornithine transcarbamylase (OTC) deficient Spfash mouse and neonatal lethal argininosuccinate synthetase (ASS) knock-out mouse. The system was next utilized in a murine model of chronic liver disease, progressive familial intrahepatic cholestasis type 3 (PFIC3), in which intervention prior to disease onset is necessary due to the development of chronic liver pathology which impedes vector delivery and hepatocyte transduction. Stable persistent expression extending into adulthood was achieved with increased mean biliary phosphatidylcholine concentration and dramatically reduced liver fibrosis. Finally, transposon integration patterns were analysed, revealing 127,286 unique integration sites which conformed to previously published piggyBac data. Conclusion: Using a hybrid rAAV/piggyBac transposon vector system we achieved stable therapeutic protection in two UCD mouse models and a murine model with chronic liver pathology. This strategy has the potential for treating a wide array of inherited liver diseases with early onset. A clinically conceivable early application of this technology in the management of severe UCDs could be as a bridging therapy while awaiting liver transplantation. Further improvement of the system will result from the development of highly human liver-tropic capsids, the use of alternative strategies to achieve transient transposase expression, and engineered refinements in the safety profile of piggyBac transposase-mediated integration.
Abstract 3902: MSS HNPCC frequently contain CNVs in chromatin regulators
Authors: WeiXiang Chen, Xia sheng, Jun Ding
Journal: Cancer Research (2015)

Abstract BACKGROUND &amp; AIMS: Approximately half of hereditary non-polyposis colorectal cancers (HNPCCs) don't display evidence of mismatch repair defects. The pathogenesis of microsatellite-stable (MSS) HNPCCs, and their effects on patients’ prognoses and responses to treatment, differ from those of other colorectal cancers (CRCs). We sought to identify genetic somatic alterations associated with MSS HNPCCs. METHODS: We examined genomic DNA samples from 95 primary HNPCCs and adjacent normal appearing mucosae from patients undergoing surgery. We performed the copy number variation (CNV) of the entire genome using the Cytoscan HD Array in 20 MSS and 4 MSI HNPCC tumors and their adjacent normal tissues. Extensive comparison with somatic alterations in MSI HNPCCs allowed segregation of MSS HNPCC-exclusive alterations. RESULTS: We found that copy number of genes that regulate chromatin was altered in MSS HNPCCs; the most frequent CNV were observed in CHD6, CHD7 and CHD8, which encode members of the chromodomain helicase/adenosine triphosphate dependent chromatin remodeling family. Somatic genetic alterations in these 3 genes were detected in 13/10/5 of 20 MSS HNPCCs. Genes altered in patients with CHARGE syndrome (congenital malformations involving the central nervous system, eye, ear, nose, and mediastinal organs) who had CHD7 mutations were also altered in CRCs with copy number amplification in CHD7. CONCLUSIONS: Genetic aberrations in chromatin remodeling could contribute to the development of MSS HNPCCs. Note: This abstract was not presented at the meeting. Citation Format: WeiXiang Chen, Xia sheng, Jun Ding. MSS HNPCC frequently contain CNVs in chromatin regulators. [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 3902. doi:10.1158/1538-7445.AM2015-3902