tbuckley/cabot-search huggingface dataset:
Abstract 1642: Antitumor activity of lurbinectedin toward ovarian clear cell carcinoma
Authors: Ryoko Takahashi, Seiji Mabuchi, Yuri Matsumoto, Mahiru Kawano, Tomoyuki Sasano, Hiromasa Kuroda, Katsumi Kozasa, Kenjirou Sawada, Tadashi Kimura
Journal: Cancer Research (2015)

Abstract Objectives:Lurbinectedin is a marine-derived covalent DNA minor groove binder and is structurally similar to trabectedin except for the C subunit. Lurbinectedin (PM01183) is a newly developed antitumor agent that is currently being investigated in phase I/II clinical trials in patients with solid tumors including ovarian cancer. The objective of this study is to investigate the effectiveness of lurbinectedin as a single agent or as combination with existing antitumor agent against ovarian clear cell carcinoma which is regarded as an aggressive chemoresistant histological subtype. Methods:Using human ovarian clear cell carcinoma cell lines, the anti-tumor effects of lurbinectedin, SN38, topotecan, doxorubicin, cisplatin and paclitaxel as single agent were assessed by MTS assay. Then the cytotoxicities of combination treatments involving lurbinectedin and 1 of the 4 agents were evaluated by isobologram analysis to examine which of these combinations displayed synergistic effects. The antitumor activities of the combination treatments were also examined using cisplatin-resistant and paclitaxel-resistant ovarian clear cell carcinoma sublines, which were derived from the parental clear cell carcinoma cells by continuously exposing them to cisplatin or paclitaxel. Finally, using nude mice inoculated with clear cell carcinoma cells, we examined the growth-inhibitory effect of lurbinectedin in vivo. Results:Lurbinectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that lurbinectedin significantly inhibits tumor growth. Concurrent exposure to lurbinectedin and SN-38 resulted in synergistic interactions in CCC cell lines. The combination of lurbinectedin plus SN-38 also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Treatment with everolimus significantly enhanced the antitumor activity of single agent lurbinectedin and combination of lurbinectedin plus SN-38. Conclusions:Lurbinectedin is a promising agent for CCC as a first-line chemotherapy and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel. Moreover, lurbinectedin combined with irinotecan may be more efficacious for the management of CCC. Citation Format: Ryoko Takahashi, Seiji Mabuchi, Yuri Matsumoto, Mahiru Kawano, Tomoyuki Sasano, Hiromasa Kuroda, Katsumi Kozasa, Kenjirou Sawada, Tadashi Kimura. Antitumor activity of lurbinectedin toward ovarian clear cell carcinoma. [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 1642. doi:10.1158/1538-7445.AM2015-1642
61. Vascular Smooth Muscle Cell RNA Aptamers for the Treatment of Cardiovascular Disease
Authors: William H. Thiel, Carla L. Esposito, David D. Dickey, Justin P. Dassie, Matthew E. Long, Joshua Adam, Jennifer Streeter, Brandon Schickling, Maysam Takapoo, Katie S. Flenker, Julia Klesney-Tait, Vittorio de Franciscis, Francis J. Miller, Paloma H. Giangrande
Journal: Molecular Therapy (2015)

Cardiovascular disease (CVD) is the leading cause of mortality in many countries. Many vascular disorders, including in-stent restenosis, arteriosclerosis, vein graft disease, and cardiac allograft arteriopathy are caused by pathological vascular smooth muscle cell (VSMC) remodeling following injury. An ideal therapeutic intervention would target the VSMCs without impairing the injured vessel re-endothelialization. However, current therapies do not selectively prevent pathological VSMC remodeling leading to impaired re-endothelization, late stent thrombosis and death. Thus, there is a clear need for cell-targeted treatment and prevention options of pathological VSMC remodeling. Our group has described the development of VSMC-specific, aptamers for (1) modulating signaling pathways associated with pathological VSMC remodeling and (2) delivering therapeutic molecules to these cells in vivo. Here we demonstrate that one of these aptamers, Vapt14, inhibits protein kinase B (PKB)/Akt activation and VSMC migration in response to multiple agonists by a mechanism that involves inhibition of platelet-derived growth factor receptor (PDGFR)-beta phosphorylation. In a murine model of carotid injury, treatment of vessels with Vapt14 reduces intimal:medial thickness to levels comparable to that of paclitaxel. Importantly, we confirm that Vapt14 cross-reacts with rodent and human VSMCs, exhibits a half-life of ~300 hours in human serum, and does not elicit immune activation of human peripheral blood mononuclear cells (PBMCs) in vitro. In addition, we confirm delivery of Vapt14 to VSMC in vitro and in vivo with fluorescence microscopy. Studies are being expanded to evaluate aptamer-mediated delivery of therapeutic biomolecules (e.g. small molecules, RNAi modulators) to areas of vascular injury. In summary this work provides an essential foundation for the translation of cell-targeted RNA therapeutics to multiple hyperplastic vascular diseases.
Localized angiosarcomas (AS): Identification of prognostic factors (PF) and analysis of treatment impact—Series from the French Sarcoma Group (GSF/GETO).
Authors: Clothilde Lindet, Agnes Neuville, Nicolas Penel, Marick Lae, Jean-Jacques Michels, Martine Trassard, Philippe Terrier, Isabelle Birtwisle-Peyrottes, Isabelle Valo, Francoise Collin, Marie-Christine Chateau, Yves Marie Robin, Jean-Michel Coindre
Journal: Journal of Clinical Oncology (2012)

10018 Background: AS represents less than 2% of all adult soft tissue sarcoma. PF and role of respective (neo)-adjuvant treatments in management of localized AS remain badly established. Methods: We have conducted a retrospective multicentre study (June 1980-October 2009) of 107 patients with localized AS. All cases have been centrally reviewed by pathologist expert. Univariate and multivariate analysis were conducted to identify independent PF. Overall survival (OS) and Local Recurrence Free Survival (LRFS) were estimated using the Kaplan-Meier method. Impact of treatments had been explored with Cox Model after adjustment to the PF. Results: The sex ratio was 18/89 (0.2). Median age was 71 years. 22% (24/107) and 62% (67/107) of patients developed AS in preexisting lymphoedema and in irradiated field, respectively. 71 cases (66%) were superficial. The most frequent primary locations were: limbs (35, 33%), chest wall (32, 29%) and breast (22, 20%). Grade was 1 in 21/103 (20%), 2 in 35/103 (34%) and 3 in 47/103 cases (46%). Treatments consisted in surgery, adjuvant radiotherapy and (neo)-adjuvant chemotherapy in, respectively, 95, 27 and 27 cases. R0 margin was obtained in 49 cases. The median OS and LRFS were, respectively, 38.8 months and 27 months. In multivariate analysis, the following PF influenced the OS: lymphedema (HR=2.02 [1.15-3.55]) and size&gt;5 cm (HR=1.48 [1.01-2.45]). After adjustment to these PF, R0 margins was the sole treatment parameter improving the OS (HR=0.19 [0.05-0.73]). In multivariate analysis, the following PF influence the LRFS: Age&gt;70 (HR=1.68 [1.02-2.76]) and pre-existing lymphedema (HR=2.07 [1.15-3.75]). After adjustment to these prognostic factors, R0 margins (HR=0.48 [0.38-0.69]) and adjuvant radiotherapy (HR=0.29 [0.10-0.83]) improved the LRFS. Conclusions: Pre-existing lymphedema, tumour size and age&gt;70 are the major PF in patients with localized AS. The achievement of R0 margins is of major importance for improving the outcome whatever the endpoint (OS, LRFS) Adjuvant radiotherapy decreased the local recurrence. (Neo)-adjuvant chemotherapy does not influence survivals.
Efficient Generation of HLA-A24-Restricted WT1-Specific Cytotoxic T Lymphocytes Using Gene-Engineered Artificial Antigen-Presenting Cells
Authors: Masahiro Ogasawara, Tomohiro Yamakawa, Yuki Katsura, Kanako Shima, Toshihiro Matsukawa, Minoru Kanaya, Koichiro Minauchi, Masanobu Nakata, Shuichi Ota, Kiyotoshi Imai, Teiichi Hirano, Naoki Kobayashi, Yoshio Kiyama, Naoto Hirano
Journal: Blood (2010)
Abstract 4290: Potent and selective next generation inhibitors of indoleamine-2,3-dioxygenase (IDO1) for the treatment of cancer
Authors: Jay P. Powers, Matthew J. Walters, Rajkumar Noubade, Stephen W. Young, Lisa Marshall, Jan Melom, Adam Park, Nick Shah, Pia Bjork, Jordan S. Fridman, Hilary P. Beck, David Chian, Jenny V. McKinnell, Maksim Osipov, Maureen K. Reilly, Hunter P. Shunatona, James R. Walker, Mikhail Zibinsky, Juan C. Jaen
Journal: Cancer Research (2015)

Abstract The IDO1 pathway has been proposed to mediate immunosuppressive effects in the tumor microenvironment through its role in the catabolism of tryptophan, resulting in effects on the differentiation and proliferation of T cells. IDO1 inhibition has shown promising clinical benefit as well as exacerbated toxicity in the treatment of melanoma, when combined with the anti-CTLA-4 antibody ipilimumab. We have discovered a novel class of highly selective small molecule inhibitors of IDO1 which surpass the potency of the compounds currently in clinical development. These compounds potently inhibit IDO1 activity in IFN-γ stimulated HeLa cells with single digit nM potency. Importantly, they also retain their potency in the presence of human serum, with IC50 values ranging between 5 and 15 nM in this more physiologically relevant media. Consistent with the role of IDO1+ dendritic cells in the suppression of T cell proliferation, this series of molecules is capable of restoring the proliferative capacity of human T cells (which is inhibited by allogeneic IDO1+ dendritic cells) with EC50 values of 2-3 nM. The molecules exhibit preclinical PK characteristics that are suitable for assessing the contribution of IDO1 to tumor growth in murine models, both alone and in combination with other therapeutic agents. The compounds have high metabolic stability against cultured human hepatocytes and exhibit preclinical PK and ADME characteristics consistent with once-daily dosing in humans. The full preclinical profile of one of these molecules, selected for clinical evaluation, will be the focus of this presentation. In conclusion, we have discovered a novel class of small molecule inhibitors of IDO1, which provides a preclinical basis for the clinical evaluation of a next generation IDO1 inhibitor in combination with other therapeutic agents. Citation Format: Jay P. Powers, Matthew J. Walters, Rajkumar Noubade, Stephen W. Young, Lisa Marshall, Jan Melom, Adam Park, Nick Shah, Pia Bjork, Jordan S. Fridman, Hilary P. Beck, David Chian, Jenny V. McKinnell, Maksim Osipov, Maureen K. Reilly, Hunter P. Shunatona, James R. Walker, Mikhail Zibinsky, Juan C. Jaen. Potent and selective next generation inhibitors of indoleamine-2,3-dioxygenase (IDO1) for the treatment of 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 4290. doi:10.1158/1538-7445.AM2015-4290
Reversion of physiological drug resistance of weakly basic drugs: The discovery of a new mechanism of PEG-PCL nanoparticles
Authors: R. Li, L. Xie, X. Li, Q. Liu, X. Qian, X. Jiang, L. Yu, Y. Ding, B. Liu
Journal: Journal of Clinical Oncology (2009)

e13528 Background: A number of studies have reported the superior antitumor effect of nanoparticles loading chemotherapeutics than the free agents, yet the underlying mechanism has not attract enough attention. The extracellular pH of cancer cells is lower than that of the intracellular pH. Due to this pH gradient, weakly basic drug will protonated extracellularly and display decreased intracellular concentration. In this study, we aimed to reveal a new mechanism of PEG-PCL nanoparticles, namely the reversion of physiological drug resistance. Methods: Tetradrine (Tet), an alkaloid isolated from traditional Chinese medicine, was incorporated into the diblock copolymer methoxy poly(ethylene glycol)-polycaprolactone (mPEG-PCL). In vitro cytotoxicity of free Tet and Tet-loaded nanoparticles at pH7.4 and pH6.8 was compared on four different cancer cell lines. Fluorescent particle cellular uptake study was also used. To evaluate the antitumor effect of the nanoparticles in a more complex model rather than monolayer cell culture, we used Histoculture Drug Resistance Assay (HDRA). The in vivo antitumor effect of the nanoparticles was also studied in ICR mice bearing H22 tumor with different in vivo pH values. Results: In vitro cytotoxicity study in four tumor cell lines showed that the cytotoxicity of free Tet decreased significantly (P&lt;0.05) when the extracellular pH decreased from 7.4 to 6.8, while the cytotoxicity of Tet-loaded nanoparticles increased or didn’t change significantly. The possible mechanism may mainly be the endocytosis of nanoparticles, which was proven by fluorescent particle cellular uptake study. HDRA indicated better tissue penetration of nanoparticles over free Tet. As to in vivo study, the mice with in vivo tumor pH 6.8 and treated with Tet-loaded nanoparticles exhibited best tumor inhibit rate and mildest side effect, suggesting that the use of nanoparticles was more preferable than the manipulation of tumor pH by the use of basic water. Conclusions: Our study clearly demonstrated that the mPEG-PCL nanoparticles could overcome the drug resistance caused by low extracellular pH and enhance drug penetration in the tumor tissue, thus increasing the antitumor efficacy of weakly basic agents. No significant financial relationships to disclose.
The impact of body mass index and height on the risk for glioblastoma and other glioma subgroups: a large prospective cohort study
Authors: Markus K.H. Wiedmann, Cathrine Brunborg, Antonio Di Ieva, Kristina Lindemann, Tom B. Johannesen, Lars Vatten, Eirik Helseth, John A. Zwart
Journal: Neuro-Oncology (2016)

Glioma comprises a heterogeneous group of mostly malignant brain tumors, whereof glioblastoma (GBM) represents the largest and most lethal subgroup. Body height and body mass index (BMI) are risk factors for other cancers, but no previous study has examined anthropometric data in relation to different glioma subgroups.This prospective cohort study includes 1.8 million Norwegian women and men between ages 14 and 80 years at baseline. Body weight and height were measured, and incident cases of glioma were identified by linkage to the National Cancer Registry. Cox regression analyses were performed to evaluate risk for different glioma subgroups in relation to anthropometric measures.During 54 million person-years of follow-up, 4,382 gliomas were identified. Overweight and obesity were not associated with risk for any glioma subgroup. Height was positively associated with risk for GBM and all other gliomas (hazard ratio [HR] per 10 cm increase: 1.24; 95% confidence interval [CI], 1.17-1.31 and 1.18; 95% CI, 1.09-1.29) but not with the proxy for isocitrate dehydrogenase (IDH)-mutant glioma (HR, 1.09; 95% CI, 0.98-1.21). In further subgroup analyses, the effect of height on glioma risk varied significantly with positive associations for oligoastrocytoma (HR, 1.74; 95% CI, 1.20-2.53) and malignant glioma not otherwise specified (NOS) (HR, 1.42; 95% CI, 1.16-1.76, but not with diffuse astrocytoma (WHO grades II and III) or oligodendroglioma.This epidemiologic study consolidates height as a risk factor for GBM and other gliomas. It further indicates that this association is not universal for gliomas but may differ between different glioma subgroups.
Poly-(amidoamine) dendrimers with a precisely core positioned sulforhodamine B molecule for comparative biological tracing and profiling
Authors: Lin-Ping Wu, Mario Ficker, Søren L. Mejlsøe, Arnaldur Hall, Valentina Paolucci, Jørn B. Christensen, Panagiotis N. Trohopoulos, Seyed M. Moghimi
Journal: Journal of Controlled Release (2016)
Immune Reconstitution after Adoptive Infusion of BPX501 Cells (donor T cells transduced with iC9 suicide gene) in Children Given Alpha/Beta T-Cell Depleted HLA-Haploidentical Hematopoietic Stem Cell Transplantation (haplo-HSCT): Preliminary Phenotypic and Functional Results of a Phase I-II Trial
Authors: Pietro Merli, Giuseppina Li Pira, Valentina Bertaina, Matilde Sinibaldi, Barbarella Lucarelli, Letizia Pomponia Brescia, Giuseppe Palumbo, Giuseppe Maria Milano, Maria Teresa Romano, Valentina Cirillo, Luisa Strocchio, Irma Airoldi, Luciana Vinti, Concetta Quintarelli, Lorenzo Moretta, Annemarie Moseley, Alice Bertaina, Franco Locatelli
Journal: Blood (2015)
Abstract 3193: Expression analysis reveals candidate genes involved in highly invasive high-hyaluronan binding subpopulations of prostate cancer cell lines
Authors: Sean J. Leith, Ann F. Chambers, James B. McCarthy, Joseph L. Chin, Eva A. Turley
Journal: Cancer Research (2015)

Abstract Tumour heterogeneity is one of the hallmarks of aggressive cancers, which can be detected by differential gene expression, DNA mutation patterns, and ligand binding profiles. Hyaluronan (HA) is an extracellular matrix polysaccharide whose elevated accumulation is associated with tumour recurrence in colon and breast carcinomas. Previously, we reported that triple-negative breast cancer cell lines exhibit heterogeneous binding of HA, with high and low binding subpopulations showing differences in proliferation and invasion. Here we assessed whether or not a similar binding heterogeneity detects prostate cancer cell subsets with differential invasive capability. Flow cytometry HA-binding profiles reveal heterogeneous binding of a fluorescent HA probe to the PC3M-LN4 prostate cancer cell line. Fluorescence-activated cell sorting (FACS) was used to isolate low and high hyaluronan binding subpopulations. Sorted cells were cultured and, after one week of growth, were analyzed for cell proliferation and invasion using alamar blue, transwell invasion and gelatin degradation assays. Results confirmed that HAhigh tumor cells displayed reduced growth but increased invasion and degradation relative to HAlow subpopulations. We then employed human gene 2.0 expression arrays to assess transcriptome changes between these two subpopulations. The expression of 7 genes was significantly elevated or lowered in HAhigh vs. HAlow cells, and these were linked to inflammation, angiogenesis, MMP9 regulation and metastasis. These results identify a novel form of heterogeneity common to both breast and prostate cancer cell lines and suggest that subpopulations binding high levels of HA can be used as indicators of aggressive tumors. Citation Format: Sean J. Leith, Ann F. Chambers, James B. McCarthy, Joseph L. Chin, Eva A. Turley. Expression analysis reveals candidate genes involved in highly invasive high-hyaluronan binding subpopulations of prostate cancer cell lines. [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 3193. doi:10.1158/1538-7445.AM2015-3193
Chromosomal Aberrations in Brazilian Patients with Hematopoietic and Lymphoid Disorders - Consecutive Analysis of 1.052 Karyotypes
Authors: Renata K Kishimoto, Daniela Borri, Andrea Barreto Castro, Priscila Ferreira Fernandes, Claudia IEC Fabris, Daniel Aquilino Oliveira, Cristina Alonso Ratis, Santos Fernanda Mauren, Silvia Helena Figueira, Elvira RP Velloso
Journal: Blood (2012)
Optimizing personalized treatment of oral mucositis secondary to cancer therapy through systems biology.
Authors: R. Srivastava, J. R. White, R. V. Lalla, L. M. Loew, D. E. Peterson
Journal: Journal of Clinical Oncology (2011)

e19690 Background: Oral mucositis (OM) can result in clinically significant adverse outcomes that require high resource utilization. Clinical trials for mucositis drug development have typically incorporated a cohort-based methodology. However, patients vary considerably in risk and severity of OM. In addition, the modeling for OM pathobiology is complex and includes up-regulation of NF-kB and TNF-a. We therefore tested the hypothesis that an individual patient-oriented systems biology approach to mucositis management will maximize treatment efficacy, while reducing drug dosage. Methods: A mathematical model of the biomolecular reaction network describing the dynamics of NF-kB and TNF-a up-regulation was developed using data derived from published studies. To represent inter-subject variation, 10,000 in silico subjects were generated, with the reaction rate constants of each being randomly distributed by up to ± 30% relative to a pre-specified base-case. OM treatment was optimized using a genetic algorithm designed to down-regulate TNF-a levels to a pre-determined level using the minimum possible drug dosage. Two in silico subjects who deviated from average cohort behavior were randomly selected for comparison. Results: When optimized for the individual, required drug dosage for the first in silico subject was 20% of the cohort-optimized dosage on average. However, TNF-a levels for the individual were maintained within 5% of the average case. The optimal drug treatment for the second subject consisted of the maximum allowable drug dosage, representing a 10-fold increase versus the cohort-optimized case. Even with maximum drug dosage, TNF-a levels were at least 7.5-fold higher than the average case. In all cases, NF-kB dynamic behavior reflected that seen for TNF-a. Conclusions: Individually-optimized OM treatment may improve therapeutic efficacy in selected patients, while limiting drug dosage and associated side-effects. Supported by NIH Career Development Award K23DE016946 and NIH grant P41RR013186.