tbuckley/cabot-search huggingface dataset:
Abstract 152: The long non-coding RNA HOTAIR affects exosome-mediated bladder cancer progression
Authors: Claudia Berrondo, Jonathan Flax, Edward M. Messing, Carla Beckham
Journal: Cancer Research (2015)

Abstract Exosomes are 30-100nM membrane-bound vesicles that participate in intercellular communication and facilitate tumor microenvironments. The mechanisms by which exosomes modify tumor niches are not fully understood. One possibility is that exosomes deliver biologically active molecules like mRNA, protein, miRNA and long non coding RNA (lncRNA) that alter the metabolism of recipient cells to produce pathological phenotypes. Exosomes may also activate the expression of genes involved in tumor progression in recipient cells. Overexpression of the lncRNA HOTAIR is associated with poor prognosis and affects tumor progression, in part, by recruiting PRC2 and LSD1 chromatin modifying complexes to thousands of target genes involved in tumor progression processes such as epithelial-to-mesenchyme transition (EMT). We show that HOTAIR is enriched in bladder cancer (BC) patient tumors and urinary exosomes. BC cell lines also express elevated levels of HOTAIR. Knockdown of HOTAIR in BC cell lines significantly reduces migration and invasion in trans-well and 3D culture, which correlates with EMT gene expression changes in these cells. Exosomes isolated from shHOTAIR vs shScramble cells fail to facilitate migration and invasion in 3D culture of a recipient BC cell line. Selected bands were isolated from a coomassie gel of shHOTAIR and shScramble exosomes and sent for mass spectrometry. Hundreds of putative proteins were identified including proteins involved in RNA binding, apoptosis, vesicle trafficking and integrins. These data support HOTAIR as an important player in exosome-mediated BC tumor progression possibly through affects on gene expression in exosome producer cells. For example, in shHOTAIR cells the loss of PRC2 and/or LSD1 complexes from key genes may ultimately affect the proteins available for packaging into exosomes. Exosomes have important roles in the tumor microenvironment and these data support a role for HOTAIR in the modulation of exosome-mediated tumor progression. Citation Format: Claudia Berrondo, Jonathan Flax, Edward M. Messing, Carla Beckham. The long non-coding RNA HOTAIR affects exosome-mediated bladder cancer progression. [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 152. doi:10.1158/1538-7445.AM2015-152
Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction
Authors: Carolyn S.P. Lam, Michiel Rienstra, Wan Ting Tay, Licette C.Y. Liu, Yoran M. Hummel, Peter van der Meer, Rudolf A. de Boer, Isabelle C. Van Gelder, Dirk J. van Veldhuisen, Adriaan A. Voors, Elke S. Hoendermis
Journal: JACC Heart Failure (2016)
P08.47 Dianhydrogalactitol (VAL-083) causes bifunctional alkylation leading to irreparable DNA double-strand breaks, S/G2 phase cell-cycle arrest and tumor cell death in an MGMT independent manner offering a unique treatment paradigm for GBM
Authors: B. Zhai, A. Steino, J. A. Bacha, D. M. Brown, M. Daugaard
Journal: Neuro-Oncology (2016)
Bleeding Events Before Coronary Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome
Authors: Björn Redfors, Ajay J. Kirtane, Stuart J. Pocock, Girma Minalu Ayele, Efthymios N. Deliargyris, Roxana Mehran, Gregg W. Stone, Philippe Généreux
Journal: Journal of the American College of Cardiology (2016)
Abstract 3366: The mechanical microenvironment and β1/FAK signaling control fibroblast accumulation in lung cancer
Authors: Jordi Alcaraz, Marta Gabasa, Óscar Busnadiego, Fernando Rodríguez-Pascual, Pere Gascón, Noemí Reguart
Journal: Cancer Research (2015)

Abstract There is growing interest in targeting the abnormal accumulation of fibroblasts in solid tumors. The current paradigm assumes that the abundance of tumor associated fibroblasts (TAFs) is largely driven by soluble growth factors as in generic repair responses irrespective of the tumor type or subtype. We recently challenged this assumption in cultured TAFs from two major subtupes of non-small cell lung cancer (NSCLC): adenocarcinoma (ADC) and squamous cell carcinoma (SQC). We reported that the increased population of SQC-TAFs is largely driven by matrix stiffening rather than by soluble growth factors. In contrast, ADC-TAFs were poorly responsive to exogenous mechanical cues. We also reported that the differential mechanoresponses in SQC- and ADC-TAFs were associated with both larger mechanosensing through FAK and β1 integrin expression in the former TAFs. To get more insights into the latter mechanoregulatory circuit, we forced either β1 integrin activation or FAK expression in fibroblasts cultured in soft (normal-like) gels. Both conditions were sufficient to increase fibroblast population to values comparable to those found in stiff (tumor-like) gels. These data reveal that an abnormally high intrinsic mechanosensing through β1 integrins and FAK can bypass the inhibitory (protective) role of an extrinsic soft microenvironment. Moreover, these results suggest that inhibiting either β1 integrin or FAK signaling may be a suitable approach to target tumor-supporting TAFs in SQC. Citation Format: Jordi Alcaraz, Marta Gabasa, Óscar Busnadiego, Fernando Rodríguez-Pascual, Pere Gascón, Noemí Reguart. The mechanical microenvironment and β1/FAK signaling control fibroblast accumulation in lung 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 3366. doi:10.1158/1538-7445.AM2015-3366
A Way to Individualized Therapy in Acute Myeloid Leukemia (AML): NGS Mutational Profile and Ex Vivo Pharmacological Test (Ex-viTech)
Authors: Esther Onecha, Joan Ballesteros, Jose L Rojas, Jose M Sanchez, Eva Barragan, Inmaculada Rapado, Santiago Barrio, David Martinez, Pau Montesinos, Pilar Herrera, Carmen Burgaleta, Joaquin Martinez-López, Rosa M. Ayala
Journal: Blood (2015)
Integrative, Multi-Platform, Whole-Genome Analyses Identify Clinically Relevant Common- and Cell-Specific Signatures in Multiple Myeloma
Authors: Jeanne Kowalski, Khanjan Gandhi, Jeffrey Switchenko, Yuan Liu, Sungjin Kim, Gregory Doho, Seung J Kim, Rendong Yang, Li Chen, Zhaohui Qin, Scott Newman, Carlos S Moreno, Paula M Vertino, Leon Bernal-Mizrachi, Michael R Rossi, Sagar Lonial, Lawrence H. Boise
Journal: Blood (2012)
Abstract 5031: A humanized mouse model for translational assessment of targeted immune checkpoint blockade
Authors: Gilson Baia, David Vasquez-Dunddel, Daniel Ciznadija, David Sidransky, Amanda Katz, Keren Paz
Journal: Cancer Research (2015)

Abstract The blockade of immune checkpoints is a promising therapeutic avenue for cancer therapy, with durable objective responses observed in patients with a variety of solid tumors. Despite these successes, current animal models do not reliably identify targets with the greatest clinical potential, due in part to differences between human and murine immune systems. Hence, robust preclinical tools to test these drugs directly against human cancers in the context of a human immune system are required. Champions Oncology has now developed the ImmunoGraft, whereby two innovative technologies, the patient-derived xenograft and humanized mice (immunodeficient mice reconstituted with a human immune system), are combined in a single platform. Immune-compromised NOG (PrkdcscidIl2rgtm1Sug) mice were reconstituted (humanized) with human CD34+ cells and twelve weeks after humanization, mature human CD45+ cells comprised close to 50% of the leukocytes detected in the circulation and secondary lymphoid tissues of the now humanized animals. Growth of NSCLC tumors implanted into humanized NOG animals was comparable to those in non-humanized counterparts, and when humanized animals harboring NSCLC tumor implants were treated with ipilimumab, tumor growth was slowed, exhibiting marked regression. Systemic immune activation was observed in humanized mice following treatment with ipilimumab, characterized by robust proliferation of huCD3+ T cells and activated huCD4+ Th1 cells, as well as an increase in tumor-infiltrating huCD8+ cytotoxic T lymphocytes (all relative to vehicle controls). We have developed an innovative new preclinical cancer model, the ImmunoGraft, which will enable novel immunotherapeutic agents to be accurately evaluated for efficacy against virtually any cancer indication that can be engrafted. As a proof-of-concept of the utility of the ImmunoGraft, we demonstrated how effectively ipilimumab restricted the growth of NSCLC implants engrafted in humanized animals. This translational platform is, therefore, more reflective of the human tumor microenvironment (both immune and non-immune cell-based) and is the most clinically-relevant model for screening immune system-targeting therapies, as single agents or in combination with standard-of-care drugs and other immuno-modulators. The ImmunoGraft has strong potential to revolutionize the application of immunotherapy to both personalized oncology and translational drug discovery. Citation Format: Gilson Baia, David Vasquez-Dunddel, Daniel Ciznadija, David Sidransky, Amanda Katz, Keren Paz. A humanized mouse model for translational assessment of targeted immune checkpoint blockade. [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 5031. doi:10.1158/1538-7445.AM2015-5031
Bioactive insulin-like growth factors as a possible molecular target for non-islet cell tumor hypoglycemia
Authors: Takashi Setoyama, Shin'ichi Miyamoto, Takahiro Horimatsu, Taro Funakoshi, Miutsuhiro Nikaido, Yuzo Kodama, Sachiko Minamiguchi, Tomoko Yamabata, Manabu Muto, Tsutomu Chiba
Journal: Annals of Oncology (2015)
Thrombin-activatable fibrinolysis inhibitor (TAFI) antigen levels and TAFI gene polymorphisms in patients with Budd-Chiari syndrome and portal vein thrombosis.
Authors: SD Murad, EL de Bruijne, MP de Maat, EB Haagsma, B van Hoek, FR Rosendaal, FW Leebeek
Journal: Hepatology (2004)
Ex Vivo Expanded HOXB4-Transduced Bone Marrow Cells Enhance Allogeneic Repopulation in a Sublethal Irradiation Model of BMT.
Authors: Mohan C. Vemuri, Cesare Campagnoli, Kirsten J. Beggs, Shuichi Ashizuka, Alan W. Flake
Journal: Blood (2004)
GENT-22. SINGLE-CELL PROFILING OF GLIOBLASTOMA BIOPSIES IDENTIFIES A FAMILY OF ACTIVATING PDGF-RECEPTOR DELETIONS
Authors: Soren Muller, Siyuan Liu, Martina Malatesta, Manish Aghi, Arnold Kriegstein, Gary Kohanbash, Daniel Lim, Aaron Diaz
Journal: Neuro-Oncology (2016)

Epidermal growth-factor (EGF) and platelet-derived growth-factor (PDGF) receptors are frequently amplified and/or possess gain-of-function mutations in glioblastoma. Despite years of research into tyrosine-kinase (RTK) inhibitors, clinical trials have shown disappointing efficacy. Subclonal acquisition of RTK mutations and regional RTK amplification provide a theoretical mechanism of resistance. To assess the effect of this intra-tumor heterogeneity on gene expression, we performed bulk exome sequencing and single-cell mRNA sequencing of fresh, surgical specimens from GBM patients. We derived a general approach to map single-cell expression profiles to sequentially-acquired mutations that were identified from exome sequencing. Based on this, we constructed high-resolution phylogenies of EGF-driven and PDGF-driven GBMs, modeling transcriptional kinetics during tumor evolution. Descending the phylogenetic tree of a proneural, PDGF-driven tumor corresponds to a progressive induction of an oligodendrocyte progenitor-like cell type. These cells harbor a deletion in a PDGF-receptor domain involved in dimerization, PDGFRAΔ. PDGFRAΔ transcripts are found in all cells expressing PDGFRA, and in roughly half of the cells it is the dominant PDGFRA variant. PDGFRAΔ correlates with an up-regulation of the PI3K/AKT pathway in patient-derived data, and ectopic expression of PDGFRAΔ in vitro enhances proliferation and invasiveness. PDGFRAΔ induces wild-type PDGFRA, as well as pro-invasive matrix metalloproteinases, growth-factor ligands and myeloid-derived suppressor-cell chemotactic factors not in the pathway of the wild-type receptor. Analysis of exome sequencing data from TCGA shows that PDGFRAΔ is one of a family of deletions targeting the PDGF-receptor’s dimerization domain. The most frequent of which occurs at 15.7% frequency in glioblastoma. Thus, PDGF-receptor deletions are a potential therapeutic target in glioblastoma.
136. First-in-Human Study of NS-065/NCNP-01; the Morpholino Based Antisense Oligonucleotide for Exon 53 Skipping in Duchenne Muscular Dystrophy
Authors: Takashi Saito, Tetsuya Nagata, Satoru Masuda, Maiko Suzuki, Harumasa Nakamura, Hirofumi Komaki, Shin'ichi Takeda
Journal: Molecular Therapy (2015)

Currently, phase 2/3 clinical trials of exon 51 skipping for Duchenne Muscular Dystrophy (DMD) are being conducted and have been shown promising results for NDA. Next to the patients treatable by exon 51 skipping, the patients amenable to exon 53 skipping are the second largest population; therefore a development of exon 53 skipping drug has high priority. National Center of Neurology and Psychiatry, with Kyoto-based pharmaceutical company Nippon Shinyaku, had jointly developed the exon 53 skipping drug since 2009 and started an investigator-initiated clinical trial from June 2013 (UMIN Clinical Trial ID: UMIN000010964, ClinicalTrial.gov: NCT02081625). The NS-065/NCNP-01 is a morpholino based antisense oligonucleotide that has been developed to skip the exon 53 of the dystrophin gene and to treat DMD patient amenable to the exon 53 skipping. It has been confirmed potent efficacy and high safety in pre-clinical studies. This clinical trial is an exploratory phase 1, single-site, first-in-human study. The primary endpoints are the safety and tolerability and the secondary endpoints are the pharmacokinetics and efficacies (dystrophin recovery). Three doses cohort design (1.25 mg/kg, 5 mg/kg and 20 mg/kg) was adopted and all subjects were dosed weekly intravenous infusion for 12 weeks. Mainly nonambulant subjects were recruited because the dose and duration in this trial was not enough to expect functional improvement. Of total 10 subjects, each three subjects were randomly assigned to 1.25 mg/kg or 5 mg/kg cohorts, and four subjects were assigned to 20 mg/kg cohort. An in vitro confirmation of dystrophin recovery and exon 53 skipping in subject-derived cells was one of inclusion criteria. Subject's mutations were classified into any of exons 45-52, 48-52 or 49-52 deletion; all NS-065/NCNP-01 treated cells satisfied the criteria. One week after an initial dosing for the first subject in each cohort, next subjects were dosed. Safety review committee advised the principal investigator whether or not to proceed to next cohort. At the end of 2014, dosing to all subjects had completed; no serious adverse events were observed. Dystrophin expression is to be evaluated by Western blotting and immunofluorescent staining. The analysis is still ongoing, but an immunofluorescent image analysis will be performed as objective and quantitative as possible by automated measurements. We would report progress of the first-in-human study of NS-065/NCNP-01; the morpholino based exon 53 skipping drug for DMD.
Structural Basis for MLL Cxxc Domain Protection against CpG DNA Methylation and the Essential Role of This Function in MLL-AF9 Leukemia.
Authors: Laurie Risner, Tomasz Cierpicki, Jolanta Grembecka, Stephen M Lukasik, Relja Popovic, David S Shultis, Nancy J. Zeleznik-Le, John H. Bushweller
Journal: Blood (2009)
Bendamustine Plus Rituximab Is Superior in Respect of Progression Free Survival and CR Rate When Compared to CHOP Plus Rituximab as First-Line Treatment of Patients with Advanced Follicular, Indolent, and Mantle Cell Lymphomas: Final Results of a Randomized Phase III Study of the StiL (Study Group Indolent Lymphomas, Germany).
Authors: Mathias J Rummel, Norbert Niederle, Georg Maschmeyer, Andre Banat, Ulrich von Gruenhagen, Christoph Losem, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Harald Ballo, Eckhart Weidmann, Heinz A Duerk, Dorothea Kofahl-Krause, Fritz Roller, Juergen Barth, Dieter Hoelzer, Axel Hinke, Wolfram Brugger
Journal: Blood (2009)
Abstract 3474: The effect of forced expression of k-ras mutation on gastrointestinal cancer cells and IGF-IR targeting therapy
Authors: Yasushi Adachi, Yasutaka Matsunaga, Yasushi Sasaki, Katsuhiko Nosho, Hiroyuki Yamamoto, Yoshiaki Arimura, Takao Endo, Yasuo Kato, Takashi Tokino, David P. Carbone, Yasuhisa Shinomura
Journal: Cancer Research (2015)

Abstract Background &amp; Aims: Mutation in k-ras plays important roles in both the progression and the resistance for anti-EGFR therapy in gastrointestinal tumors. Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of many tumors. We have previously shown successful therapy for gastrointestinal cancer cell lines with k-ras mutation using recombinant adenoviruses expressing dominant negative IGF-IR (IGF-IR/dn) and an anti-IGF-IR monoclonal antibody. In this study, we sought to evaluate the effect of k-ras mutation on gastrointestinal cancer cell lines and IGF-IR targeting therapies for those cells. Methods: We made stable transfectants of mutated k-ras in gastrointestinal cancer cell lines. We assessed the effect of forced expression of mutated k-ras on proliferartion, apoptosis induction, migration, and invasion in gastrointestinal cancer cell lines. Then we assessed the anti-tumor effect of IGF-IR/dn on mutated k-ras transfctomas. Results: Overexpression of mutated k-ras let gastrointestinal cancer cell lines be more agrressive phenotypes, such as more proliferative, more anti-apoptotic, more movable, and more invasive. IGF-IR/dn inhibited cell growth, colony formation, migration, and invasion, but induceed apoptosis of gastrointestinal cancer cells with or without mutated k-ras expression. Conclusions: K-ras mutation might be inportant for progressive phonotype in gastrointestinal cancers. IGF-IR might be a good molecular therapeutic target for gastrointestinal cancers even if k-ras is mutated. Citation Format: Yasushi Adachi, Yasutaka Matsunaga, Yasushi Sasaki, Katsuhiko Nosho, Hiroyuki Yamamoto, Yoshiaki Arimura, Takao Endo, Yasuo Kato, Takashi Tokino, David P. Carbone, Yasuhisa Shinomura. The effect of forced expression of k-ras mutation on gastrointestinal cancer cells and IGF-IR targeting therapy. [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 3474. doi:10.1158/1538-7445.AM2015-3474
234. Hydrodynamic Cell Delivery for Assessment of Tumor Growth and Drug Sensitivity in Different Organs and Microenvironment
Authors: Mohammad H. Alsaggar, Qian Yao, Dexi Liu
Journal: Molecular Therapy (2015)

Tumor metastasis often confers poor prognosis for cancer patients because successful treatment of metastatic tumors remains as an unmet need in clinic. Currently used subcutaneous and orthotopic models have failed to truly recapitulate metastatic tumor biology, particularly tumor-stroma interactions within tumor microenvironment in different organs. This certainly accounts for insufficient therapeutic outcomes of current antimetastatic therapies that were designed assuming metastatic tumors behave the same in all organs. Therefore, relevant tumor models are urgently needed for reliable anticancer drug screening and development, and assessment of tumor-environment interactions in different metastatic sites. Toward this end, we have developed a multi-organ tumor growth model using hydrodynamic cell delivery method to establish simultaneous growth in liver, lung and kidney in mice by hydrodynamic tail vein injection of cell suspension. We hypothesized that tumors growing in different organs are biologically heterogeneous in growth characters, as well as in tumor response to a given anti-cancer therapy. Using luciferase-expressing murine melanoma cells that can be quantified by luciferase assay, our results showed that the liver is the primary organ to be seeded with tumor cells upon hydrodynamic injection, with 35% of tumor cells in liver, 21% in the lungs, and 8% in kidneys. Growth rate assessment revealed that liver microenvironment was the most supportive to melanoma tumor growth compared to lungs and kidneys; where tumors grew minimally at early phase, and aggressively thereafter. Tumors in different organs were also heterogeneous in tumor response to chemotherapy and immune gene therapy using dacarbazine and interferon beta gene, respectively. While lung tumors responded to chemotherapy better than tumors in liver, lung tumors showed minimal response to interferon beta, with around 25% tumor suppression in lung, compared to more than 80% in liver and kidneys. On the other hand, tumors in liver showed superior response to interferon beta compared to dacarbazine (81% vs 45% suppression). Differential behavior of metastatic tumors was also confirmed using metastatic colon cancer model established in different organs. These results point out the increasing need for better understanding of differences in tumor microenvironment in different organs, as it greatly determines therapeutic outcomes of antimetastatic therapies. Moreover, the biological heterogeneity of metastatic tumors necessitates precluding of "one size fits all" therapies, and rethinking of organ-specific therapies and combined treatments to act globally on metastatic tumors in different organs.
Individualized Pazopanib Dosing—Letter
Authors: Olivier Mir, Sophie Broutin, Audrey Perret, Axel Le Cesne, Angelo Paci
Journal: Clinical Cancer Research (2016)

We have read with interest the recent article by Verheijen and colleagues ([1][1]) reporting the feasibility of the individualization of pazopanib dosing, based on therapeutic drug monitoring of steady-state trough plasma concentrations ( C ss trough). The authors should be congratulated for this
PET MRI Coregistration in Intractable Epilepsy and Gray Matter Heterotopia
Authors: Nikhil Seniaray, Anuj Jain
Journal: Clinical Nuclear Medicine (2016)

A 25-year-old woman with intractable seizures underwent FDG PET/MRI for seizure focus localization. MRI demonstrated bilateral carpetlike nodular subependymal gray matter and asymmetrical focal dilatation in the right temporal horn. PET/MRI showed increased FDG within subependymal gray matter with significant hypometabolism in right anterior temporal lobe. EEG and ictal semiology confirmed the right temporal seizure origin. This case highlights the importance of identification of gray matter heterotopia on FDG PET/MRI.