tbuckley/cabot-search huggingface dataset:
Abstract 2891: Chemokine-targeted models of human orthotopic colorectal cancer in immunocompetant mice
Authors: Steven M. Lipkin, Huanhuan Joyce Chen, Jian Sun, Zhiliang Huang, Harry Hou, Myra Arcilla, Nikolai Rakhilin, Daniel Joe, Jiahn Choi, Poornima Gadamsetty, Jeff Milsom, Govind Nandakumar, Randy Longman, Kathy Zhou, Robert Edwards, Kai Yuan Chen, Pengcheng Bu, Lihua Wang, Yitian Xu, Robert Munroe, Christian Abratte, Andrew Miller, Zeynep Gümüş, Michael Shuler, Nozomi Nishimura, Winfried Edelmann, Xiling Shen
Journal: Cancer Research (2015)

Abstract Colorectal cancer (CRC) is a leading cause of cancer death. Current human CRC orthotopic xenograft models require survival surgery and do not robustly form tumors in liver, the most common site of metastasis in patients. Here, we use chemokine-targeting to develop cell line and primary patient-derived xenograft models that recapitulate the vast majority of common human somatic CRC mutations as primary gastrointestinal (GI) tumors in mice without requiring surgery. Importantly, we utilize early-stage mouse blastocyst microinjection techniques to extend this approach and model primary human CRCs in immunoproficient mouse hosts. Next, we show that primary GI tumors can inducibly and robustly metastasize to liver. Finally, we demonstrate that human CRC liver metastases in vivo have higher levels of DKK4 and NOTCH signaling and are more chemoresistant than paired sub-cutaneous xenografts. Overall, we anticipate that this experimental system can help improve our mechanistic understanding of human primary CRC progression to liver metastasis, and augment sub-cutaneous xenografts for pre-clinical drug screening. Citation Format: Steven M. Lipkin, Huanhuan Joyce Chen, Jian Sun, Zhiliang Huang, Harry Hou, Myra Arcilla, Nikolai Rakhilin, Daniel Joe, Jiahn Choi, Poornima Gadamsetty, Jeff Milsom, Govind Nandakumar, Randy Longman, Kathy Zhou, Robert Edwards, Kai Yuan Chen, Pengcheng Bu, Lihua Wang, Yitian Xu, Robert Munroe, Christian Abratte, Andrew Miller, Zeynep Gümüş, Michael Shuler, Nozomi Nishimura, Winfried Edelmann, Xiling Shen. Chemokine-targeted models of human orthotopic colorectal cancer in immunocompetant mice. [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 2891. doi:10.1158/1538-7445.AM2015-2891
659. Precision Genome Engineering in Human Induced Pluripotent Stem Cells Using CRISPR/CAS9
Authors: Jon P. Connelly, Amber M. Neilson, Sam T. Peters, Rita Martinez, Jeffrey D. Milbrandt, Shondra M. Miller
Journal: Molecular Therapy (2015)

Site-specific nucleases are engineered to create a double-stranded DNA break at a defined genomic locus. Subsequent repair of these DNA breaks by the cellular endogenous DNA repair pathways can then be exploited to create genetically modified cell lines. Genes can be knocked out, disease relevant mutations introduced, or proteins can be tagged for subsequent monitoring in differentiation assays and high throughput small molecule screens. Human induced pluripotent stem cells (iPSCs) have the potential to differentiate into any somatic cell in the body. Importantly, they can be derived from both normal individuals, as well as from patients. The combination of these two technologies allows investigators to create custom modified cell lines harboring site specific genetic changes of interest relevant to their field of study. Here, we present two examples of precise and efficient genome editing without the use of antibiotic selection using the CRISPR/Cas9 system in iPSCs. First we demonstrate the steps involved in the creation of a knockout (SARM1) iPSC line. Second, we outline the workflow for creating a custom iPSC line that has been tagged with a fluorescent protein at the endogenous locus (CHAT).
414. CAR Spacers Including NGFR Domains Allow Efficient T-Cell Tracking and Mediate Superior Antitumor Effects
Authors: Monica Casucci, Laura Falcone, Barbara Camisa, Chiara Bonini, Attilio Bondanza
Journal: Molecular Therapy (2015)

Chimeric antigen receptors (CARs) frequently include an IgG1-CH2CH3 spacer conferring optimal flexibility for antigen engagement and allowing the selection and tracking of CAR-expressing T cells. A serious drawback of CH2CH3-spaced CARs is however their interaction with Fcγ receptors (FcgRs). Indeed, this antigen-independent binding may lead to the unintended elimination of cells expressing these receptors (mainly phagocytes), foster the development of non-specific immune reactions and drastically decrease the efficacy of the strategy due to the premature clearance of transduced T cells in vivo.
Clinical Features and Prognosis of Patients with Myelodysplastic/Myeloproliferative Syndrome-Unclassified (MDS/MPD-U): Refractory Anemia with Ringed Sideroblasts with Thrombocytosis (RARS-T) Is a Favorable Prognostic Subgroup.
Authors: Ehab Atallah, Hagop Kantarjian, Jorge Cortes, Sherry Pierce, Elihu Estey, Guillermo Garcia-Manero, Deborah Thomas, Farhad Ravandi-Kashani, Francis Giles, Srdan Verstovsek
Journal: Blood (2006)
Abstract 1126: Differential effects of metformin and phenformin vs. other complex 1 inhibitors in vitro and in vivo
Authors: Carolyn Algire, Alexander Ehrmann, Sven Christian, Roland Neuhaus, Stephan Menz, Wolfgang Schwede, Michael Haerter, Andrea Haegebarth
Journal: Cancer Research (2015)

Abstract Biguanides, such as metformin and phenformin, are currently under investigation for their potential use as anti-neoplastic therapy. Recent publications suggest that both metformin and phenformin exert effects through inhibition of Complex 1 in the electron transport chain. We investigated the effects of metformin and phenformin compared to rotenone, in vitro, and known Complex 1 inhibitor BAY 872243, in vitro and in vivo. As expected, rotenone and BAY 872243 showed strong inhibition of Complex I in cell-based and enzymatic assays with IC50 values in the nanomolar range. The high affinity binding to Complex I was also reflected by induction of cellular reactive oxygen species (ROS) with EC50 values in the nanomolar range. In contrast, the biguanides neither inhibited Complex I in cell-based and biochemical assays, nor led to an induction of ROS at concentrations up to 300 μM. In vivo exposure analysis shows that at the maximal tolerated dose (100 mg/kg QD i.p for phenformin and 350 mg/kg i.p QD for metformin), neither metformin nor phenformin had plasma exposure levels over the IC50 for proliferation in vitro. Recent reports have suggested that biguanides, via the inhibition of Complex 1 and subsequent reduction in oxygen consumption, can be used to re-oxygenate tumor areas prior to radiation therapy. Pimonidazole staining demonstrated that metformin and phenformin effectively eliminated hypoxic regions in NCI-H460 xenografts in a time course dependent manner that reflected the exposure. In contrast to the biguanides, BAY 87-2243 effectively eliminated hypoxic regions up to 24 hours post compound administration. Finally, both phenformin and metformin had minimal effects on inhibition of tumor growth, even in LKB1-deleted xenografts which have been reported to be especially sensitive to biguanides. In conclusion, our in vitro experiments on the mode of action of biguanides raise questions as whether the in vivo effects on hypoxic tumor regions are related to direct inhibition of Complex I. Citation Format: Carolyn Algire, Alexander Ehrmann, Sven Christian, Roland Neuhaus, Stephan Menz, Wolfgang Schwede, Michael Haerter, Andrea Haegebarth. Differential effects of metformin and phenformin vs. other complex 1 inhibitors in vitro and in vivo. [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 1126. doi:10.1158/1538-7445.AM2015-1126
Progressive Chromatin Repression and Promoter Methylation of a-catenin Correlates with AML Transformation in Patients with and without 5q Deletions.
Authors: Michael McDevitt, Ying Ye, Mingzhou Guo, Hetty E. Carraway, Oliver Galm, Judith E. Karp, Steven D. Gore, Jaroslaw Maciejewski, Jeanne Kowalski, Xiao-Fei Wang, B. Douglas Smith, James G. Herman
Journal: Blood (2008)
Abstract 5093: Pre-clinical assessment of a novel anti-invasion nanoparticle therapeutic in combination with bevacizumab for the treatment of glioblastoma
Authors: David W. Murray, Philip O'Halloran, Monika Jarzabek, Brian MacCarthy, Jann N. Sarkaria, Raymond M. Schiffelers, Marc Symons, Annette T. Byrne
Journal: Cancer Research (2015)

Abstract Glioblastoma (GBM), a highly invasive primary brain tumour, remains an incurable disease (1). Angiogenesis, the formation of new blood vessels, is a defining feature of GBM (2). Targeting GBM angiogenesis with Bevacizumab (Bev) is associated with improved progression free survival, but may also significantly enhance local tumour invasion (3). RhoGTPases and their activators, guanine nucleotide exchange factors (GEFs), play central roles in the invasive process (4). Herein, we sought to identify and target GEFs of importance in meditating GBM invasion with a view to improving Bev response. We report a novel strategy by which GBM tumours invade and proliferate via overexpression of the GEF beta-PIX which was shown to be increased at the invasive edge in 74% of GBM tumours assessed (n = 19) compared with tumour core (5). We have further shown that siRNA-mediated knockdown of beta-PIX in GBM patient-derived xenograft cell cultures and cell lines resulted in decreased cell invasion in 3D, cell proliferation and survival assays in vitro. Furthermore, we have uncovered a role for beta-PIX expression in endothelial cell function, as knockdown of beta-PIX inhibits HUVEC cell migration in vitro. To interrogate in vivo effects, we established an imagable orthotopic model of invasive GBM in mice, by stereotactically implanting GBM cells stably overexpressing firefly luciferase (U87R-GFP-luc2). beta-PIX-(human and mouse) specific siRNA or scrambled control siRNA (2 × 10 μg i.c.) were delivered to tumours using an alphaVbeta3 integrin targeting-(RGD peptide conjugated)-nanoparticle (InVivoPlex Aparna Bio Corp, Rockville, MD). Animals were treated with- or without- Bev (6 × 10mg/kg i.p. over 12 days). Initial data has shown that animals treated with beta-PIX siRNA nanoparticles in combination with Bev had an improved median survival of 100 days compared with Bev- alone treated mice (median: 88 days). Our data may support the future clinical use of a beta-PIX-targeting nanoparticle therapeutic, to improve Bev outcomes in GBM. 1. Kohler BA et al J Natl Cancer Inst. 2011; 103, 714-736 2. Jain RK et al Nat Rev Neurosci. 2007; 8(8):610-22 3. Norden AD et al Neurology 2008; 70: 779-787 4. Murray D et al Brit J Can 2014; 110(5):1307-15 5. Hoelzinger DB et al Neoplasia 2005; 7(1): 7-16 Citation Format: David W. Murray, Philip O'Halloran, Monika Jarzabek, Brian MacCarthy, Jann N. Sarkaria, Raymond M. Schiffelers, Marc Symons, Annette T. Byrne. Pre-clinical assessment of a novel anti-invasion nanoparticle therapeutic in combination with bevacizumab for the treatment of glioblastoma. [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 5093. doi:10.1158/1538-7445.AM2015-5093
Novel Deletion Mutants in the Juxtamembrane Domain of Fms-like Tyrosine Kinase 3 (FLT3) Induce Transformation By Release from Autoinhibition in AML
Authors: Nicolas Chatain, Janine Rossa, Giulia Rossetti, Rodrigo Casasnovas Perera, Paolo Carloni, Torsten Haferlach, Tim H. Brümmendorf, Susanne Schnittger, Steffen Koschmieder
Journal: Blood (2014)
Wnt/β-Catenin Signaling Is Essential for the Transdifferentiation of Monocytes into Endothelial Cells by mCSF and Pleiotrophin.
Authors: Haiming Chen, Mingjie Li, Richard Campbell, Cathy S. Wang, Jennifer Li, Eric Sanchez, Jeffrey Steinberg, Michael Share, Dror Shalitin, James Wang, Shi-Jason Xie, Yunchao Chang, Benjamin Bonavida, Thomas F. Deuel, James R. Berenson
Journal: Blood (2007)
Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199)
Authors: V M Patel, K Balakrishnan, M Douglas, T Tibbitts, E Y Xu, J L Kutok, M Ayers, A Sarkar, R Guerrieri, W G Wierda, S O'Brien, N Jain, H M Stern, V Gandhi
Journal: Leukemia (2016)
Phase I study of everolimus (E; RAD001) + low-dose weekly cisplatin (C) for patients with advanced solid tumors: Preliminary results
Authors: M. G. Fury, E. Sherman, H. Stambuk, S. Haque, D. Lisa, R. Shen, D. Carlson, D. G. Pfister
Journal: Journal of Clinical Oncology (2009)

e14527 Background: Preclinical studies demonstrate synergistic anti-tumor activity with the combination of E + C. Methods: Patients received E per oral for days 1–21 of a 28 day cycle. E was dose escalated though 4 planned dose levels (DLs): 2.5 mg/day, 5 mg/day, 7.5 mg/day, and 10 mg/day. Cisplatin dose was fixed at 20 mg/m 2 intravenously on days 1, 8, 15. A standard 3 + 3 dose escalation scheme was used. Blood samples for pharmacokinetics were collected on Day 1 and Day 8 of Cycle 1. Response was assessed by RECIST after 2 cycles. Results: 24 patients enrolled: 13 M, 11F; median age 62 (32–77); median number of prior cytotoxic chemotherapy regimens 1 (0–3; 75% with prior RT). At DL1, 3 patients were inevaluable (1 withdrawal of consent prior to treatment, 1 disease progression during cycle 1, 1 recurrent diverticulitis during cycle 1) and were replaced. DL 1 was expanded after a patient with melanoma metastatic to liver had sudden death of unclear cause, and the protocol was amended to exclude patients with hepatic dysfunction. At DL2, one patient experienced grade 3 small bowel obstruction of uncertain etiology, and the dose level was expanded to 6 evaluable patients without additional DLT. No DLTs occurred at DL3. No DLTs have occurred to date among 6 patients enrolled at DL 4. Adverse events per cycle (total n = 63 cycles; 20 patients evaluable for toxicity) include: lymphopenia G3 (19%), AST G3 (3.2%), alkaline phosphatase G3 (3.2%), ALT G3 (1.6%), hyponatremia (1.6%). Median cycles per patient, 2 (range &lt;1 to 10+). Minor response seen in pulmonary carcinoid (n = 1); prolonged SD ≥ 6 cycles seen in pulmonary carcinoid (n=2), basal cell carcinoma (n=1), and esthesioneuroblastoma (n=1). Conclusions: Pending safety analysis at the final planned dose level, the phase II recommended dose is E 10 mg/day (days 1 - 21) + C 20 mg/m 2 (days 1, 8, and 15) on a 28-day cycle. [Table: see text]
The determinants of internet use for health information among patients with breast cancer: Cross-sectional data from 2007 to 2010.
Authors: H. Pfaff, L. Ansmann, E. Kahana, C. Kowalski
Journal: Journal of Clinical Oncology (2011)

e19678 Background: The number of people with access to the Internet and who actually use it to obtain health information is continuously on the rise. Gynecologists must, therefore, adapt their practice to these changing circumstances. However, there is still virtually no data available on the determinants of patient Internet use. This study aims to determine the percentage of breast cancer patients using the Internet for health information and to ascertain which socio-demographic and disease characteristics are associated with this use. Methods: The study population consisted of female patients with primary breast cancer who had undergone surgery in one of the breast centers in the German state of North Rhine-Westphalia between February and July of the years 2007 to 2010. Patients from the four cohorts were surveyed postoperatively by mail using the Cologne Patient Questionnaire for Breast Cancer (CPQ-BC). Of the patients who consented to participating in the survey (consent rate: 90 %), an average of 88 % responded to the questionnaire. The total sample size for the study in 2007 to 2010 was N = 14,923. Frequency and logistic regression analyses were used for statistical analysis. Results: Over the three years of the study, there was an increase in the percentage of breast cancer patients using the Internet to obtain information on their condition (2007: 30.9%; 2008: 32.7%; 2009: 34.3%; 2010: 37.2%). Significant differences were found in the correlations between the different age and social status groups and Internet use. Older patients, patients with lower levels of formal education, patients without a partner, and patients without private medical insurance are significantly less likely to search for health information online. Conclusions: One-third of breast cancer patients in the sample use the Internet to obtain information on their condition, and this number is rising. Patient Internet use is associated with age, education, and insurance status in all four cohorts.
633. Reconstruction of Vascularized Subcutaneous Liver Tissue for Minimally Invasive Cell Therapy
Authors: Yusuke Sakai, Makiko Koike, Kosho Yamanouchi, Akihiko Soyama, Masaaki Hidaka, Mitsuhisa Takatsuki, Tamotsu Kuroki, Susumu Eguchi
Journal: Molecular Therapy (2015)

Subcutaneous liver tissue construction is an attractive and minimally invasive approach used to overcome the chronic shortage of donor livers for the curative treatment of hepatic failure. However, graft failure occurs frequently due to lack of blood vessels. In this study, we describe a subcutaneous human liver reconstruction approach allowing for rapidly vascularized grafts by transplanting engineered hepatocyte/fibroblast sheets (EHFSs). Human primary hepatocytes were isolated and purified from surgically resected human liver tissues by the collagenase perfusion method. EHFSs were fabricated using temperature-responsive culture dishes (TRCDs) (UpCell; CellSeed, Tokyo). The hepatocytes were plated onto a confluent layer of normal human dermal fibroblasts (TIG-118 cells). After 4 days in culture, EHFSs were harvested and transplanted subcutaneously into immunodeficient mice. The expression levels of angiogenic factors in vitro, liver-specific functions and structures in vivo, and therapeutic potential of serious liver diseases were evaluated. EHFSs exhibited significantly higher synthesis rates of VEGF, TGF-b1, and HGF than the hepatocyte-only sheets (HSs) from 1 to 3 days in culture. This result indicate the possibility of using a one-step subcutaneous hepatocyte transplantation procedure without a pre-transplant vascularization step such as implanting a FGF-releasing device. The transplanted EHFSs were laminated and formed a vascularized subcutaneous human liver tissues (VSLTs). The VSLTs had liver-specific features such as glycogen stores and albumin, A1AT, and coagulation factor IX syntheses. The aggregated hepatocytes formed several linear structures. Furthermore, subacute hepatic failure model mice (TK-NOG mice) with VSLT were alive at least 7 weeks after liver damage. The present study describes a new approach for vascularized human liver organogenesis under mouse skin. This approach could prove valuable for establishing novel minimally invasive cell therapies for liver diseases.
"Post-Pulmonary Embolism Syndrome" after a First Episode of PE: Results of the E.L.O.P.E. Study
Authors: Susan R Kahn, Andrew Hirsch, Margaret Beddaoui, Arash Akaberi, David Anderson, Philip S Wells, Marc Rodger, Susan Solymoss, Michael J. Kovacs, Lawrence Rudski, Avi Shimony, Carole Dennie, Chris Rush, William H. Geerts, Paul Hernandez, Shawn Aaron, John T Granton
Journal: Blood (2015)
Abstract 1804: The role of adipose derived stromal cells for reversal of radiation fibrosis
Authors: Xiao Zhao, Ju Hee Lee, Kenneth Yip, Laurie Ailles, Fei-Fei Liu
Journal: Cancer Research (2015)

Abstract Hypothesis: Up to 70% of patients after radiotherapy develop radiation fibrosis (RF), an irreversible scarring of normal tissue resulting in functional morbidity and increased risk of surgical complications. Adipose-derived stromal cells (ADSCs) have been used effectively for the treatment of complex wounds in animal models and clinical trials. We hypothesize that ADSCs may reverse RF by repopulating mesenchymal precursor cells and by providing angiogenic, anti-inflammatory, and matrix remodeling factors. Methods: A RF animal model was developed and ADSC isolation was confirmed by immunophenotype and differentiation assay. GFP and luciferase labelled ADSCs were used to assess biodistribution after transplantation. To determine the therapeutic effect of ADSC transplantation for RF, we assessed functional changes to leg contracture, oxygen saturation and perfusion and molecular changes to inflammation, vascularization, and matrix remodeling. To determine the mechanism of ADSC-mediated fibrosis reversal, we assessed transcriptomic and epigenetic changes to RF tissue. Results: A RF model was created by radiating the hind limb of C3H mice. This model showed a dose dependent leg contracture and histological findings of fibrosis. We confirmed the immunophenotype of isolated ADSC and their ability to differentiate into adipogenic, chondrogenic, and osteogenic lineages. ADSC transplantation showed a statistically significant trend towards improved leg contracture (2-way ANOVA, p&amp;lt;0.05). Biodistribution studies confirmed the presence of ADSCs in the subdermis of RF tissue with persistence for at least 18 days post-transplantation. Preliminary RNA-seq analysis using unsupervised hierarchical clustering showed ADSC treated radiation tissue was more similar to normal tissue than control. In depth RNA-seq data analysis is underway. Conclusions: ADSC transplantation may be an effective treatment for the reversal of radiation fibrosis. As cancer survivorship increases, the prevalence of radiation fibrosis will rise and necessitate increased focus on effective treatment strategies for this condition. Citation Format: Xiao Zhao, Ju Hee Lee, Kenneth Yip, Laurie Ailles, Fei-Fei Liu. The role of adipose derived stromal cells for reversal of radiation fibrosis. [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 1804. doi:10.1158/1538-7445.AM2015-1804