tbuckley/cabot-search huggingface dataset:
Abstract 4756: Genomic profile of AML-ETO rearranged acute myeloid leukemia
Authors: Youngil Koh, Dae-Yoon Kim, Jong-Kwang Kim, Yeun-June Chung, Sung-Soo Yoon, Hyung-Lae Kim
Journal: Cancer Research (2015)

Abstract Introduction Although it is well known that core-binding factor(CBF) acute myeloid leukemia(AML) harbors good prognosis, some patients with CBF-AML have dismal outcome. In this study, we tried to find out genomic alterations in CBF-AML so as to find genetic changes that determine prognosis of CBF-AML. Materials and methods We performed whole genome sequencing (WGS) of 9 AML-ETO rearranged AML patients. For whole genome sequencing, we used Hiseq 2000 (Illumina, SanDiego, CA, USA). Single nucleotide variant (SNV) calling was performed using 4 different callers. Structural variant calling was performed using three different callers. Results Among 9 patients, two patients had excellent prognosis, while 3 patients showed unfavorable outcome with conventional chemotherapy. 4 patients had undetermined prognosis. As for SNV, the most frequent common non-synonymous SNV was KIT mutation, while ADAMTS17 and CFAP46 mutation was found in 2/9 patients respectively. Noticeable non-synonymous SNV found only in patients with poor prognosis included NRAS, ADAM29, AGO1, and ALAS2 mutation. For structural variation, LOC44166 inversion, ANKRD26P1 deletion, EMBP1 translocation were noticeable structural variants other than AML-ETO rearrangement in these patients. Conclusion Not a single genetic factor was attributable to the prognosis in CBF-AML. Further validation of genetic alterations found study in this study is ongoing. Citation Format: Youngil Koh, Dae-Yoon Kim, Jong-Kwang Kim, Yeun-June Chung, Sung-Soo Yoon, Hyung-Lae Kim. Genomic profile of AML-ETO rearranged acute myeloid leukemia. [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 4756. doi:10.1158/1538-7445.AM2015-4756
93. Macrophages Are a Barrier to AAV5 Mediated Gene Expression in the Air Pouch Synovial Inflammation (APSI) Model
Authors: Susanne A. Snoek, Emiel Kramer, Mariska van Geldorp, Ronne Brunekreef, Niels Broekstra, Jan van Ittersum, Paul P. Tak, Margriet J. Vervoordeldonk, Jonathan D. Finn
Journal: Molecular Therapy (2015)

Our group is investigating the application of AAV gene therapy for inflammatory disease, especially rheumatoid arthritis (RA). The air pouch synovial inflammation (APSI) model is commonly used for studying local inflammation in rodents and is often used to test anti-rheumatic compounds. It involves the subcutaneous injection of air in the back of the animal, promoting the formation of an air pouch lining. After ~6 days, this lining bears a strong resemblance to the synovial membrane of a joint, being composed primarily of fibroblast-like and macrophage-like cells. Inflammation can be induced by injecting a stimulus (e.g. LPS, TNF, synovial fluid) into the air pouch cavity. While not a true RA model, the APSI model has a number of advantages over standard mouse arthritis models, including a short time frame (2 weeks versus 2 months), low discomfort for the animals, and allows for analysis of inflammatory markers in the air pouch fluid and membrane. Additionally, many of the treatments that have proved effective in human RA (e.g. methotrexate, TNF-blockers, steroids) are also effective in the APSI model. In order to use the APSI model for testing new gene therapies for RA, we investigated the kinetics of AAV5 mediated gene expression. An AAV5-CMV-Luciferase vector was used to determine optimal vector doses by non-invasive in vivo whole animal bioluminescent imaging. To our surprise, when vector was injected at day 6 after formation of the air pouch, we were unable to detect any luciferase expression up to day 30, over a wide range of vector doses (1×10E9 to 1×10E12 vg). Subsequent studies confirmed that similarly to synovial fibroblasts, air pouch fibroblasts were able to be transduced by AAV5 in vitro. As immunohistochemistry (IHC) staining (F4/80) revealed a high density of macrophages in the air pouch lining at day 6, we hypothesized that the presence of these cells might be inhibiting AAV5 mediated transduction in the APSI model. To test this hypothesis we either suppressed macrophage activity using triamcinolone (steroid) in combination with AAV5-CMV-Luciferase injection at day 6, or avoided macrophages by administering vector before the influx of macrophages into the air pouch lining (day 0). We observed that either suppressing or avoiding macrophages allowed for expression of luciferase following AAV5-CMV-Luciferase administration. These data suggest that macrophages are a previously underappreciated barrier to gene transfer, and that strategies, such as immune suppression or macrophage depletion, should be explored further when administering vector to macrophage rich tissue.
Flavopiridol Is Active in Genetically High-Risk, Relapsed Chronic Lymphocytic Leukemia (CLL): Analysis of 56 Patients by Cytogenetic Abnormality.
Authors: Thomas S. Lin, Nyla A. Heerema, Beth Fischer, Kristie A. Blum, Mollie E. Moran, Michelle B. McEldowney, Sara Broering, Gerard Lozanski, Dimitrios Colevas, Michael R. Grever, John C. Byrd
Journal: Blood (2006)
Racial and Ethnic Differences in Serum Cotinine Levels of Cigarette Smokers
Authors: Ralph S. Caraballo, Gary A. Giovino, Terry F. Pechacek, Paul D. Mowery, Patricia A. Richter, Warren J. Strauss, Donald J. Sharp, Michael P. Eriksen, James L. Pirkle, Kurt R. Maurer
Journal: JAMA (1998)
PTU-065 Non-invasive assessment of systemic haemodynamics to determine oesophageal variceal size in cirrhotic patients: Abstract PTU-065
Authors: K A Rye, G Mortimore, A Austin, J Freeman
Journal: Gut (2010)

<h3>Introduction</h3> Portal pressure underlies variceal development, bleeding and mortality but is not routinely assessed. Universal endoscopic screening is advised in cirrhosis with primary prophylaxis given if varices &gt;5 mm diameter. This is labour intensive and costly, but non-invasive predictors of varices are unreliable. Cirrhosis is associated with a hyperdynamic circulation and quick, easy, non-invasive assessment of this is now possible. The aim of this study was to evaluate whether non-invasive assessment of systemic haemodynamics in cirrhosis can identify patients with significant oesophageal varices. <h3>Methods</h3> We studied 29 cirrhotic patients. Systemic haemodynamics were assessed non-invasively using the Finometer® (TNO instruments, Amsterdam), and analysed with Beatscope® software. Portal pressure was assessed by measurement of the hepatic venous pressure gradient (HVPG). Gastroscopy assessed variceal size, Japanese score and 1-year probability of bleeding according to the NIEC index. <h3>Results</h3> 69% male, median age 47 (42–55) years, Child-Pugh (CP) score 6 (Class A 18, Class B 10, Class C 1) and MELD 10 (8–13). 90% alcoholic cirrhosis, 66% abstinent. HVPG positively correlated with CP score (r=0.58, p=0.001), cardiac index (r=0.53, p=0.005) and heart rate (r=0.62, p&lt;0.001) but not with peripheral vascular resistance (PVR) (r=−0.17, p=0.632). A significant negative correlation was seen between PVR and both cardiac output (r=−0.95, p&lt;0.001) and cardiac index (r=−0.81, p&lt;0.001). HVPG correlated positively with variceal size (r=0.64, p&lt;0.001). Cardiac output and cardiac index positively correlated whereas PVR negatively correlated with variceal size (r=0.53, p=0.003, r=0.61, p&lt;0.001, r=−0.41, p=0.029, respectively). Significant differences in haemodynamics were seen between patients with no or small varices and medium or large varices (Abstract 065). No significant differences were seen in serum albumin, prothrombin time, platelet count or presence of stigmata of chronic liver disease and size of varices. <h3>Conclusion</h3> Non-invasive assessment of systemic haemodynamics in cirrhosis identifies the hyperdynamic circulation and can distinguish between absent/small and medium/large sized varices. This technique appears promising as a tool to help identify a group of patients who would most benefit from endoscopic screening and primary prophylaxis.
Factors Associated With Pulmonary Embolism-Related Sudden Cardiac Arrest
Authors: Wulfran Bougouin, Eloi Marijon, Benjamin Planquette, Nicole Karam, Florence Dumas, David S. Celermajer, Daniel Jost, Lionel Lamhaut, Frankie Beganton, Alain Cariou, Guy Meyer, Xavier Jouven
Journal: Circulation (2016)
From Bone Marrow to Skin: The Transient Increase in Circulating Endothelial Progenitor Cells in Patients with Superficial and Full Thickness Burns Correlates with Surface Area and Depth of Injury and Circulating Chemokine Levels.
Authors: Suzanne M. Watt, Andreas Fox, Adrian L. Harris, Nita Fisher, Mike, P.H. Tyler, Duncan A. McGrouther, Emma Frith, Jon Smythe
Journal: Blood (2005)
558. Targeted Gene Therapy in CD34+ Cells from Healthy Donors and Fanconi Anemia Patients
Authors: Begoña Díez, Pietro Genovesse, Giulia Schiroli, Lara Álvarez, Francisco J. Román-Rodriguez, Philip D. Gregory, Michael Holmes, Angelo Lombardo, Luigi Naldini, Paula Rio, Juan A. Bueren
Journal: Molecular Therapy (2016)

Gene targeting is rapidly progressing thanks to the development of improved nucleases and donor constructs, and represents a new gene therapy-based strategy for the treatment of inherited diseases, such as Fanconi anemia (FA). Because FA can be generated by multiple mutations in up to 19 different genes, we focused our interests in the insertion of therapeutic FA genes in safe harbor loci, since this approach could serve as a platform for treating all FA subtypes and pathogenic mutations. In previous studies we demonstrated the feasibility of correcting the phenotype of hematopoietic progenitors through the genome editing and reprogramming of fibroblasts from FA patients. Because of the limited repopulating properties so far reported for iPSC-derived hematopoietic precursor cells, here we aimed to investigate the possibility of conducting a similar gene targeting approach using human primary CD34+ cells. In a first set of experiments we investigated the efficiency of targeting the AAVS1 locus in cord blood HSPCs. Pre-stimulated CD34+ cells were transduced with integrase-defective lentiviral vectors (IDLV) encoding an EGFP reporter gene under the control of the PGK promoter, flanked by sequences homologous to the AAVS1 target site. The cells were then nucleofected with AAVS1 -specific ZFN mRNAs. The average targeting efficiencies ranged from 10-20% both in in vitro cultured cells and NSG mice-repopulating cells. In subsequent experiments, the EGFP reporter gene was replaced by the hFANCA therapeutic gene. Gene targeting experiments conducted in lymphoblast cell lines and primary CD34+ cells from FA-A patients reverted the characteristic hypersensitivity of FA cells to mitomycin C (MMC), and also restored the formation of FANCD2 foci after DNA damage, evidencing the phenotypic correction of these cells. Our data confirm the efficacy of AAVS1-gene targeting in hHSPCs and demonstrate the feasibility of conducting these approaches in primary CD34+ cells from FA patients.
Relationship between levels of HER-2 amplification and pathologic complete response to trastuzumab-based neoadjuvant treatment
Authors: C. Masini, A. Bisagni, G. Falco, C. Bassano, L. Baldi, G. Bisagni, G. Moretti, A. Albini, C. Boni, G. Ferrari, G. Gardini
Journal: Annals of Oncology (2015)
Disease-free survival (DFS) as surrogate end-point for overall survival (OS) in early breast cancer (EBC): Correlation may be different according to drugs and/or strategies tested
Authors: D. Giannarelli, E. Bria, P. Carlini, M. Di Maio, F. Cuppone, I. Sperduti, C. Nisticò, V. Vaccaro, E. Terzoli, F. Cognetti
Journal: Journal of Clinical Oncology (2008)

6622 Background: DFS is considered an accepted end-point for adjuvant trials in EBC. Two are the implications in using surrogates: 1) the chance for a smaller sample size/shorter follow-up (for clinical trial design optimization) and 2) for pursuing the approval of new drugs/strategies by regulatory boards. Although this correlation is linked to the explored disease, it is likely that drugs acting with different mechanisms have a different impact on that. A validation in all settings, and a comparison between the correlation-coefficients given by different drugs' families/strategies is required. Methods: 4 different settings in EBC were selected: 1) the evaluation of a experimental chemotherapeutic (Chemo-setting); 2) the evaluation of a strategy (Strategy-setting); 3) the evaluation of an hormonal-drug (Hormonal-setting); 4) the evaluation of a targeted-agent (Targeted-setting). Literature-based meta-analyses were accomplished, and a linear- regression-model considering outcome rates was used for correlation, estimated with the Pearson, R2 (parametric) and Spearman (non-parametric) coefficients. The comparison of coefficients was accomplished with the normally distributed Fisher's transformation. Results: All randomized trials (RCTs) exploring the efficacy of the following drugs/strategies as EBC-adjuvant treatment were gathered: 1) Chemo-setting: taxanes; 2) Strategy-setting: dose-dense; 3) Hormonal-setting: aromatase inhibitors; 4) Targeted-setting: trastuzumab. Results are listed in the table. No significant differences between coefficients were found. Conclusions: Cooperative groups designing RCTs and regulatory boards should take into account that, although DFS is a good surrogate of OS in EBC, the strength of the correlation may be different in the same disease-setting, in accordance with the experimental drugs and/or strategies to be tested. Setting Pts (#RCTs) Pearson (p) R2 (p) Spearman (p) Chemo 17,067 (10) 0.74 (<0.001) 0.55 (<0.001) 0.63 (<0.001) Strategy 4,411 (3) 0.97 (<0.001) 0.95 (<0.001) 0.89 (0.02) Hormonal 26,707 (9) 0.78 (0.001) 0.60 (0.001) 0.77 (0.001) Targeted 10,205 (5) 0.82 (0.01) 0.65 (0.01) 0.65 (0.06) No significant financial relationships to disclose.
458. Development of a Stable Producer Cell Line for Scalable Lentiviral Vector Production for Gene Therapy of Hemoglobinopathie
Authors: Sarah Slauson, Amelia Thomas, Byoung Ryu, Melissa Bonner, Gretchen Lewis, Gabor Veres, Janet Chung, Geoffrey B. Parsons
Journal: Molecular Therapy (2016)

Current manufacturing of clinical grade lentiviral vectors (LVVs) for gene therapy applications commonly relies on transient transfection of adherent 293T cells. Improvements in production efficiency and scalability would provide value in meeting the needs for increased amounts of vector required for clinical development. An inducible producer cell line grown in suspension culture represents a potentially more scalable manufacturing process for LVV production which eliminates the need for costly plasmid and transfection reagents. We have engineered a packaging cell line by introducing doxycycline-inducible Gag-Pol, Rev, and VSVG envelope genes into a suspension cell line. Packaging cell clones were isolated by single cell sorting and screened by qPCR for the presence of the delivered genes. Virus production was assessed by transient transfection of a lentiviral vector and doxycycline treatment. A titer of up to 5.0E6 transduction units per milliliter (TU/mL) was observed with packaging cell line stability demonstrated after greater than four months of continuous passage. Next, a self-inactivating lentiviral vector was excised from its plasmid backbone and ligated in vitro to a linear neomycin resistance cassette and used to transfect the lentiviral packaging cell line to generate a panel of producers. Following two weeks of G418 drug selection, adherent colonies were plucked and screened for viral production followed by single cell sorting to isolate individual producer clones. From five different plucked colonies with titers greater than 3.0E6 TU/mL, more than 100 clones were screened and 7 were identified that produced a harvest titer greater than 1.0E7 TU/mL. Four of these clones were successfully re-adapted to suspension and scaled up to 3L culture. LVV generated from individual producer clones was compared for the ability to transduce adult mobilized CD34+ hematopoietic stem cells (HSCs). Interestingly, the vector copy number (VCN) in CD34+ HSCs for the LVV derived from the producer cells varied between clones. Clones that produced the highest VCN have been chosen for further characterization in order to better understand the differences in HSC transduction. These lentiviral producer cell lines represent an important first step toward the creation of a manufacturing process that can better support clinical and commercial development of HSC lentiviral gene therapy.
Abstract 1995: Developing integrated single-cell metabolic/proteomic assays
Authors: Min Xue, Wei Wei, Yapeng Su, Young Shik Shin, Jungwoo Kim, James R. Heath
Journal: Cancer Research (2015)

Abstract The technology boom of single-cell metabolomics and proteomics has led to exciting biological discoveries in the past decade. It has become widely acknowledged that resolving the intratumoral heterogeneity at single cell resolution can aid the understanding of cancer therapeutic response and progression, as well as facilitate the development of therapeutic interventions. Here we present an integrated assay that simultaneously quantifies the intracellular metabolites, glucose uptake, metabolic proteins and functional signaling proteins at the single-cell level. The measurement of metabolites is achieved through a series of competitive binding assays and is incorporated into the microfluidic-based single cell barcode chip platform. We demonstrate that this assay is capable of obtaining information from both protein and metabolic signaling pathways associated with tumor survival and progression, providing new insights into cancer heterogeneity and drug responsiveness. Citation Format: Min Xue, Wei Wei, Yapeng Su, Young Shik Shin, Jungwoo Kim, James R. Heath. Developing integrated single-cell metabolic/proteomic assays. [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 1995. doi:10.1158/1538-7445.AM2015-1995
328. FP3, a Novel VEGF Blocker, Expressing Oncolytic Adenovirus Induces Potent Antiangiogenic and Antitumor Efficacy
Authors: Il-Kyu Choi, Hyewon Shin, Eonju Oh, Ji Young Yoo, June Kyu Hwang, De-Chao Yu, Chae-Ok Yun
Journal: Molecular Therapy (2015)

Various ways to inhibit VEGF, a key facilitator in tumor angiogenesis, are being developed to treat cancer. The soluble VEGF decoy receptor (FP3), due to its high affinity to VEGF, is a highly effective and promising strategy to disrupt VEGF signaling pathway. Despite potential advantage and potent therapeutic efficacy, its employment has been limited by very poor in vivo pharmacokinetic properties. To address this challenge, we designed a novel oncolytic Ad expressing FP3 (RdB/FP3). To demonstrate the VEGF-specific nature of RdB/FP3, replication-incompetent Ad expressing FP3 (dE1/FP3) was also generated. dE1/FP3 was highly effective in reducing VEGF expression and functionally elicited an antiangiogeneic effect. Furthermore, RdB/FP3 exhibited a potent antitumor effect compared with RdB or recombinant FP3. Consistent with these data, RdB/FP3 was shown to greatly decrease VEGF expression level and vessel density, and increase apoptosis in both tumor endothelial and tumor cells, verifying potent suppressive effects of RdB/FP3 on VEGF-mediated tumor angiogenesis in vivo. Importantly, the therapeutic mechanism of antitumor effect mediated by RdB/FP3 is associated with prolonged VEGF silencing efficacy and enhanced oncolysis via cancer cell-specific replication of oncolytic Ad. Taken together, RdB/FP3 provides a new promising therapeutic approach in the treatment of cancer and angiogenesis-related diseases.
Economic Analysis of Reduced-Intensity Cord Blood Transplantation.
Authors: Koichiro Yuji, Shigesaburo Miyakoshi, Tomohiro Myojo, Yuji Miura, Daisuke Kato, Osamu Imataki, Hiroto Narimatsu, Eiji Kusumi, Tomoko Matsumura, Masahiro Kami, Kazuhiro Masuoka, Junichi Ueyama, Atsushi Wake, Shinichi Morinaga, Shuichi Taniguchi
Journal: Blood (2004)
A Novel Pro-Survival Function of Cyclin-D1 Underlies Its Oncogenic Role and Potential as a Therapeutic Target In Mantle Cell Lymphoma
Authors: Elena Beltran, Vicente Fresquet, Javier Martinez-Useros, Jose A. Richter-Larrea, Ainara Sagardoy, Izaskun Sesma, Luciana L. Almada, Santiago Montes-Moreno, Stefan Gesk, Reiner Siebert, MaJose Calasanz, Felipe Prosper, Miguel A. Piris, Martin E. Fernandez-Zapico, Jose A Martinez-Climent
Journal: Blood (2010)
The Geldanamycin Derivative DMAG Demonstrates Improved Cytotoxicity and Down-Modulation of Hsp90 Client Proteins Relative to 17-AAG in Chronic Lymphocytic Leukemia (CLL) Cells: Justification for Clinical Trials in CLL.
Authors: Amy J. Johnson, Amy J. Wagner, Lisa L. Smith, David M. Lucas, Michael D. De Lay, Jamie M. Allison, S. Percy Ivy, Thomas S. Lin, John C. Byrd
Journal: Blood (2006)
A Maker Movement for Health
Authors: Jonathan Awori, Joyce M. Lee
Journal: JAMA Pediatrics (2016)

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Monitoring of Calr Allele Burden in Patients with Essential Thrombocythemia Treated with Imetelstat, a Telomerase Inhibitor, Reveals Rapid and Substantial Molecular Responses
Authors: Gabriela M. Baerlocher, Monika Haubitz, Oliver G. Ottmann, Olatoyosi Odenike, Alexander Roeth, Michael A McDevitt, Ted Shih, Bart Burington, Dianne Morfeld, Neeru Batra, David Snyder, Elisabeth Oppliger Leibundgut
Journal: Blood (2014)