tbuckley/cabot-search huggingface dataset:
1. Measles Virus Glycoprotein Pseudotyped Lentiviral Vectors Transduce Cytokine Stimulated and Resting Hematopoietic Stem Cells at an Efficiency Without Precedent
Authors: Camille Lévy, Fouzia Amirache, Anais Girard-Gagnepain, Cecilia Frecha, Caroline Costa, Ornellie Bernadin, Didier Negre, Rik Gijsbers, François-Loïc Cosset, Els Verhoeyen
Journal: Molecular Therapy (2015)

Hematopoietic stem cell (HSC) based gene therapy holds promise for the cure of many inherited and acquired diseases. The field is now moving towards the use of lentiviral vectors (LVs) evidenced by recent clinical trials. In these trials, VSV-G-LVs were applied at high doses in combination with strong cytokine-cocktails, which might compromise the 'HSC' character of the cells. Thus, a challenge in the field is to be able to transduce HSCs with high efficiency without compromising their stemness. Previously, we have shown that measles virus glycoprotein displaying LVs (MV-LVs) were able to transduce efficiently resting T, and B cells and dendritic cells. Now, we evaluated these MV-LVs for hCD34+-cell transduction under mild cytokine prestimulation in order to better preserve the 'HSC' characteristics. After a single application, MV-LVs transduced 100% of TPO+SCF stimulated hCD34+-cells. Even more striking was that these MV-LVs allowed efficient transduction of up to 70% of quiescent hCD34+-cells, while VSV-G-LVs reached 5% of transduction at the most. This indeed coincided with the fact that resting hCD34+ early progenitor cells express barely the low density lipid receptor, recognized by VSVG-LVs for cell entry (Frecha et al., Blood 2014). Importantly, reconstitution of primary and secondary recipient NSG mice with MV-LV transduced pre-stimulated or resting hCD34+-cells demonstrated that this high transduction levels in all analyzed myeloid and lymphoid engrafted lineages in all hematopoietic tissues. Notably, we found increased transduction levels (up to 100%) in all human cells in these secondary recipients for the resting MV-LV transduced hCD34+ cells, emphasizing that these vectors preferentially gene-marked HSCs. Solely the MV receptor, CD46, was found responsible for high level MV-LV entry into hCD34+-cells as shown by antibody blocking. Interestingly, a significantly different integration pattern for MV-LVs was revealed in resting and cytokine-pre-stimulated hCD34+-cells. All together, these MV-LVs paves the way towards HSC-based gene therapy of multiple diseases including diseases characterized by low numbers of HSCs such as Fanconi Anemia, for which high level HSC correction is needed combined with minimal cell activation to be successful in the clinic.
401. AAV Therapy Attenuates Respiratory Dysfunction and Glycogen Accumulation in a Murine Model of Glycogen Storage Disease Type II
Authors: Darin J. Falk, Meghan S. Soustek, A. Gary Todd, Cathryn S. Mah, Denise A. Cloutier, Nathalie Clement, David D. Fuller, Barry J. Byrne
Journal: Molecular Therapy (2015)

Cardiac dysfunction and respiratory muscle weakness are primary features in patients with early onset Pompe disease. To reduce the progressive and rapid accumulation of glycogen resulting in cardiorespiratory dysfunction, adult Gaa-/- mice were administered a single systemic injection of rAAV2/9-DES-hGAA (AAV9) or bi-monthly injections of recombinant human GAA (ERT). Cardiac function and morphology was assessed one and three months after initiation of treatment while whole-body plethysmography and diaphragmatic contractile function was evaluated at three months post-treatment in all groups. Gaa-/- animals receiving either AAV9 or ERT demonstrated a significant improvement in cardiac function and diaphragmatic contractile function as compared to control animals. AAV9 treatment resulted in a significant reduction in cardiac dimension (end diastolic left ventricular mass/gram wet weight; EDMc) at three months post-injection. Neither AAV9 nor ERT therapy altered minute ventilation during quiet breathing (eupnea). However, breathing frequency and expiratory time were significantly improved in AAV9 animals. Glycogen deposition was significantly elevated in Gaa-/- and ERT but not AAV9 when compared to control animals. These results indicate systemic delivery of either strategy improves cardiac function but improvement in respiratory parameters and glycogen reduction are limited to AAV9 therapy at three-months post treatment in a murine model of Pompe disease.
The prognostic value of desmoglein 1 and desmocollin 1 in squamous cell carcinoma of the anal region.
Authors: M. P. Myklebust, O. Fluge, O. Bruland, H. Immervoll, O. Dahl
Journal: Journal of Clinical Oncology (2011)

e21061 Background: The desmosomes, where desmogleins (DSG) and desmocollins (DSC) are major components, maintain the tissue integrity and cell-cell adherence in epithelial tissue. Our hypothesis was that reduced membranous expression of DSG1 and DSC1 proteins would be associated with poorer outcome in squamous cell carcinoma (SCC) of the anal region. Methods: A tissue microarray was constructed from formalin fixed paraffin embedded biopsy samples from 53 patients with SCC of the anal region. Sections were stained for DSG1 and DSC1 by immunohistochemistry. The patients were all treated with radiation alone or combined with chemotherapy. Chemotherapy given was 5-fluorouracil, 1000 mg/m2 days 1-4, and mitomycin C, 10 mg/m2 day 1. The median radiation dose was 50 Gy, radiation fields covered primary tumor and regional lymph nodes. Mean follow-up time was 6.9 years. The outcome, cancer specific survival (CSS), was assessed using the Kaplan-Meier method and log-rank test. Cox regression was employed for multivariate survival analyses. Results: On univariate survival analyses, negative membranous DSG1 and negative cytoplasmic DSC1 were found to be favorable: The 5-year CSS was 74% vs. 42% (p=0.012) and 81% vs. 40% (p=0.016), respectively. When DSG1 and DSC1 expression was assessed as one variable, the difference in 5-year CSS was more pronounced (both negative 83%, DSG1 pos+DSC1 neg 58%, DSG1 neg+DSC1 pos 55%, both positive 0%, p=0.004). Significant factors in Cox regression analyses were stage (T1-2N0 vs.T3-4N+, hazard ratio (HR) 6.44, p=0.004), treatment (chemoradiotherapy vs. radiotherapy alone, HR 6.73, p=0.004) and DSG1+DSC1 expression (DSG1+DSC1 negative vs. positive, HR 6.95, p=0.044). Conclusions: Our initial hypothesis could not be verified as negative DSG1 (membranous) and DSC1 (cytoplasmic) staining are favorable predictors of CSS in squamous cell carcinoma of the anal region. Recent preclinical studies have shown that these proteins may be mediators of the Wnt/β-catenin pathway. The desmosomes might therefore have a role in cell signaling in addition to serving as rigid cell-cell anchors.
Busulphan Metabolism Via Flavin-Containing Monooxygenase 3 (FMO3) Can Explain Several Interactions with Other Drugs
Authors: Ibrahim El Serafi, Manuchehr Abedi-Valugerdi, Seán Naughton, Maryam Saghafian, Jonas Mattsson, Ali Moshfegh, Ylva Terelius, Zuzana Potacova, Moustapha Hassan
Journal: Blood (2014)
MUC16/CA125 specific targeting of critical signaling kinases in ovarian cancer
Authors: R. G. Manson, D. Thapi, X. Ma, N. Rosales, D. Spriggs
Journal: Journal of Clinical Oncology (2009)

e22112 Background: The serum marker CA125 is known to originate from the transmembrane protein, MUC16; however, the biological importance of MUC16 is not known. Our lab previously created fluorescent-labeled transfectants, containing truncated versions of the MUC16 molecule. MUC16 expression vectors were transfected into CA125-negative ovarian cancer cell lines. These cell lines have allowed for a unique means of studying MUC16 biology. In vivo data suggest that MUC16 drives a more aggressive phenotype in ovarian cancer, including increased growth, invasion and dissemination. MUC16 transfection is also associated with the upregulation of specific signaling kinases, including EGFR, Erk, Src and Akt. To validate these findings and explore the potential of MUC16 signal targeting through inhibition of downstream kinases, we are examining the effect of a kinase-directed siRNA library on the A2780 ovarian cancer cell line transfected with a carboxy-terminus MUC16-expression vector. With the identification of kinases important to the survival of CA125+ ovarian cancer tissue, we will identify molecular targets for novel, tumor-specific therapies. Methods: Pilot plates containing candidate kinase-directed, negative control and total kill siRNA (Qiagen) were applied to MUC16+ and MUC16- cells. Cells were grown in culture in parallel 96-well plates. Immunofluorescent readings and Alamar Blue viability staining were performed at 72 hours. Results: Transfection reagents and nonspecific siRNA did not substantially change the survival of fluorescent protein expression in MUC16± cells; while hrGFP and mCherry proteins were decreased by ∼75%. None of the final transfection conditions altered Alamar Blue survival. Preliminary studies suggest that siRNA against AKT2 and SRC had specific inhibition against MUC16+ cells compared to MUC16- controls. Studies of three additional AKT2 siRNAs and a full complement of 714 human kinases are now being tested. Kinases with MUC16-specifc effects will be confirmed with three additional siRNAs. Conclusions: Dual fluorescence isogenic cell lines can be used to explore the kinase profile of MUC16+ ovarian cancer cells. Identified target kinases will enhance our knowledge about MUC16/CA125 biology and provide future leads for the treatment of ovarian cancer. No significant financial relationships to disclose.
Top of the Basilar Syndrome Presenting With Convulsions
Authors: William L. Conte, Chandler E. Gill, Jose Biller
Journal: JAMA Neurology (2016)

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Histone Deacetylase Inhibition Improves Differentiation of Dendritic Cells from Leukemic Blasts of Patients with TEL/AML1-Positive Acute Lymphoblastic Leukemia
Authors: Kerstin Schmidt, Karl Seeger, Carmen Scheibenbogen, Roderich Bender, Sina Süßmilch, Abdulgabar Salama, Anja Moldenhauer
Journal: Blood (2008)
Bortezomib Continues Demonstrates Superior Efficacy Compared with High-Dose Dexamethasone in Relapsed Multiple Myeloma: Updated Results of the APEX Trail.
Authors: Paul Richardson, P. Sonneveld, M. Schuster, D. Irwin, E. Stadtmauer, T. Facon, J. Harousseau, D. Ben-Yehuda, S. Lonial, H. Goldschmidt, D. Reece, J. San Miguel, J. Blade, M. Boccadoro, J. Cavenagh, W. Dalton, A. Boral, D. Schenkein, K. Anderson
Journal: Blood (2005)
398. Sustained Expression of a Canine Micro-Dystrophin Lead To Improvement of Limb Muscle Function in Dystrophic Dogs Following Large Scale AAV-Mediated Treatment
Authors: Christine Halbert, Melissa Goddard, Donghoon Lee, David Mack, Tiffany Butts, Robert Grange, Mackenzie Johnson, Rainer Storb, Dusty Miller, Jeffrey Chamberlain, Stephen Tapscott, Martin Childers, Zejing Wang
Journal: Molecular Therapy (2015)

Adeno-associated viral (AAV) vectors as gene delivery vehicles have shown promise both in preclinical studies and clinical trials for a number of acquired and inherited diseases, including Duchenne Muscular Dystrophy (DMD). Studies have shown that host immune responses against AAV can compromise vector delivery and prevent sustained therapeutic gene expression in animal models and humans. We developed and demonstrated a novel AAV production system that prevents aberrant packaging of the AAV capsid (cap) genes. Compared to conventional AAV production methods, our new approach eliminates unwanted in vivo expression of AAV capsid proteins and significantly reduces host immune responses. Here, we demonstrated in a pilot study that we were able to reduce a tripledrug immunosuppressive regimen to a mild 2-drug regimen while retaining sustained canine micro-dystrophin expression in CXMD dogs following large scale delivery of an AAV vector carrying the canine micro-dystrophin to a group of muscles in the hind limb. Amelioration of muscle pathology as a result of sustained expression of the therapeutic gene was demonstrated by histological analysis of muscle tissues and by non-invasive magnetic resonance imaging (MRI). Further, we determined functional benefit of micro-dystrophin expression by muscle force measurement and gait analysis. Significant improvement in muscle force, as indicated by more than 100% increase in strength (torque), was observed in the treated limb compared to that in the untreated limb. In conclusion, by combining newly improved AAV production and mild clinically applicable immunosuppression, the finding of long term robust dystrophin expression in CXMD dogs' limb with significant functional improvement opens the possibility of translating these strategies to a human DMD trial, which can improve patients' immediate quality of life.
MEF2C as Novel Oncogene for Early T-Cell Precursor (ETP) Leukemia
Authors: Irene Homminga, Rob Pieters, Anton Langerak, Johan de Rooi, Andrew Stubbs, Monique Verstegen, Maartje Vuerhard, Jessica Buijs-Gladdines, Clarissa Kooi, Petra Klous, Pieter Van lierberghe, Adolfo Ferrando, Jean-Michel Cayuela, Brenda Verhaaf, Berna Beverloo, Martin A. Horstmann, Valerie de Haas, Anna-Sophia Wiekmeijer, Karin Pike-Overzet, Frank Staal, Wouter de Laat, Jean Soulier, Francois Sigaux, Jules Meijerink
Journal: Blood (2010)
Abstract 4784: Effect of epigenetic drugs on chromatin remodeling complexes disrupted in cancer
Authors: Montserrat Pérez-Salvia, Laia Simó-Riudalbas, Manel Esteller
Journal: Cancer Research (2015)

Abstract Chromatin remodeling complexes undergo dynamic assembly of chromatin to facilitate the access to DNA packed in nucleosomes during DNA-template cellular processes. They present genetic alterations in multiple of its components in a broad range of hematological and solid malignancies. The SWI/SNF ATP-dependent chromatin remodeling complex subunits BRG1 and ARID1A were reported to act as tumor suppressors and they are mutated in a variety of human cancers including breast cancer, prostate cancer, lung cancer and pancreatic cancer. In contrast with the irreversible genomic mutations, epigenetic modifications can be reversed by therapeutic treatment. New generation of epigenetic drugs consists on specific inhibitors against chromatin associated proteins which present abnormal expression in tumors. Bromodomain and BET inhibitors block the assembly of a protein complex at a particular gene locus by impairing the interaction of the bromodomain with the acetylated lysine of a histone tail. To date, some BET inhibitors have been tested for the treatment of the rare NUT midline carcinoma disease, acute myeloid leukemia and multiple myeloma. Our aim was to find new potential biomarkers for a personalized cancer treatment with new generation epigenetic drugs. Thus, we tested whether cell lines with a component of the SWI/SNF complex disrupted (BRG1 or ARID1A) present more sensitivity to bromodomain inhibitors. Citation Format: Montserrat Pérez-Salvia, Laia Simó-Riudalbas, Manel Esteller. Effect of epigenetic drugs on chromatin remodeling complexes disrupted in 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 4784. doi:10.1158/1538-7445.AM2015-4784
511. Engineered Donor Marrow Macrophages Phagocytose Cancer Cells and Aggressively Shrink Solid Tumor Xenografts Compared to Tumor Associated Macrophages
Authors: Cory Alvey, Kyle Spinler, Manu Tewari, Dennis Discher
Journal: Molecular Therapy (2016)

Cell-based immunotherapies such as those based on engineered T-cells appear safe and often effective against liquid tumors. In solid tumors, macrophages are typically abundant, but the density of tumor associated macrophages (TAMs) correlates with poor clinical outcomes as they promote tumor growth, immunosuppression, and are nonphagocytic. In our studies, less differentiated donor marrow phagocytes are engineered to target tumors and selectively phagocytose cancer cells. Xenograft tumors were made on the flanks of NSG mice using a tdTomato human lung carcinoma cell line (A549). Systemic injections of anti-human IgG (anti-hum) with large tumors (~70 mm2) showed no effect on tumor growth. However, systemic injection of bone marrow from donor NSG mice together with biweekly anti-hum treatments effectively stopped growth of the solid tumors. Replacing anti-hum with a non-specific antibody had no effect on tumor growth. Based on tdTomato signal intensity within macrophages isolated from tumors, 10-fold more donor macrophages are phagocytic compared to resident TAMs (2-3% are phagocytic). Since cancer cells express on their surface 'self' markers that limit the phagocytosis of these cells, we inhibited the 'self' receptors on the injected donor phagocytes prior to systemic injection of the donor marrow. This combination of 'self'-receptor inhibition with anti-hum causes a rapid decrease in tumor burden, shrinking tumors by ~40% in just 10 days compared to a similar growth of untreated tumors in the same time period. The anti-hum injection was again necessary as injection of a non-specific antibody failed to affect tumor growth. Tumor analysis showed that >85% of macrophages that were 'self'-receptor inhibited had phagocytosed the tdTomato A549 cells, which is ~30-fold greater than resident macrophages. Importantly, these cell therapy treatments appear safe with no significant decreases in hematocrit or platelets, which is unlike the anemia that has been reported upon systemic injection of 'self' inhibitors. Our results thus suggest that therapies based on engineered macrophages can be safe and effective against solid tumors if three requirements are met: a phagocytic phenotype, target opsonization, and inhibition of 'self' signaling.
Results of Intensive Chemotherapy in 434 Adult Patients (pts) with Philadelphia-Negative Acute Lymphoblastic Leukemia (ALL): Predictive Prognostic Model for Survival
Authors: Musa Yilmaz, Hagop M. Kantarjian, Jorge Cortes, Guillermo Garcia-Manero, Jad Chahoud, Farhad Ravandi, Koji Sasaki, Marina Konopleva, Koichi Takahashi, William G. Wierda, Nitin Jain, Srdan Verstovsek, Zeev Estrov, Prithviraj Bose, Sherry Pierce, Elias Jabbour
Journal: Blood (2015)
232. High Levels of iCasp9 Expression Are Needed for Suicide Gene Transfer
Authors: Sabrina Donnou, Catherine Poinsignon, Anne Galy, Sylvain Fisson
Journal: Molecular Therapy (2015)

Primary central nervous system lymphomas are aggressive tumors with no efficient treatment. In this study, we wanted to take advantage of a lentiviral vector (LV) specifically designed to target murine MHC II expressing cells (eg. lymphoma B-cells) to evaluate the feasibility of an in vivo targeted suicide gene therapy in a murine model of primary intraocular lymphoma. The inducible caspase 9 (iCasp9) (*) strategy used efficiently in T cells was tested as a suicide gene for this approach. As a first step, we showed that 15-20% of A20. IIA lymphoma tumor cells were transduced in vitro with the MHC II targeted LV expressing iCasp9, however, apoptosis could not be induced in these cells even after enrichment and cloning. None of the stably-expressing clones could be induced to apoptose by the inductor of dimerization. These clones had integrated only 1 copy of the transgene suggesting that levels of iCasp9 were insufficient or that cells were resistant to treatment. The same results were obtained with LV expressing iCasp9 from the cellular promoters (PGK or EF1α). In contrast, clones transduced with only 1 copy of a gammaretroviral LTR-driven-iCasp9 vector were efficiently induced to apoptose. The MLV clones expressed higher levels of transgene than LV clones and 90% of the cells died 24 hours after iCasp9 activation showing that A20.IIA tumor cells were not resistant to the mechanism. Clearly, a threshold of iCasp9 expression must be achieved to induce apoptosis by gene transfer. In other cells such as 3T3 cells, Jurkat T cells, HCT116 cells and Raji cells, more than 2 copies of the LV PGK-iCasp9 must be integrated to induce apoptosis since cells expressing only 1 copy survive. Whereas this threshold of LV transduction may be easily attained in T cells, it is very difficult to integrate more than 2 copies of LV per B cell in spite of repeated cycles of infection coupled with various preactivation stimuli. We are currently exploring solutions to augment B cell transduction and to increase iCasp9 expression from LV. Altogether, our results provide benchmark values for iCasp9 efficacy and show that highly expressing vectors must be developed to apply iCasp9 suicide gene therapy strategies in B-lymphoma but also with other target cells, to avoid escape to treatment.
A Randomized Controlled Trial Comparing the Combination Therapy of Deferiprone (DFP) and Desferrioxamine (DFO) Versus DFP or DFO Monotherapy in Patients with Thalassemia Major.
Authors: Yesim Aydinok, Amal El-Beshlawy, Claudia von Orelli-Leber, Claudia Czarnecki-Tarabishi, Chantal Y. Manz
Journal: Blood (2006)