tbuckley/cabot-search huggingface dataset:
Abstract 4982: Increased core fucosylation, a glycan alteration associated with cancer, is the result of hepatocyte dedifferentiation
Authors: Anand S. Mehta, Mary Ann Comunale, Siddhartha Rawat, Jessica Garner, Lucy Betesh, Mengjun Wang, Laura Steel, Michael Bouchard
Journal: Cancer Research (2015)

Abstract Alterations in N-linked glycosylation have been associated with the development of cancer. One such modification, core fucosylation has been observed in many cancers and is actually used clinically in the diagnosis of hepatocellular carcinoma (HCC). However, the reason why core fucosylation is increased in cancer is unclear. In this study, we show that the activation of specific cancer-associated cellular signaling pathways can increase core fucosylation and induce additional glycoform alterations on hepatocyte proteins. Specifically, we were able to determine that increased levels of protein sialylation and alpha-1,6-linked core fucosylation were observed following activation of the beta catenin pathway. Activation of the AKT pathway or induction of hypoxia also resulted in increased levels of fucosylation and sialylation. Furthermore, we show that increased core fucosylation was directly associated with de-differentiation of hepatocytes and with the transition of cells from an epithelial to a mesenchymal state. In conclusion, we show that increased core fucosylation, a modification of N-linked glycoproteins associated with HCC, occurs as a result of the process of cellular de-differentiation. We believe that this knowledge may help in the use of this glycan modification in the management of those with HCC. Citation Format: Anand S. Mehta, Mary Ann Comunale, Siddhartha Rawat, Jessica Garner, Lucy Betesh, Mengjun Wang, Laura Steel, Michael Bouchard. Increased core fucosylation, a glycan alteration associated with cancer, is the result of hepatocyte dedifferentiation. [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 4982. doi:10.1158/1538-7445.AM2015-4982
Highly Efficient Ex Vivo Expansion of Human Hematopoietic Stem Cells Using Delta1-Fc Chimeric Protein.
Authors: Takahiro Suzuki, Yasuhisa Yokoyama, Keiki Kumano, Minoko Takanashi, Shiro Kozuma, Tsuyoshi Takato, Tatsutoshi Nakahata, Mitsuo Nishikawa, Seiji Sakano, Mineo Kurokawa, Seishi Ogawa, Shigeru Chiba
Journal: Blood (2006)
115. Correction of the Sickle-Cell Disease Mutation in Human Hematopoietic Stem/Progenitor Cells
Authors: Megan D. Hoban, Matthew C. Mendel, Zulema Romero, Michael L. Kaufman, Alok V. Joglekar, Michelle Ho, Dianne Lumaquin, David Gray, Georgia R. Lill, Aaron R. Cooper, Fabrizia Urbinati, Shantha Senadheera, Allen Zhu, Pei-Qi Liu, David E. Paschon, Lei Zhang, Edward J. Rebar, Andrew Wilber, Xiaoyan Wang, Philip D. Gregory, Michael C. Holmes, Andreas Reik, Roger P. Hollis, Donald B. Kohn, Gregory J. Cost
Journal: Molecular Therapy (2015)

Sickle-cell disease (SCD) is characterized by a single point mutation in the seventh codon of the beta-globin gene. Site-specific correction of the sickle mutation in hematopoietic stem cells (HSCs) would allow for permanent production of normal red blood cells. Using zinc-finger nucleases (ZFNs) designed to flank the sickle mutation, we demonstrated efficient targeted cleavage at the beta-globin locus with minimal off-target modification. By co-delivering a homologous donor template (either an integrase-defective lentiviral vector [IDLV] or a DNA oligonucleotide), high levels of gene modification were achieved in CD34+ hematopoietic stem and progenitor cells (HSPCs). Modified cells maintained their ability to engraft NOD/SCID/IL2rgnull (NSG) mice and to produce cells from multiple lineages. Importantly, ZFN-driven gene correction in CD34+ cells from the bone marrow of sickle patients resulted in the production of wild-type hemoglobin tetramers.
PP-016 Timing referral of patients with intestinal failure – accumulation of preoperative comorbidities adversely affects outcome of subsequent intestinal transplantation
Authors: A Wiles, S Nishida, A Tzakis, R Sivaprakasam, C Watson, A Butler, N Jamieson, S Duncan, J Woodward, S Gabe, S J Middleton
Journal: Gut (2010)

<h3>Introduction</h3> The decision to refer patients for intestinal transplantation is often taken at a stage when patients are physically and psychologically weak due to an accumulation of multiple comorbidities which may impair their post operative survival. To assist with the assessment of these patients we have developed a scoring system which can be used to prospectively follow patients and avoid untimely referral. We have developed a preliminary preoperative scoring system for transplantation of the small intestine either alone or as a composite graft. <h3>Methods</h3> The score combines putative risk factors for survival. Factors included were loss of venous access, impairment of organs or systems not corrected by transplantation. Each factor was scored 0–3. A score of 3 indicated comorbidity approaching a contraindication for transplantation, that which might lead to but was not currently an adverse risk factor scored 1 and that presenting a definite but moderate increase in risk scored 2. The preoperative scores for 20 patients, who had either been followed up post operatively for at least 10 years or died, was compared to their survival. <h3>Results</h3> Post operative survival and CaMi score inversely correlated when analysed using (Spearman9s test) r = -0.82 p = 0.0001. A score of &lt;3 associated with survival ≥3 years (12/12 patients) and above 3 with survival of &lt;6 months (4/4). Patient Km survival curves for patients grouped according to CaMi score became significantly different from group 0 at group 3. Using this as a threshold score patients were grouped as either &gt;2 or below 3 and had significantly different survival rates, (logrank, p= 0.0001), Km median survival hazard ratio (HR) 6, rate of death Km HR of 5. Receiver – operator characteristics indicate a high degree of accuracy for prediction of death at 3 years, area under curve (C statistic): 0.98; 5 years: C statistic 0.82; 10 years: C statistic 0.65. <h3>Conclusion</h3> In this initial validation the preoperative CaMi score seems to predict postoperative survival and will now be applied to a larger population of patients for further validation and may be of use to physicians caring for patients with established intestinal failure as an additional guide to the timing of referral for transplantation.
597. Development of Non-Viral Gene Delivery Systems with Antibacterial Effects Deliverable via Aerosol for Lungs Gene Therapy
Authors: Angélique Mottais, Tony Le Gall, Mathieu Berchel, Yann Sibiril, Paul-Alain Jaffrès, Tristan Montier
Journal: Molecular Therapy (2016)

Objective: Cystic Fibrosis (CF) is a genetic disorder caused by the absence or malfunction of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). CF gene therapy would consist in delivering a normal copy of the CFTR gene in the nucleus of respiratory epithelial cells. The presence of bacteria in the pulmonary tract can alter the transported DNA, the transfection efficiency as well as targeted cells. At present, the leading method to target the respiratory epithelium being the nebulisation, the goal of this research project is to develop a formulation that can be delivered as an aerosol exhibiting both a transfection activity and an antibacterial activity. Methods: The formulated complexe was composed of 50% (molar percentage) of cationic lipid (an arseno-phospholipid whose transfection efficiency and antibacterial activity against Gram-positive bacteria have already been demonstrated) and 50% of a silver salt (active against Gram-negative bacteria). The transfection activity was evaluated according to the expression of a luciferase reporter gene into human bronchial epithelial cells grown in liquid culture or at air-liquid interface. The antibacterial activity was determined according to the difference of growth in agar plate between a protected area and an exposed area to the aerosol. Results: Contrary to the aerosolization of the classical lipoplexe, the formulation developed containing a silver salt possesses an antibacterial activity against the Gram-negative bacteria. The transfection activity is maintained post-aerosolization with some similar levels of expression to those observed with the cationic lipid used alone, and this both in liquid culture and at air-liquid interface. Discussion and Conclusion: This study shows that an equimolar combination of two compounds: an arseno-phospholipid and a silver salt (i) is simultaneously effective on bacteria frequently isolated from patients, (ii) has a very low human bronchial epithelial cells toxicity, and (iii) exhibits a transfection efficacy under clinically relevant conditions. Unlike a gene transfer system devoid of an antibacterial activity, such a combination may therefore participate in the eradication of bacteria, thus reducing the stress on the bronchial epithelial cells while promoting the transfection process and finally, the expression of the transgene.
OP63METASTATIC MEDULLOBLASTOMA - ARE DRUG RESISTANT CANCER STEM CELLS TWIST1NG AWAY?
Authors: Aishah Nasir, Ramadhan T. Othman, Lisa Storer, David Onion, Anbarasu Lourdusamy, Ian D. Kerr, Anna Grabowska, Beth Coyle
Journal: Neuro-Oncology (2015)

INTRODUCTION: Medulloblastoma is an aggressive malignant neuroectodermal tumour of the cerebellum that is frequently metastatic resulting in poor outcome.Here we use a 3D model of the tumour microenvironment (TME) to investigate whether an epithelial-mesenchymal transition (EMT)like process underlies metastasis.METHOD: Expression of EMT genes and the multidrug transporter ABCB1 was assessed by qRT-PCR on cell lines cultured either in 3D, within basement membrane extract for 8 days, or as 2D monolayers.TWIST1 and ABCB1 protein expression were assessed by immunohistochemistry. Time lapse imaging (Cell IQ) was used to investigate cell migration in 3D.RESULTS: Metastatic MED1 formed metabolically active branched interconnecting aggregates in 3D-culture whilst non-metastatic MED6, C17.2WNT and non-tumourigenic C17.2 cells demonstrated low metabolic activity and differentiation.EMT transcription factor TWIST1 expression doubled in MED1 cells grown in 3D compared to 2D, with no increase in expression observed in other cell types.Both TWIST1 and ABCB1 showed high focal positivity in the MED1 primary tumour and were significantly correlated with metastasis in patient samples (p , 0.02 and p , 0.04 respectively).TWIST1 and ABCB1 demonstrated a similar pattern of expression in spinal metastases in a MED1 orthotopic mouse model.The ABCB1 inhibitor vardenafil reduced formation of branched interconnecting aggregates in 3D without affecting MED1 cell metabolism.CONCLUSION: We have identified a TWIST1 controlled EMT-like process in metastatic medulloblastoma.Using a 3D-TME model we have shown that TWIST1 and ABCB1 may be interconnected and that ABCB1 inhibition could be sufficient to block metastatic induction.
336. Delivery Highways: Tunneling Nanotubes Facilitate Transfer of Therapeutic Molecules for Gene Therapy Treatment of Cystinosis
Authors: Spencer Goodman, Swati Naphade, Jay Sharma, Héloïse P. Gaide Chevronnay, Pierre J. Courtoy, Stephanie Cherqui
Journal: Molecular Therapy (2016)

Cystinosis is a lysosomal storage disorder caused by mutations in the CTNS gene, encoding the lysosomal transmembrane transporter cystinosin. As a consequence, cystine builds up in all tissues and eventually causes multi-organ degeneration, especially affecting the kidney and eye. We previously showed in Ctns−/− mice that transplantation of ex vivo lentiviral-transduced hematopoietic stem and progenitor cells (HSPCs) resulted in abundant integration of bone marrow-derived cells into all tissues and long-term kidney and eye preservation. We observed that HSPCs differentiated into macrophages that extended intercellular bridges called tunneling nanotubes (TNTs). TNTs are thin long actin-rich structures that provide a dynamic cytosol-cytosol connection enabling cellular communication as well as transfer of protein and organelles. In vitro co-culture of DsRed Ctns−/− fibroblasts with macrophages expressing cystinosin-GFP allowed visualization of bidirectional lysosome transfer through these TNTs. In vivo, we visualized TNTs in multiple tissues in lentiviral-modified HSPC-transplanted Ctns−/− mice. We observed the transfer of cystinosin-bearing lysosomes from macrophages into diseased host cells such as proximal tubular cells in the kidney and keratocytes in the eye. These findings represent the first observed instance of TNTs delivering a functional protein to facilitate tissue regeneration following gene therapy. Utilizing both genomic and proteomic approaches, putative novel constituents of TNTs were discovered and subsequently validated via RNAi. We also designed an application using ImagePro to automatically quantify and measure TNTs in vitro via morphological filters. With our ImagePro workflow and FACS-assisted immunoblotting, contributions of candidate proteins to TNT frequency, morphology and transfer efficiency were assessed. We further investigate the molecular nature of the TNTs and established new important protein candidates. In conclusion, HSPC transplantation can preserve near-normal kidney and eye architecture in cystinosis via a TNT-based transfer of functional protein. Understanding the mechanisms underlying TNT repair could spur the development of novel stem cell-based gene therapies for numerous genetic disorders.
Molecular profile of brain metastases from colorectal cancer and concordance with matched primary tumors
Authors: M. Casagrande, K. Rihawi, C. Fontanella, G. De Maglio, F. Tuniz, L. Ferrari, M. Bonotto, E. Ongaro, S.K. Garattini, V. Fanotto, L. Pagani, G.G. Cardellino, N. Pella, E. Iaiza, P. Ermacora, M. Giovannoni, S. Pizzolitto, G. Aprile, G. Fasola
Journal: Annals of Oncology (2015)
Novel Protein Glycan–Derived Markers of Systemic Inflammation and C-Reactive Protein in Relation to Glycemia, Insulin Resistance, and Insulin Secretion
Authors: Carlos Lorenzo, Andreas Festa, Anthony J. Hanley, Marian J. Rewers, Agustin Escalante, Steven M. Haffner
Journal: Diabetes Care (2016)

OBJECTIVE N-acetylglucosamine/galactosamine (GlycA) and sialic acid (GlycB) moieties of glycosylated serum proteins are nonspecific measures of inflammation, but conclusive data on their relationship with insulin resistance or insulin secretion are missing. Therefore, we aimed to examine the relation of GlycA, GlycB, and C-reactive protein (CRP) to direct measures of insulin sensitivity (insulin sensitivity index [SI]) and insulin secretion (acute insulin response [AIR]). RESEARCH DESIGN AND METHODS This study used cross-sectional analyses and included 1,225 participants with and without type 2 diabetes in the Insulin Resistance Atherosclerosis Study (IRAS). SI and AIR were measured using the frequently sampled intravenous glucose tolerance test, and GlycA and GlycB were measured using nuclear magnetic resonance spectroscopy. RESULTS GlycA and GlycB had a strong correlation with CRP (r = 0.60 [P &amp;lt; 0.001] and r = 0.46 [P &amp;lt; 0.001], respectively). In a linear regression model with both GlycA and CRP as independent variables, GlycA (β × 1 SD, −0.04 ± 0.02; P &amp;lt; 0.01) and CRP (−0.06 ± 0.02; P &amp;lt; 0.001) were independently associated with SI even after adjusting for demographics, smoking, physical activity, plasma glucose, and BMI. However, neither CRP nor GlycA had an independent relationship with AIR. CONCLUSIONS GlycA may complement CRP in evaluating the relationship between inflammation, glucose tolerance, and insulin resistance.
542. A Novel In Vitro/Vivo Selection/Suicide Strategy for Lentiviral Vectors
Authors: Sandra Ivic, Renier Myburgh, Francis Rousset, Karl-Heinz Krause, Roberto F. Speck
Journal: Molecular Therapy (2015)

Genetic engineering of hematopoietic progenitor cells (HPC) by lentiviral-based vectors suffers from their low transduction rate with ~20% when aiming a single integration event. This amount of modified cells may not be sufficient for the correction of a number of diseases and therefore enrichment of transduced cells would be needed. We propose a novel in vitro/in vivo selection/suicide system based on the expression of the human reduced folate carrier 1 (hRFC1) and the human ribonucleoside-diphosphate reductase subunit M2 (RRM2). These genes are encoding for proteins which are responsible for drug resistances/sensitivities. The vector design is based on a bicistronic self-inactivating vector, meaning that the vector comprises the ubiquitin promoter (UBI) which drives the expression of EGFP in order to track transduced cells. The PGK promoter drives the expression of hRFC1 and the RRM2, which are connected through the cleavage peptide T2A. The hRFC1 is the main transport protein for the uptake of folates which are indispensable for purine synthesis and therefore for DNA synthesis. A greater expression level of hRFC1 should render cells more sensitive to the antifolate Methotrexate (suicide), which mainly enters the cells via the hRFC1. In contrast, it is possible to enrich for the transduced cells with Trimetrexate, which is an analog of Methotrexate. Its very lipophilic nature allows Trimetrexate to passively diffuse through cell membranes. As a result, transduced cells can escape the toxic effects from Trimetrexate due to their augmented transport of folic acid trough the overexpressed hRFC. In contrast, non-transduced cells are expected to show the opposite effects with higher resistance to Methotrexate but lower threshold killing to Trimetrexate. The second resistance gene RRM2 catalyzes the reduction of ribonucleotides into desoxyribonucleotides and its overexpression should lead to resistance to the drug hydroxyurea. When applying both selection drugs (Trimetrexate and Hydroxyurea) we expect an additive or even synergistic toxic effect on non-transduced cells while the transduced cells experience lower side effects. We are currently examining the concept proposed in vitro using various cell lines. Providing promising results, we would like to use the vector on CD34+ hematopoietic stem cells derived from umbilical cord blood. In addition, we would like to transplant immunocompromised NSG mice with a mixture of transduced and non-transduced CD34+ cells and then apply the Trimetrexate/Hydroxyurea in vivo to select and then Methotrexate in order to remove the transduced cell from the circulation.
Smoking Adversely Affects Survival in Acute Myeloid Leukemia Patients.
Authors: Ramya Varadarajan, Andrea Licht, Andrew J. Hyland, Laurie Ann Ford, Maurice Barcos, Sheila N.J. Sait, AnneMarie W. Block, Maria R. Baer, James E. Thompson, Eunice S. Wang, Meir Wetzler
Journal: Blood (2009)
CCL3 and CCL4, the Major Chemokines Produced by CD38+ Chronic Lymphocytic Leukemia Cells, Facilitate Microenvironmental Interactions of Neoplastic Cells Via the CD49d/VCAM Pair.
Authors: Antonella Zucchetto, Dania Benedetti, Riccardo Bomben, Claudio Tripodo, Fleur Bossi, Michele Dal-Bo, Daniela Marconi, Massimo Degan, Giovanni Del Poeta, Silvia Deaglio, Francesco Tedesco, Gianluca Gaidano, Fabio Malavasi, Valter Gattei
Journal: Blood (2008)
A phase I trial of cabazitaxel ± rhenium-188-HEDP in patients with metastatic castration resistant prostate cancer who progressed on or after a docetaxel containing treatment.
Authors: Esther W. Bouman-Wammes, Joyce M. van Dodewaard-de Jong, Haiko Bloemendal, John M. H. de Klerk, Henk M.W. Verheul, Alfonsus Johannes Maria van den Eertwegh
Journal: Journal of Clinical Oncology (2016)

e16508 Background: In patients with metastatic castration resistant prostate cancer (mCRPC), bone-seeking radiopharmaceuticals such as rhenium-188-HEDP (re-188), are effective for pain palliation and have a marked anti-tumor effect. Cabazitaxel is the standard second-line chemotherapy for mCRPC patients. We performed a phase I study investigating the safety and feasibility of combined treatment with re-188 and cabazitaxel in mCRPC patients. Methods: Patients with mCRPC and documented disease progression on or after docetaxel were eligible for inclusion. The dose escalating schedule consisted of 2 dose levels, both containing 6 cycles of 3-weekly cabazitaxel. In the first level, 4 cycles of cabazitaxel 25 mg/m2 where followed by 2 cycles of cabazitaxel 20 mg/m2. Dose level 2 consisted of 6 cycles of cabazitaxel 25 mg/m2. In both levels, re-188 40 MBq/kg was administered 3 weeks after the 2nd and the 4th cycle of cabazitaxel with a 4 week interval to the next treatment cycle. Three patients were planned for each dose level, expanding to 6 in case of a dose limiting toxicity (DLT). A DLT was defined as any grade 4 toxicity (neutropenia grade 4 only if ≥ 7 days) or grade 3 toxicity leading to delay of the next cycle of treatment. Results: Twelve patients were included, of whom 3 had progressive disease before the 3rd cycle of cabazitaxel. Eight patients completed the whole integrated treatment, 1 patient was withdrawn after cycle 6 due to a DLT. This DLT occurred in dose level 1, after the 2nd cycle of re-188 (thrombopenia grade 3 causing delay of the next cycle of treatment). The cohort was expanded to 6 patients, with no further DLTs. No DLT occurred in dose level 2. The most important adverse events were of hematological origin (see table), followed by mild fatigue and diarrhea (46% and 12% respectively). We will perform a randomized phase II study using dose level 2. Conclusions: Combination therapy with cabazitaxel and re-188 is feasible and generally well tolerated. Clinical trial information: NTR3233.Adverse events (in 70 treatment cycles) Grade 1 Grade 2 Grade 3 / 4 Anemia 50 (71%) 20 (29%) 0 / 0 Thrombopenia 21 (30%) 8 (11%) 3 (4%) / 0 Neutropenia 0 5 (7%) 8 (11%) / 16 (23%) Neutropenic fever 1 (1%) / 0
Novel candidate genes underlying extreme trophic specialization in Caribbean pupfishes
Authors: Joseph A. McGirr, Christopher H. Martin
Journal: Molecular Biology and Evolution (2016)

The genetic changes responsible for evolutionary transitions from generalist to specialist phenotypes are poorly understood. Here we examine the genetic basis of craniofacial traits enabling novel trophic specialization in a sympatric radiation of Cyprinodon pupfishes endemic to San Salvador Island, Bahamas. This recent radiation consists of a generalist species and two novel specialists: a small-jawed "snail-eater" and a large-jawed "scale-eater." We genotyped 12 million single nucleotide polymorphisms (SNPs) by whole-genome resequencing of 37 individuals of all three species from nine populations and integrated genome-wide divergence scans with association mapping to identify divergent regions containing putatively causal SNPs affecting jaw size—the most rapidly diversifying trait in this radiation. A mere 22 fixed variants accompanied extreme ecological divergence between generalist and scale-eater species. We identified 31 regions (20 kb) containing variants fixed between specialists that were significantly associated with variation in jaw size which contained 11 genes annotated for skeletal system effects and 18 novel candidate genes never previously associated with craniofacial phenotypes. Six of these 31 regions showed robust signs of hard selective sweeps after accounting for demographic history. Our data are consistent with predictions based on quantitative genetic models of adaptation, suggesting that the effect sizes of regions influencing jaw phenotypes are positively correlated with distance between fitness peaks on a complex adaptive landscape.
Molecular Characterization Of Myeloid Neoplasms Harboring Isochromosome 17q Abnormality
Authors: Valeria Visconte, Ali Tabarroki, Li Zhang, Edy Hasrouni, Chris Gerace, Robyn Frum, Anjali S. Advani, Hien K. Duong, Matt Kalaycio, Yogen Saunthararajah, Mikkael A. Sekeres, Eric D. Hsi, Shashirekha Shetty, Heesun J. Rogers, Ramon V. Tiu
Journal: Blood (2013)