tbuckley/cabot-search huggingface dataset:
Clinical effects of Wilms tumor protein (WT) 1 peptide vaccination in patients with WT1-expressing solid tumors as compared to patients with AML/MDS.
Authors: A. Letsch, C. Scheibenbogen, A. M. Asemissen, K. Zimmermann, S. Bauer, M. Voelker-Call, D. Stather, E. Thiel, U. Keilholz
Journal: Journal of Clinical Oncology (2011)

2560 Background: WT1 holds great promise for cancer immunotherapy, is expressed in many hematologic and solid malignancies, and is essential for tumor proliferation. After demonstrating good immunological and clinical efficacy of WT1 peptide vaccination in patients with active AML and MDS, we have initiated a vaccination trial for patients with WT1 expressing carcinomas. We here compare immunogenicity and clinical efficacy among carcinoma patients (CP) and AML/MDS patients. Methods: Patients with ovarian (n=8), thyroid (n=2), breast (n=1), gastric (n=1), and larynx cancer (n=1), astrocytoma (n=1) and mesothelioma (n=3) received 0.2mg HLA-A0201-restricted WT1.126-134 peptide admixed with 1 mg KLH (day 3), and 62.5µg GM-CSF (day 1-4). Quantitation of WT1 specific T cells was performed in peripheral blood (PB) of CP by tetramer staining and compared with analogue analyses in 25 AML/MDS patients. Results: Seventeen CP received a median of 11 vaccinations (range 1-35) and 12 of 17 are evaluable for T cell response. None of the 12 had WT1-specific T cells at baseline, in contrast to 28% of AML/MDS patients. After 4 vaccinations WT1-specific T cells were detectable in 67% of CP and in 54% of AML/MDS patients. After 6 vaccinations WT1-specific T cells were present in 40% of CP and in 78% of AML/MDS patients. Thus, the overall conversion rate was 75% in CP and 56% in AML/MDS. WT1 specific CD8+ T cells in most AML/MDS patients remained detectable during the course of vaccination, whereas in CP WT1 specific CD8+ T cells were only transient, despite of continuation of vaccination and ongoing clinical efficacy, which was demonstrated with 1 partial remission and 6 disease stabilisations between 2 and 22+ months. Conclusions: These results demonstrate profound differences in spontaneous and vaccine induced T cell response among patients with haematological and solid malignancies, suggesting considerably higher spontaneous immunogenicity of AML/MDS, but a higher conversion rate in CP. In contrast to AML/MDS WT1 specific T cells in PB of CP were despite ongoing clinical efficacy only transient, possibly due to migration into the tumor.
Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma Leads to Early Identification of At-Risk Individuals
Authors: Emmanuelle Souzeau, Kien Hou Tram, Martin Witney, Jonathan B. Ruddle, Stuart L. Graham, Paul R. Healey, Ivan Goldberg, David A. Mackey, Alex W. Hewitt, Kathryn P. Burdon, Jamie E. Craig
Journal: Ophthalmology (2016)
494. Development of a pH Sensor to Probe Endosomal Buffering of Polymeric Nanoparticles Effective for Gene Delivery
Authors: David R. Wilson, Denis Routkevitch, Karl J. Wahlin, Don J. Zack, Alfredo Quinones-Hinojosa, Jordan J. Green
Journal: Molecular Therapy (2016)

Introduction: Polymeric gene delivery suffers from low efficacy compared to viral gene delivery with one of the primary barriers to successful transfection being efficient endosomal escape. Cationic polymers have been hypothesized to facilitate endosomal escape via the proton sponge mechanism by buffering hydrogen ions in the endosomal compartment. Here we have created a nucleic acid based pH sensor and applied it using flow cytometry and confocal microscopy to investigate endosomal buffering of synthetic biodegradable cationic polymers for gene delivery, correlating the pH of delivered DNA with transfection. Methods: We created a nucleic acid pH sensor by conjugating pH sensitive (FITC, OG) and insensitive (Cy5) fluorophores to plasmid DNA. The fluorescence ratio of the sensor was calibrated to pH using flow cytometry and confocal microscopy following electroporation into cells. Cells were transfected with the plasmid pH sensor complexed with cationic polymers including poly(beta-amino ester)s (PBAEs) of variable transfection efficacy to investigate endosomal buffering. Additionally, confocal microscopy was used to assess colocalization of the plasmid pH sensor with a lysosomal dye. Results: PBAEs were demonstrated to effectively buffer endosomes and avoid lysosomal fate, whereas the negative controls poly-L-lysine (PLL) and polyethylenimine (PEI) were shown to accumulate in lysosomes by 24h post-transfection. The polymer molecular weight and weight-weight ratio to plasmid DNA was shown to have an effect on endosomal buffering as well as transfection efficacy in the case of PBAEs. From confocal microscopy analysis of endosomes, local pH was observed to be higher at the endosomal membrane than in the center, which may be indicative of polymer enrichment along the membrane due to excess soluble polymer. Conclusions: The constructed DNA sensor gave a linear relationship with intracellular pH. When investigating PBAE-induced buffering, results were consistent with the hypothesized proton sponge mechanism. These cationic polymers were demonstrated to affect endosomal pH and DNA lysosomal fate and lead to successful transfection.
Osteoporosis in Sickle Cell/β-Thalassemia Is Primarily Caused by an Imbalance at the RANKL/OPG Pathway.
Authors: Ersi Voskaridou, Ioannis Papassotiriou, Evangelos Premetis, John Meletis, Dimitris Loukopoulos, Evangelos Terpos
Journal: Blood (2005)
Human Factor VIII Expression and Normalization of Bleeding Following AAV Gene Therapy in a Double Knockout Mouse Model of Hemophilia
Authors: Stuart Bunting, Lening Zhang, Lin Xie, Sherry Bullens, Rajeev Mahimkar, Sylvia Fong, Krystal Sandza, Peter Colosi, Shinong Long, Gordon Allen Vehar, Barrie Carter
Journal: Blood (2015)
Cyclophosphamide, Thalidomide and Dexamethasone (CTD) Versus Melphalan Plus Dexamethasone (MD) for Newly-Diagnosed Systemic AL Amyloidosis – Results From the UK Amyloidosis Treatment Trial.
Authors: Julian Gillmore, Kim Cocks, Simon DJ Gibbs, Prayman T Sattianayagam, Thirusha Lane, Helen Lachmann, Stephen Schey, James D. Cavenagh, Heather Oakervee, Gareth J Morgan, Atul B Mehta, Suzan Bourne, E. Skinner, G. Booth, Philip N Hawkins, Ashutosh D Wechalekar
Journal: Blood (2009)
Leukemic Blasts Secondary to Myelodysplastic Syndromes Are Molecularly Programmed To Differentiate into Functionally Mature Dendritic Cells.
Authors: Serena K. Perna, Monica Casucci, Attilio Bondanza, Zulma Magnani, Massimo Bernardi, Alessandro Crotta, Alessandro Cignetti, Ferderico Caligaris Cappio, Fabio Ciceri, Claudio Bordignon, Chiara Bonini
Journal: Blood (2007)
Combination Therapy with Alemtuzumab and Pentostatin Is Effective and Has Acceptable Toxicity in Patients with T-Lymphoid Neoplasms.
Authors: Farhad Ravandi-Kashani, Hagop Kantarjian, Stefan Faderl, Srdan Verstovsek, Charles Koller, Shirley Odinga, William Wierda, Gautam Borthakur, Dan Jones, Francis Giles, Susan O’Brien, Michael Keating
Journal: Blood (2006)
Abstract 4448: Identification of a small molecule inhibitor of aldolase A for the targeting of hypoxic cancer cells
Authors: Petrus R. de Jong, Geoffrey V. Grandjean, Ashwini K. Devkota, Eun Jeong Cho, Kevin N. Dalby, Garth Powis
Journal: Cancer Research (2015)

Abstract Cancer cells are critically dependent on glycolysis. Currently, there is no effective pharmacotherapy that exploits this metabolic vulnerability. We have uncovered a feed forward cycle of anaerobic glycolysis and hypoxia-inducible factor-1 (HIF-1). Glycolysis under hypoxic conditions normally maintains high ATP levels, which is driven by transcriptional activity of HIF-1. Glycolysis inhibition results in a cellular energy crisis, i.e. an increased AMP:ATP ratio, leading to AMPK-mediated phosphorylation of the HIF-1 co-activator p300/CBP. This prevents HIF-1 activity, although HIF-1 protein levels are unchanged, abrogating the feed forward cycle. We identified fructose-1,6-bisphosphate aldolase A (ALDOA) as a top glycolytic enzyme target for inhibiting hypoxic cancer cell glycolysis and HIF-1 activity. Our aim was to identify small molecule inhibitors for ALDOA that may yield compounds for further preclinical development. To this end, a primary high-throughput screen (HTS) was performed with 65,936 compounds using a fluorescence-based NADH oxidation aldolase (cell-free) assay. 640 compounds were further tested in a cherry-pick confirmation screen, from which 112 hits underwent concentration-response curve validation in cell-free assays. From these, 4 hits were further tested in cell-based assays by using colorectal, breast and pancreatic cancer cell lines. A lead compound that showed micromolar potency in inhibiting ALDOA, induced cell death under hypoxic conditions with IC50 values ranging between 2 - 8 μM in the cancer cell lines tested. It also inhibited extracellular flux in a real-time glycolysis assay, inhibited extracellular lactate production under hypoxic conditions as a measure of glycolysis, and blocked hypoxia responsive element (HRE) HIF-1 reporter activity but not HIF-1 protein levels. No effect of the lead compound was observed on mitochondrial respiration. Thus, this compound provides a valuable chemical probe for inhibiting glycolysis in cancer cells. Furthermore, the work provides proof-of-concept that targeting glycolysis with a small molecule inhibitor exerts potent antitumor effects in vitro and is currently being tested in preclinical models as a first-in-class oncological agent. Citation Format: Petrus R. de Jong, Geoffrey V. Grandjean, Ashwini K. Devkota, Eun Jeong Cho, Kevin N. Dalby, Garth Powis. Identification of a small molecule inhibitor of aldolase A for the targeting of hypoxic cancer cells. [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 4448. doi:10.1158/1538-7445.AM2015-4448
323. Efficient Generation of CART Cells by Homology Directed Transgene Integration into the TCR-Alpha Locus
Authors: Baeckseung Lee, Hang Leung, Jordan Jarjour, Alexander Astrakhan
Journal: Molecular Therapy (2016)

Genetically engineered cancer targeting CAR-T cells have generated promising results in a series of B cell derived cancers. Development of these therapies for solid tumor applications has been much more difficult and will likely require extensive T cell engineering to improve both efficacy and safety. Advanced gene editing approaches were developed to enable simultaneous disruption of a target gene combined with introduction of exogenous transgenes at the disrupted locus. A gene specific megaTAL nuclease was used to generate double stranded DNA breaks followed by transduction with adeno-associated virus (AAV) encoding new genetic information flanked by regions of homology proximal to the nuclease breakpoint. Highly efficient introduction of a CD19-specific CAR transgene into the T cell receptor-alpha constant (TRAC) locus was demonstrated using this approach. T cells treated with the TRAC megaTAL and corresponding AAV encoding a CD19 CAR and TRAC homology arms generated greater than 50% of CD19-CAR positive T cells that no longer expressed the T cell receptor complex. In vitro assays confirmed that TRAC-targeted CD19-CAR T cells were comparable to CD19 CAR-T cells generated by lentiviral transduction in their cytotoxicity and cytokine responses against CD19+ Nalm-6 cells. These findings demonstrate the potential of megaTAL driven homology directed T cell genome engineering to obviate the need for traditional integrating viral vectors and generate a defined and potentially more potent T cell product by combining gene disruption with targeted transgene integration.
Abstract 601: Glycodelin expression in lung cancer and melanoma
Authors: Laura Hautala, Hannu Koistinen
Journal: Cancer Research (2015)

Abstract Glycodelin (PAEP) is a lipocalin protein mainly expressed in well-differentiated epithelial cells in reproductive tissues. Previously, glycodelin has been shown to induce cell differentiation in endometrial and breast cancer cells. In breast cancer this was associated with reduced xenograft tumor growth. In ovarian and breast cancers glycodelin expression has been found to associate with a favorable prognosis as compared to glycodelin non-expressing tumors. Some preliminary studies suggest that glycodelin expression is increased also in lung cancer and melanoma. We studied the expression of glycodelin in these cancers using immunohistochemical staining of tissue arrays. Furthermore, the levels of mRNA were addressed utilizing in silico transcriptomics database (IST Online). Glycodelin transcripts were more abundant in lung adenocarcinoma and melanoma as compared to non-malignant lung or squamous cell carcinoma of the lung and skin tissues, respectively. While immunohistochemical staining also showed increased staining of glycodelin in lung adenocarcinoma as compared to squamous cell carcinoma of the lung, there was no clear difference in staining as compared to normal lung tissue. Weak staining of glycodelin was observed both in normal skin and melanoma tissues. However, some melanoma cases showed very strong staining. In conclusion, our data show that glycodelin is expressed both in melanoma and lung adenocarcinoma, and in some cases the expression is increased. However, the clinical relevance of these findings remains to be established. Citation Format: Laura Hautala, Hannu Koistinen. Glycodelin expression in lung cancer and melanoma. [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 601. doi:10.1158/1538-7445.AM2015-601
Abstract 1095: <i>In silico</i> mapping of oncogene networks implicate the WNT pathway in the glioblastoma MES subtype
Authors: Anna M. Joy, Ivan Smirnov, Mark Reiser, Seungchan Kim, Burt Feuerstein
Journal: Cancer Research (2015)

Abstract It is clear that glioblastoma (GBM) is a collection of molecular subtypes, however little is known of their oncogene signaling. To address this we are currently developing a new method to map PI3K/AKT/mTOR network activity. It uses TCGA reverse-phase protein array data and is based on correlations between active pathway members. This approach provides evidence the WNT pathway is active in the Mesenchymal subgroup and we are currently validating these results. Based on this data we hypothesize Mesenchymal patients will respond to WNT inhibitors. Citation Format: Anna M. Joy, Ivan Smirnov, Mark Reiser, Seungchan Kim, Burt Feuerstein. In silico mapping of oncogene networks implicate the WNT pathway in the glioblastoma MES subtype. [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 1095. doi:10.1158/1538-7445.AM2015-1095
Abstract 1950: Emerging role of CITED2 in hypoxia and TGF-beta mediated proliferation and invasion in lung cancer
Authors: Ming-Han Kuo, Cheng-Han Hsieh, Yuan-Hung Wang, Cheng-Wen Wu, Yu-Ting Chou
Journal: Cancer Research (2015)

Abstract Lung cancer remains the leading cause of cancer mortality in the world. Metastatic property is one of the major reasons for treatment failure in lung cancer patients. Tumor microenvironment plays a key role in shaping tumor progression. In solid tumors, a decreased oxygen and nutrient supply creates a hypoxic microenvironment in the central region, which elicits a set of genes to endow cancer cells with increased survival or proliferation abilities. On the other hand, TGF-beta, which is often released by tumor stroma cells, attenuates cell proliferation but induces invasion of lung cancer. How cancer cells are shaped by tumor microenvironment with elevated proliferation and invasion abilities are elusive. Here, we report that CITED2, a MYC interacting transcriptional modulator, responds to hypoxia induction and TGF-beta suppression to orchestrate cellular proliferation and invasion, respectively. We observed that hypoxia induced CITED2 expression in a group of lung cancer cells, the proliferation and survival of which were dependent on CITED2 signaling. TGF-beta stimulation inhibited CITED2 expression, causing decreased cell proliferation. Nonetheless, hypoxia potentiated TGF-beta mediated invasion and rendered cell resistant to TGF-beta induced cell growth arrest by elevating CITED2 dependent signaling. Our findings provide that CITED2 functions as an oncogeneic switch for hypoxia and TGF-beta mediated proliferation and invasion in lung cancer, deserving additional evaluation as a biomarker for lung cancer progression. Citation Format: Ming-Han Kuo, Cheng-Han Hsieh, Yuan-Hung Wang, Cheng-Wen Wu, Yu-Ting Chou. Emerging role of CITED2 in hypoxia and TGF-beta mediated proliferation and invasion 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 1950. doi:10.1158/1538-7445.AM2015-1950
Imatinib Mesylate (IM) Versus IM + Low Dose of Pegylated Interferon Alfa 2a (Peg-IFN 2a) In Newly-Diagnosed Chronic-Phase (CP) Chronic Myeloid Leukemia (CML).
Authors: Luis Antonio Meillon, Salvador Campos-Cabrera, Nancy Delgado-Lopez, Angel A. Fernandez-Martinez, Jesus Medrano-Contreras, Guillermo Gutierrez, Juan F. Perez-Rocha, Eduardo Terreros-Muñoz, Sue C. Gomez-Cortes, Susana Guerrero-Rivera, Kevin A. Nacho-Vargas
Journal: Blood (2010)
High Dose Cytarabine and Mitoxantrone in Combination with Dasatinib As Active Induction Therapy in Adult Patients with Philadelphia Chromosome Positive (ph+) Acute Lymphoblastic Leukemia (ALL)
Authors: Nicole Lamanna, Mark Weiss, Ellin Berman, Mark G. Frattini, Mark Heaney, Joseph G. Jurcic, Todd L. Rosenblat, Heather Landau, Hanna Weissbrot, Peter G. Maslak
Journal: Blood (2012)
651. Integration of Dual Signal Inputs Strategies in Novel Chimeric Antigen Receptors to Control the CAR T-Cell Functions
Authors: Alexandre Juillerat, Alan Marechal, Jean Marie Filhol, Yannick Valogne, Valérie Guyot, Anne-Sophie Gautron, Julien Valton, Aymeric Duclert, Laurent Poirot, Philippe Duchateau
Journal: Molecular Therapy (2016)

Adoptive immunotherapy using engineered T-cells has emerged as a powerful approach to treat cancer. The potential of this approach relies on the ability to redirect the specificity of T cells through genetic engineering. Novel specificities in T cells have been typically implemented through the genetic transfer of the so-called chimeric antigen receptors (CARs). CARs are synthetic receptors composed of an extracellular targeting moiety and one or more intracytoplasmic signaling domain derived from lymphocyte activation receptors. Present CAR architectures are designed to combine all relevant domains within a single polypeptide, thereby; they combine advantages of MHC unrestricted target recognition to the potent native effector mechanisms of the T cell. Although adoptive transfer of CAR T cells is proven to be an effective cancer therapy, potential adverse effects such as cytokine release syndrome (CRS) and/or the risk of on-target off-tumor targeting are still a major concern. Synthetic biology applies many of the principles of engineering to the field of biology in order to create biological devices which can ultimately be integrated into increasingly complex systems. Our ability to engineer synthetic systems in primary T-cells that function as Boolean logic gates responding to multiple inputs would benefit adoptive immunotherapy using engineered T-cells. Exogenous or endogenous environmental signal integration by a modular AND gate may represent an important advancement in improving our control of the safety of the CAR T-cell technology. Here, we describe the development of novel CAR designs that integrate new components directly within the CAR architecture to improve our capacity to spatiotemporally control and switch the CAR T-cells functions between on and off states. In particular, we showed that such a system can be engineered to control the CAR through addition of an exogenous small molecule (Rapamycin or synthetic rapalogs) ultimately inducing the cytolytic properties of the engineered T-cell. Alternatively, properties of the tumor microenvironment can also be used as additional endogenous input to the target antigen recognition. We showed that low oxygen levels can be used to trigger the CAR surface presentation, creating a so called "self-decision making" CAR T-cell.
Randomized Phase III Trial of Erlotinib versus Docetaxel in Patients with Advanced Squamous Cell Non–Small Cell Lung Cancer Failing First-Line Platinum-Based Doublet Chemotherapy Stratified by VeriStrat Good versus VeriStrat Poor. The European Thoracic Oncology Platform (ETOP) EMPHASIS-lung Trial
Authors: Solange Peters, Rolf A. Stahel, Urania Dafni, Santiago Ponce Aix, Bartomeu Massutí, Oliver Gautschi, Linda Coate, Ana López Martín, Robbert van Heemst, Thierry Berghmans, Peter Meldgaard, Manuel Cobo Dols, Javier Garde Noguera, Alessandra Curioni-Fontecedro, Daniel Rauch, Michael T. Mark, Sinead Cuffe, Bonne Biesma, Arjen M.J. van Henten, Óscar Juan Vidal, Ramón Palmero Sanchez, José Carlos Villa Guzmán, Ricardo Collado Martin, Sergio Peralta, Amelia Insa, Yvonne Summers, István Láng, Anne Horgan, Fortunato Ciardiello, Sander de Hosson, Remge Pieterman, Harry J.M. Groen, Paul M. van den Berg, Christoph C. Zielinski, Yojena Chittazhathu Kurian Kuruvilla, Adriana Gasca-Ruchti, Marie Kassapian, Silvia Novello, Valter Torri, Zoi Tsourti, Vanesa Gregorc, Egbert F. Smit
Journal: Journal of Thoracic Oncology (2016)

Docetaxel and erlotinib are registered second-line treatments for wild-type EGFR NSCLC. Previous studies suggested a predictive value of the VeriStrat test in second-line therapy of NSCLC, classifying patients as either VeriStrat good or VeriStrat poor. EMPHASIS-lung aimed at exploring this predictive effect in patients with squamous cell NSCLC. The trial closed prematurely because of low accrual and results from other trials. Our analysis includes an exploratory combined analysis with results from the PROSE trial.EMPHASIS-lung was a randomized phase III multicenter trial exploring the differential effect of second-line erlotinib versus docetaxel on progression-free survival (PFS) in VeriStrat good versus VeriStrat poor patients with squamous cell NSCLC.A total of 80 patients were randomized, with 72.5% categorized as VeriStrat good. Patient characteristics were balanced between VeriStrat status and treatment groups. The median PFS times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 4.1 and 1.6 months, respectively, versus 1.9 and 2.1 months, respectively, in the VeriStrat poor cohort. The median overall survival (OS) times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 7.8 and 8.4 months, respectively, and 4.4 and 5.2 months, respectively, in the VeriStrat poor cohort. An additional exploratory analysis was performed; in it, 47 patients from the squamous cell subgroup of PROSE were included in a combined analysis, contributing with 45 PFS and 41 OS events.The final analysis of EMPHASIS-lung did not show a differential effect on PFS for erlotinib versus docetaxel stratified by VeriStrat status. Similarly, in the combined analysis, no significant treatment by VeriStrat status interaction was observed (interaction p = 0.24 for PFS and 0.45 for OS, stratified by study).