tbuckley/cabot-search huggingface dataset:
704. Long-Term Correction of Crigler-Najjar Syndrome and Scale-Up Production of an Optimized AAV8 Vector Expressing the UGT1A1 Transgene
Authors: Giulia Bortolussi, Fanny Collaud, Remco van Dijk, Giuseppe Ronzitti, Severine Charles, Samia Martin, Alban Vignaud, Florence Lacoste, Christine Le Bec, Matthias Hebben, Fulvio Mavilio, Piter Bosma, Andres F. Muro, Federico Mingozzi
Journal: Molecular Therapy (2015)

Crigler-Najjar syndrome (CN) is an autosomal recessive rare disorder caused by mutations in the UDP-glucuronosyltransferase 1 isotype A1 (UGT1A1) gene. In severe CN, lack or reduced activity of UGT1A1 results in high levels of serum unconjugated bilirubin (UCB), which can lead to brain damage and death. Treatment of CN consists of phototherapy for 10-12 hours per day to convert UCB into soluble photoisomers without the need of conjugation, which presents several limitations and has a major impact on life quality of the patients. Liver transplantation is the only curative option for CN. The limited therapeutic options available prompted us to develop a new therapy for CN based on the transfer of a corrected copy of the UGT1A1 gene to hepatocytes. We developed an AAV8 vector optimized for the liver expression of the hUGT1A1 transgene (AAV8-hUGT1A1). Safety and efficacy of correction of total serum bilirubin (TB) levels with AAV-hUGT1A1 were demonstrated in mouse and rat models of CN at vector doses as low as 5×10 11 vector genomes (vg)/kg, a result confirmed also by the detection of conjugated bilirubin in bile of treated rats. In juvenile CN rats, long-term correction of total bilirubin levels were observed for more than 8 months following AAV8-hUGT1A1 gene transfer. In neonate Ugt1a1–/– mice, intraperitoneal delivery of the vector at doses as low as 1×10 9 vg/mouse resulted in correction of TB at 4 weeks. However, vector delivery in P2 and P4 animals resulted in lower efficiency of correction when compared with P11-transduced mice, a finding likely due to the more advanced development of the liver at later time points. Based on these data, dose finding studies were performed in CN rats, which showed a profile of liver transduction with AAV8 vectors similar to humans, i.e. lower efficiency of transduction than mice. No differences in efficacy of correction of TB were observed in male vs. female rats. A scalable process for the production of AAV8-hUGT1A1 production was established based on a protocol of triple transfection of suspension HEK293 cells, leading to high yield vector preparations with excellent purity profile. In vitro transduction assays in human hepatocytes based on Western blot for hUGT1A1 protein and in vivo studies in CN rats demonstrated that vectors produced with the suspension process have potency characteristics undistinguishable from research grade vectors produced by triple transfection of adherent cells and purified by cesium chloride gradient centrifugation. In conclusion, our data demonstrate the safety and efficacy of gene transfer for Crigler-Najjar syndrome in two relevant animal models of the disease and provide tools and a strong rationale for the translation of these results in human subjects.
ALL Xenografts Reveal the Importance of Anti-CD19-Chimeric Antigen Receptor Cell Dose, Cell Persistence and Surprising Antitumor Activity of CD4+ Anti-CD19-CAR T Cells in Eradicating Pediatric Acute Lymphocytic Leukemia In Vivo
Authors: Daniel W. Lee, James N Kochenderfer, Rimas J Orentas, Elizabeth G. Gardner, Crystal L Mackall
Journal: Blood (2011)
453. Protection Against Lethal Dengue Challenge By IM Delivery of Synthetic, EP-Delivered DNA Encoding Designed Anti-Dengue Neutralizing Antibodies
Authors: Seleeke F. Flingai, Emily M. Plummer, Ami Patel, Sujan Shresta, Janess M. Mendoza, Kate E. Broderick, Niranjan Y. Sardesai, Kar Muthumani, David B. Weiner
Journal: Molecular Therapy (2015)

Dengue virus (DENV) is the most important mosquito-borne viral infection in humans, with nearly 400 million infections occurring each year and a continually expanding geographic reach. While vaccines are being developed, none are currently available that provide balanced protection against all DENV serotypes. Advances in human antibody isolation have uncovered DENV neutralizing antibodies (nAbs) that are capable of preventing infection from multiple serotypes. Yet delivering monoclonal antibodies using conventional methods is impractical due to high costs. Engineering nucleic acid-based strategies for delivering monoclonal antibodies could tip the scale in the fight against DENV, as well as other emerging infectious diseases. Here, we describe an approach to delivering cross-reactive neutralizing antibodies against DENV into the host circulation using DNA plasmid-mediated antibody gene transfer. This approach, which we term DNA mAb (DMAB) delivery, generates biologically relevant levels of mAbs after a single intramuscular injection of antibody-encoding DNA followed by in vivo electroporation (EP). Since this approach allows for genetic tailoring of the exact features of the desired antibody, we incorporated Fc region modifications to a naturally occurring human anti-DENV neutralizing antibody to enhance antibody function in vivo. We demonstrate that intramuscular delivery in mice of pDVSF-3 LALA, which encodes a human anti-DENV1-3 IgG1 neutralizing antibody modified with a mutation that abrogates FcgR binding, produces anti-DENV antisera capable of binding and neutralizing DENV1-3. Importantly, mice receiving pDVSF-3 LALA, but not the unmodified pDVSF-3 WT, were protected from both virus-only disease and antibody-enhanced lethal disease. These data establish this novel platform as a safe, effective means of delivering protective monoclonal antibodies to a host. This work was supported by grants funded to DBW through the National Institutes of Health, the DARPA-PROTECT award, and Inovio Pharmaceuticals Inc.
Loss of Structural Maintenance of Chromosomes 1A Protein Expression Is Associated with a Poor Prognosis in Acute Myelogenous Leukemia.
Authors: Utz O. Krug, Claudia Hömme, Nicola Tidow, Horst Buerger, Gabriele Koehler, Achim Heinecke, Thomas Buchner, Wolfgang E Berdel, Steffen Koschmieder, Carsten Mueller-Tidow
Journal: Blood (2009)
Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma and methylated <i>O<sup>6</sup>-methylguanine-DNA methyltransferase</i> (<i>MGMT</i>) gene promoter: Key results of the multicenter, randomized, open-label, controlled, phase III CENTRIC study.
Authors: Roger Stupp, Monika E. Hegi, Thierry Gorlia, Sara Erridge, Danica Grujicic, Joachim Peter Steinbach, Wolfgang Wick, Rafal Tarnawski, Do-Hyun Nam, Astrid Weyerbrock, Peter Hau, Martin JB Taphoorn, Louis B. Nabors, David A. Reardon, Martin J. Van Den Bent, James R. Perry, Yong Kil Hong, Christine Hicking, Martin Picard, Michael Weller
Journal: Journal of Clinical Oncology (2013)

LBA2009 Background: Cilengitide (CIL) is a selective αvβ3 and αvβ5 integrin inhibitor. In a phase II study in patients with newly diagnosed glioblastoma, CIL added to standard temozolomide (TMZ) and radiotherapy (RT) was well tolerated and appeared to confer improved survival in patients with glioblastoma and methylated MGMT gene promoter (Stupp et al. J Clin Oncol. 2010;28:2712-8). Methods: This multicenter, randomized, controlled, open-label, phase III study randomized (1:1) patients (≥ 18 years) with newly diagnosed, histologically proven supratentorial glioblastoma (WHO Grade IV) and centrally determined MGMT gene promoter methylation. Treatment consisted of CIL 2000 mg twice weekly i.v. plus standard TMZ/RT→TMZ (concomitant and adjuvant temozolomide and radiotherapy; Stupp et al. N Engl J Med. 2005;352:987-96) or standard TMZ/RT→TMZ alone. CIL was to be administered for ≥ 18 months, or until disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) per investigator read and safety. Results: 272 patients received CIL plus TMZ/RT→TMZ, and 273 were treated with TMZ/RT→TMZ alone (intention-to-treat population). 54% and 52% of patients were male, and 42% and 44% had ECOG-PS ≥ 1, respectively. 75% of patients of both arms were ≥ 50 years old. Overall, baseline characteristics were well balanced across treatment arms. Median OS was 26.3 months in both arms (Hazard Ratio [HR] = 1.02 [95%CI: 0.81-1.29], p = 0.86). Median PFS per investigator read was 13.5 months in the CIL arm and 10.7 months in the control arm (HR = 0.93 [95%CI: 0.76-1.14], p = 0.48). Treatment was generally well tolerated and the known safety profile of CIL was confirmed. Conclusions: CIL failed to prolong PFS or OS in patients with newly diagnosed glioblastoma and methylated MGMT gene promoter. The previously reported safety profile of CIL in addition to standard therapy was confirmed. Clinical trial information: NCT00689221.
168. A Novel TNF-alpha siRNA Formulation for Potential Treatment of Chronic Inflammation
Authors: Abdulaziz M. Aldayel, Mengmeng Niu, Zhengrong Cui
Journal: Molecular Therapy (2015)

Small interfering RNA (siRNA) can be used to selectively reduce protein expression. Tumor necrosis factor-α (TNF-α) plays a critical role in chronic inflammation. The purpose of this study is to develop, characterize and evaluate a novel TNF-α siRNA-loaded PLGA nanoparticle formulation for potential treatment of chronic inflammation.
Abstract 5068: Treatment with regorafenib inhibits the tumor-promoting effect of bone marrow-derived mesenchymal stem cells in an orthotopic nude mice model of colon cancer
Authors: Kei Shinagawa, Yasuhiko Kitadai, Ryo Yuge, Mieko Onoyama, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama
Journal: Cancer Research (2015)

Abstract Bone marrow-derived mesenchymal stem cells (MSCs) have been reported to migrate to tumor stroma as well as injured tissue. We reported that, in an orthotopic nude mice model of colon cancer, MSCs travel to tumor stroma and differentiate into carcinoma-associated fibroblasts (CAFs), and then, they promote growth and metastasis of colon cancer. We also found that CAFs express platelet-derived growth factor receptor-beta (PDGFR-β), at a high level and that imatinib therapy targeting PDGFR in CAFs combined with administration of a cytotoxic drug significantly inhibits growth and metastasis of human colon cancer. A novel oral multi-kinase inhibitor, regorafenib not only inhibits oncogenic receptor tyrosine kinases such as c-KIT, RET, and B-RAF, but also inhibits stromal cells which express VEGFR1-3, TIE2, PDGFR-β, and fibroblast growth factor receptor 1 (FGFR1). These cell surface receptor tyrosine kinases are known to be involved in tumor neovascularization, vessel stabilization, lymphatic vessel formation as well as activation of stroma. We examined whether the effect of MSCs on tumor growth and metastasis was inhibited by regorafenib. KM12SM human colon cancer cells alone or KM12SM cells mixed with MSCs in a 1:2 ratio were transplanted into the cecal wall of nude mice. Orthotopic transplantation of KM12SM cells + MSCs, in comparison to transplantation of KM12SM cells alone, resulted in tumors of greater weight and volume, and higher rate of lymphatic metastasis. Co-injection of MSCs with tumor cells promoted tumor growth and metastasis of colon cancer by enhancing angiogenesis, lymphangiogenesis, and tumor cell proliferation and by inhibiting tumor cell apoptosis. When CRC tumor + MSCs bearing animals were treated with regorafenib (by oral gavage once daily at 10 mg/kg for 35 days), primary tumor size or the number of lymph node metastases were significantly decreased compared to those treated with vehicle, and reached to the level with no significant difference from KM12SM tumor cells alone. Our data suggest that targeting tumor microenvironmental signaling pathways by regorafenib influences the interaction between bone marrow-derived MSCs and tumor cells and, hence, inhibits the progressive growth of colon cancer. Citation Format: Kei Shinagawa, Yasuhiko Kitadai, Ryo Yuge, Mieko Onoyama, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama. Treatment with regorafenib inhibits the tumor-promoting effect of bone marrow-derived mesenchymal stem cells in an orthotopic nude mice model of colon 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 5068. doi:10.1158/1538-7445.AM2015-5068
Dual Inhibition of mTOR and Pim Kinase Pathways Using Small Molecule Inhibitors Synergistically Kills Myeloid Leukemic Cells In Vitro and In Vivo.
Authors: Yingwei Lin, Amanda M Graham, Luciano J Costa, Zanna M Beharry, Michael S Rosol, Zuping Xia, Baby Tholanikunnel, Robert K Stuart, Andrew S Kraft
Journal: Blood (2010)
Prognostic Impact of Percentage CD34 Expression in Bone Marrow Trephines of Patients with Chronic Myeloid Leukaemia in Chronic Phase Treated with Imatinib.
Authors: David Marin, Donna Horncastle, Catherina Andreasson, Victoria Elliot, Jonhn M. Goldman, Jane F. Apperley, Kirkkeri Naresh, Irvin A. Lampert
Journal: Blood (2004)
High incidence of Philadelphia chromosome-like acute lymphoblastic leukemia in older adults with B-ALL
Authors: S K Tasian, C Hurtz, G B Wertheim, N G Bailey, M S Lim, R C Harvey, I-M Chen, C L Willman, R Astles, A Zebrowski, S C Reshmi, M M Li, N V Frey, S M Luger, M Carroll, A E Perl
Journal: Leukemia (2016)
RESTART: Rehabilitation Evaluation in Survivors of Testicular Cancer after Radical Treatment—Pilot study effect on HADS-anxiety subscore.
Authors: Jeff D. White, Gordon J. S. Rustin, Jennifer Harrington, Chris Hewitt, Sandra White, Teresa Young, Claire Lawless, Elaine McCartney, Vivienne Abbas, Christine Brannan, Lesley Somerville, Nicola Thomson, Melanie Winterbotham, James Paul
Journal: Journal of Clinical Oncology (2013)

9590 Background: Most testis cancer (TC) patients are cured, but some experience significant physical and psychological consequences. Multi-dimensional rehabilitation programmes have largely been studied in breast cancer, with positive effects on physical and psychological well being. The needs of young males are likely to be significantly different. Addressing the ‘Survivorship agenda’, we performed a study of the feasibility, composition and acceptability of a rehabilitation programme for TC patients. Methods: TC patients, aged &gt;16, who had completed all radical treatment within the preceding 8 weeks, with no major cardio-respiratory problems were eligible. The 6 week multi-dimensional programme consisted of the following; exercise, psychological wellbeing, nutrition, finance, fertility, return to work and follow up. Primary end point was change in the HADS anxiety sub-score from pre (Week 1) to post the programme (Week 6). To detect with 90% power at the 10% 1-sided level of statistical significance a within patient change of 1.5 in the HADS anxiety sub-score (assuming a within patient SD of 3), 26 evaluable participants were required. Secondary objectives were the effect on QOL, HADS depression, exercise capacity and BMI. Results: 35 patients were recruited in 5 cohorts between Feb 2012 and Nov 2012 from 2 UK Cancer Centres; 32 patients were evaluable for the primary end point. Mean age at registration was 38 years (SD =10.45). 94% of the evaluable participants attended 5 or more sessions (30/32 participants). Participant feedback; 36.7% rated their overall score as 10 out of 10, with 93% of participants rating the programme ≥8. Conclusions: A multi-faceted rehabilitation programme appears deliverable and acceptable in TC patients. The study demonstrates a positive effect with a reduction in HADS anxiety score following participation. Having established the feasibility of this programme, a RCT of the programme vs. standard care is planned. Clinical trial information: ISRCTN77608320. [Table: see text]
A Phase I/II Trial of the Kinesin Spindle Protein (KSP) Inhibitor SB- 743921 Administered on Days 1 and 15 Every 28 Days without and with Prophylactic G-CSF in Non-Hodgkin or Hodgkin Lymphoma.
Authors: John Gerecitano, O. O’Connor, H. Van Deventer, J. Hainsworth, J. Leonard, A. Goy, B. Afanasyev, M. Chen, K. Saikali, M. G Conlan, R Escandon, A Wolff
Journal: Blood (2008)
Angiogenic Cytokines Are Increased in the Serum of Patients with Waldenstrom’s Macroglobulinemia: Correlations with Clinical Data.
Authors: Athanasios Anagnostopoulos, Evangelos Terpos, Efstathios Kastritis, Aristotelis Bamias, Konstantinos Tsionos, Meletios A. Dimopoulos
Journal: Blood (2005)
Abstract 665: Inhibition of mitochondrial complex I enhances the therapeutic benefit of BRAF inhibition in mutant melanoma cell lines
Authors: Laura Schoeckel, Katharina Bitschar, Mélanie Héroult, Charlotte Kopitz, Andrea Hägebarth
Journal: Cancer Research (2015)

Abstract Metabolic reprogramming is considered to be one of the major hallmarks of cancer. Selective inhibitors of mutant BRAFV600E, are a widely used targeted therapy for melanoma. Unfortunately, acquired drug resistance, which commonly occurs, represents a major limitation to clinical efficacy. Recent studies have highlighted the role of BRAF inhibition in promoting oxidative phosphorylation (OXPHOS), over glycolysis, in BRAFV600E melanomas, a switch commonly seen in conjunction with development of drug resistance. This metabolic switch occurs at the transcriptional level, indicated by the up-regulation of PGC1α through the lineage-specific transcription factor MITF. Based on these data, we propose that increased OXPHOS is required for melanoma cells to acquire resistance against the BRAF inhibition, which supports our investigation of the therapeutic benefit of combining BRAF and OXPHOS inhibitors. For the latter, respiratory Complex I, an essential enzyme in the mitochondrial respiratory chain, is a logical target for OXPHOS inhibition. We investigated the molecular, metabolic and bioenergetic effects of a selective mutant BRAF inhibitor (Vemurafenib/PLX4032) and BAY 87-2243, a small molecule inhibiting respiratory Complex I, in vitro using various BRAF-mutant melanoma cell lines. First, our study revealed that BRAF inhibition increased the expression of mitochondrial genes and mitochondrial respiration, which is associated with elevated mitochondrial oxidative stress, independent of the expression of PGC1α. Furthermore, BAY 87-2243 inhibited OXPHOS, down-regulated the expression of mitochondrial genes and increased reactive oxygen species (ROS) production. We also demonstrated that inhibition of BRAF increased the OXPHOS phenotype and therefore enhanced the effect of BAY 87-2243 on mitochondrial metabolism; the combination of both inhibitors showed synergistic effects in vitro.Interestingly, long term BRAF inhibition resulted in BRAFV600E melanoma cells to become resistant to BAY 87-2243. Preliminary studies suggest that melanoma cells pretreated with a BRAF inhibitor, with higher rates of mitochondrial respiration and elevated ROS levels, are prone to cell death when targeted by pro-oxidants. Further studies are currently ongoing to understand this resistance phenotype as well as the underlying mechanism which drives the synergistic drug effect. Citation Format: Laura Schoeckel, Katharina Bitschar, Mélanie Héroult, Charlotte Kopitz, Andrea Hägebarth. Inhibition of mitochondrial complex I enhances the therapeutic benefit of BRAF inhibition in mutant melanoma cell lines. [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 665. doi:10.1158/1538-7445.AM2015-665
Abstract 1142: COP1 functions as a sensor of cellular lipids and regulator of lipogenesis in human cancer cells
Authors: Chenfei Huang, Yiwen Bu, Deliang Cao
Journal: Cancer Research (2015)

Abstract Background Constitutive photomorphogenesis protein 1 (COP1; also known as Rfwd2), an evolutionally conserved E3 ubiquitin ligase, has been defined to mediate the degradation of several important proteins, such as p53, c-Jun, ETS, FOXO1 and ACC1, being involved in tumorigenesis. In response to DNA damage, COP1 is autodegraded in the context of ATM, which is triggered by 14-3-3σ. However, the biological function and expression regulation of COP1 remain to be fully understood. This study reports a novel function of COP1 in lipid metabolism. Methods We targeted COP1 expression in cancer cells MCF-7 and HepG2 with COP1 shRNA lentivirus and COP1 overexpression lentivirus, respectively. We investigated the lipid synthesis, glucose oxidation and conversion into lipids in these cells using radiolabeled acetate and glucose and lipid complex analysis. Quantitative real-time PCR and Western blot were used to examine gene expression. Acetyl CoA carboxylase-1 (ACC1) siRNA and TOFA, an inhibitor of ACC1, were used to modulate the intracellular lipid synthesis. Results Lipid depletion induced by acetyl CoA carboxylase-1 (ACC1) knockdown or the inhibition of ACC1 by TOFA induced COP1 expression, but palmatic acid, the end-product of de novo fatty acid synthesis pathway, reversed TOFA-induced COP1 expression. In addition, U73122, an inhibitor of phospholipase C that cleaves PIP2 into DAG and IP3, triggered COP1 expression. These data suggest that COP1 expression is mediated by cellular lipid state, and the lipid second messengers (PIP2 and DAG) are involved in the expression regulation of COP1. In contrast, the ectopic expression of COP1 greatly reduced pAMPK and pACC1 levels, but elevated fatty acid synthase (FASN) expression, leading to the increase of fatty acid (FA)/lipid synthesis. In sharp contrast, siRNA-mediated COP1 knockdown in cancer cells significantly increased pACC1 and pAMPK levels and reduced FASN expression, leading to decrease of lipid synthesis. The cell growth and proliferation was accordingly changed in response to the alterations of lipid synthesis. Altogether our data suggest that COP1 expression is regulated through the lipid second messenger mediated signaling, and the upregulated COP1 in turn enhances lipid synthesis, functioning as a positive feedback. Conclusion COP1 functions as a sensor of cellular lipid state and promoter of lipogenesis, facilitating tumorigenesis. Note: This abstract was not presented at the meeting. Citation Format: Chenfei Huang, Yiwen Bu, Deliang Cao. COP1 functions as a sensor of cellular lipids and regulator of lipogenesis in human 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 1142. doi:10.1158/1538-7445.AM2015-1142