tbuckley/cabot-search huggingface dataset:
690. Development of a Clinical Lentiviral Vector for Gene Therapy of SCID-X1
Authors: Sabine Charrier, Valentina Poletti, Samia Martin, Bernard Gjata, Matthias Hebben, Alban Vignaud, Fang Zhang, Karen Buckland, Michael Rothe, Axel Schambach, Bobby Gaspar, Adrian Thrasher, Fulvio Mavilio
Journal: Molecular Therapy (2016)

X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the gene encoding the interleukin-2 receptor γ chain (IL2RG), and is characterized by profound immunological defects caused by a partial or complete absence of T and NK cells and the presence of non-functional B cells. To overcome the safety issues raised by the use of MLV-based retroviral vectors in previous gene therapy clinical trials, we designed a SIN lentiviral vector (LV) carrying the codon-optimized human IL2RG cDNA under the control of the human EF1αS promoter and a mutated WPRE. Replacement of the native IL2RG open reading frame by a codon-optimized sequence resulted in a 3-fold increase in mRNA expression and a 1.5-fold increase in IL2RG protein expression per integrated vector copy. The vector was VSV-G-pseudotyped and produced by a new manufacturing process based on quadri-transfection of suspension-adapted 293T cells grown in serum-free conditions in 50- to 200-L bioreactors, purified by ion-exchange chromatography and concentrated by tangential-flow filtration. The efficacy of this vector was demonstrated in vitro by the restoration of a normal level of IL2RG mRNA or protein in a human IL2RG-deficient T-cell line at a VCN of 1 to 3 and by high efficiency (81±7%) transduction of human mobilized CD34+ hematopoietic stem/progenitor cells with no impact on viability or clonogenic capacity. A biosafety evaluation study of the IL2RG LV in the murine model of the disease showed biodistribution of the transgene in hematopoietic organs only, restoration of T, B and NK cell counts, normalization of lymphoid organs (thymus and spleen) and a low frequency of hematopoietic malignancies, comparable to that of untreated animals. An in vitro assay (IVIM) showed a safe genotoxic profile, while insertion site analysis in transplanted mice revealed a standard lentiviral integration profile and no signs of clonal dominance. These studies will enable a multicenter phase-I/II clinical trial aimed at establishing the safety and clinical efficacy of lentiviral vector-mediated gene therapy for SCID-X1.
Type I interferon signaling in systemic immune cells from patients with alcoholic cirrhosis and its association with outcome
Authors: Emmanuel Weiss, Pierre-Emmanuel Rautou, Magali Fasseu, Mikhael Giabicani, Marc de Chambrun, JingHong Wan, Charlotte Minsart, Thierry Gustot, Alain Couvineau, Rakhi Maiwall, Margarita Hurtado-Nedelec, Nathalie Pilard, Didier Lebrec, Dominique Valla, François Durand, Pierre de la Grange, Renato C. Monteiro, Catherine Paugam-Burtz, Sophie Lotersztajn, Richard Moreau
Journal: Journal of Hepatology (2016)
Mitochondrial Genome Instability in AML Is Associated with Reduction in the Mitochondrial Replication.
Authors: Myung-Geun Shin, Hyeoung-Joon Kim, Hye-Ran Kim, Il-Kwon Lee, Duck Cho, Seung-Jung Kee, Hoon Kook, Tai-Ju Hwang, Jong-Hee Shin, Soon-Pal Suh, Dong-Wook Ryang
Journal: Blood (2005)
Significant Improvement In Overall Survival In Patients Who Underwent Autologous Hematopoietic Cell Transplant In the US or Canada Between 1994 and 2005
Authors: Philip L. McCarthy, Theresa Hahn, Anna Hassebroek, John P. Klein, J. Douglas Rizzo, Susan Parsons, Steven Joffe, Navneet S. Majhail
Journal: Blood (2010)
Abstract 1740: Allosteric Hsp70-family inhibitors as targeted anticancer therapeutics
Authors: John Koren, Chao Xu, Anna Rodina, Liza Shrestha, Tony Taldone, Gabriela Chiosis
Journal: Cancer Research (2015)

Abstract Background: Hsp70, a molecular chaperone responsible, in part, for the folding of nascent peptides following translation, has been implicated as a survival factor and a poor prognostic marker in cancer cells. These pro-cancer mechanisms originate in the ability of Hsp70 to preserve and maintain oncogenic and transformative proteins responsible for the cancer phenotype. Hsp70 is a stress response protein such that expression increases under proteomic/proteotoxic stress events. This increased expression is also evident in cancer cells, an environment under proteomic stress brought on by transformation, and is known to be protective against programmed cell death. Hypothesis: We predict that by interrupting the chaperoning capacity of Hsp70 through allosteric inhibition, we can destabilize oncogenic proteins dependent on Hsp70 for structure and function. Additionally, as Hsp70 is a survival factor, we believe that a loss of Hsp70 activity will result in cancer specific cell death both in vitro and in vivo. Approach: Using chemical tools, primarily novel allosteric Hsp70 inhibiting small molecules, we will determine the fate of oncogenic proteins dependent on Hsp70 for stability. We will also examine the cellular response to the disruption of cancer-specific networks which require Hsp70. In vivo tumor models will be used to examine the pharmacokinetics and pharmacodynamics of small molecule Hsp70 inhibitors and to evaluate the therapeutic potential of Hsp70 inhibition. Significance: The stress response machinery is responsible for the stability of proteins, maintenance of signaling pathways, and evasion from programmed cell death while a cell is under stress; stressors including oncogenic transformation. These pathways maintained by the molecular chaperones have been directly linked to deleterious cancer phenotypes including aggressiveness and the emergence of therapeutic resistances. Targeted therapeutics, and uniquely those targeting the molecular chaperone system, can provide therapeutic options capable of ablating the specific mechanisms involved in proteomic stability and cell survival unique to each tumor cell; effects which can be delivered with minimal effect to normal tissue. This work highlights the potential for therapeutics targeting Hsp70 as anti-cancer agents. Citation Format: John Koren, Chao Xu, Anna Rodina, Liza Shrestha, Tony Taldone, Gabriela Chiosis. Allosteric Hsp70-family inhibitors as targeted anticancer therapeutics. [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 1740. doi:10.1158/1538-7445.AM2015-1740
Abstract 1000: Tyrosine kinase receptor EGFR regulates the switch between cell survival and cell death induced by autophagy under hypoxia in cancer cells
Authors: Spencer B. Gibson, Yongqiang Chen, Elizabeth S. Henson, Daniel Huang
Journal: Cancer Research (2015)

Abstract Autophagy is an intracellular lysosomal degradation pathway characterized by the formation of autophagosomes. The primary function of autophagy is to allow cells to survive under stressful conditions. Autophagy is, however, a double-edge sword that can either promote cell survival or cell death. In cancer, hypoxia regions contribute to poor prognosis due to the ability of cancer cells to adapt to hypoxia in part through autophagy. In contrast, we have previously demonstrated that autophagy contributes to hypoxia induced cell death in cancer cells. In this study, we demonstrated that autophagy flux increased under hypoxia over time. At 4 hours of hypoxia, autophagy promoted cell survival whereas, at 48 hours of hypoxia, autophagy increased cell death. Furthermore, we found that the tyrosine phosphorylation of epidermal growth factor receptor (EGFR) increased at 4 hours and decreased at later times. This correlated with the ability of EGFR to bind with Beclin-1 at 4 hours but not 48 hours under hypoxia. Knocking down or inhibiting EGFR resulted in increased autophagy and cell death under hypoxia. In contrast, when EGFR was re-activated by the addition of EGF, the level of autophagy was reduced and amount of cell death decreased. Hypoxia led to autophagic excessive degradation of the lipid raft protein caveolin-1 (CAV1) that is known to bind to EGFR and activate EGFR in a ligand-independent manner under hypoxia. By knocking down CAV1, the amount of EGFR phosphorylation was increased under hypoxia and amount of autophagy and cell death decreased. This indicates that the activation of EGFR plays a critical role in the switch between cell survival and cell death induced by autophagy under hypoxia. Citation Format: Spencer B. Gibson, Yongqiang Chen, Elizabeth S. Henson, Daniel Huang. Tyrosine kinase receptor EGFR regulates the switch between cell survival and cell death induced by autophagy under hypoxia in 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 1000. doi:10.1158/1538-7445.AM2015-1000
Abstract 3706: Risk of bladder and kidney cancers in end-stage renal disease patients: a nationwide, population-based study in Taiwan
Authors: Wei-Tang Kao, Cheng-Huang Shen, Kee-Thai Kiu, Hsin-An Chen, Chia-Chang Wu, Yuan-Hung Wang
Journal: Cancer Research (2015)

Abstract Chronic kidney disease (CKD) was the tenth leading cause of death in Taiwan. as the fifth stage of progressive CKD. Various therapeutic modalities including hemodialysis (HD),peritoneal dialysis (PD) and renal transplantation (RT) modify the risks of systemic chronic diseases in end-stage renal disease (ESRD) patients remains unclear. A total of 18,081 newly diagnosed ESRD patients and 54,243 controls matched for age, gender and index date were recruited from the National Health Insurance Research Database in Taiwan. The ESRD status was confirmed by the registry of catastrophic illness. The incidence of cancer was identified through cross-referencing with the National Cancer Registry Database. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox proportional hazards model. Kaplan-Meier method were used for all analyses. Significant higher incidence rate ratios (IRRs) of bladder cancer of 7.0, 9.5 and 14.4 were found for ESRD patients undergoing HD, PD and RT, respectively. The IRRs of kidney cancer also represent a similar risk pattern. We observed that significant bladder cancer risks were observed among ESRD patients undergoing HD (HR = 10.0), PD (HR = 12.8) and RT (17.7) after the adjustment for age, gender and co-morbidities. In addition, significant kidney cancer risks of 11.2, 17.1 and 33.7 were also found for ESRD patients undergoing HD, PD and RT, respectively. In conclusion, different therapeutic modalities could modify the risks of bladder and kidney cancers in ESRD patients in Taiwan. Citation Format: Wei-Tang Kao, Cheng-Huang Shen, Kee-Thai Kiu, Hsin-An Chen, Chia-Chang Wu, Yuan-Hung Wang. Risk of bladder and kidney cancers in end-stage renal disease patients: a nationwide, population-based study in Taiwan. [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 3706. doi:10.1158/1538-7445.AM2015-3706
Abstract 2525: MLN4924 synergistically enhances cisplatin-induced cytotoxicity via JNK and Bcl-xL pathways in human urothelial carcinoma - In vitro and in vivo study
Authors: I-Lin Ho, Kuan-Lin Kuo, Chien-Tso Chou, Chen-Hsun Hsu, Yeong-Shiau Pu, Ju-Ton Hsieh, Kuo-How Huang
Journal: Cancer Research (2015)

Abstract Introduction Cisplatin-based chemotherapy is the main treatment for metastatic bladder urothelial carcinoma; however, the response rate is only approximately 40-65%. Many patients will encounter drug resistance to chemotherapy eventually. Therefore, combination therapies to enhance the efficacy of cisplatin and to overcome drug resistance are imperative for the treatment of urothelial carcinoma. The aim of this study was to investigate the antitumor effect and underlying mechanisms for the combination of cisplatin and MLN4924, a NEDD8-activating enzyme inhibitor, in human bladder urothelial carcinoma. Materials &amp; Methods We used MTT assays and CalcuSyn software to calculate the combination index of cisplatin and MLN4924. The expression levels of DNA damage response regulators, apoptotic-related molecules, MAPK and Bcl-xL were revealed by western blot. c-Jun N-terminal kinase (JNK) inhibitor (SP600125) and overexpression of Bcl-xL were used to investigate the relationship between JNK and Bcl-xL. The in vitro findings were further confirmed in vivo via xenograft mouse model. Results The combination of cisplatin and MLN4924 exerted synergistic cytotoxicity on two high-grade bladder urothelial carcinoma cell lines, NTUB1 and T24 (combination index &amp;lt;1). In addition, MLN4924 potentiated cisplatin-induced apoptosis and activation of caspase-3, 7, phospho-histone H2A.X and PARP. We also observed c-Jun N-terminal kinase (JNK) activation with down-regulation of Bcl-xL during cisplatin and MLN4924 treatment. The inhibition of JNK activation partially restored cell viability as well as the expression of B-cell lymphoma-extra large (Bcl-xL); moreover, the overexpression of Bcl-xL rescued cell viability. In the in vivo study, MLN4924 significantly potentiated cisplatin-induced tumor suppression in urothelial carcinoma xenograft mice. Conclusion In summary, MLN4924 synergistically enhanced the antitumor effect of cisplatin through increasing DNA damage, JNK activation and down-regulating Bcl-xL in urothelial carcinoma cells. These findings provide a new therapeutiuc strategy for bladder cancer. Citation Format: I-Lin Ho, Kuan-Lin Kuo, Chien-Tso Chou, Chen-Hsun Hsu, Yeong-Shiau Pu, Ju-Ton Hsieh, Kuo-How Huang. MLN4924 synergistically enhances cisplatin-induced cytotoxicity via JNK and Bcl-xL pathways in human urothelial carcinoma - In vitro and in vivo study. [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 2525. doi:10.1158/1538-7445.AM2015-2525
High Dose Melphalan Followed By Autologous Stem Cell Transplant in AL Amyloidosis: a Single-Center Experience
Authors: Mariella D'Adda, Francesca Schieppati, Samantha Ferrari, Claudia Crippa, Annalisa Peli, Alessandro Re, Enrico Morello, Paola Tozzi, Vincenza Orlando, Giuseppe Rossi
Journal: Blood (2014)
Abstract 797: Discovery of a highly selective and potent small molecule inhibitor against c-MET for cancer therapy
Authors: Rudi Bao, Zhongzong Pan, Zhiming Zhao, Hongping Yu, Yaochang Xu
Journal: Cancer Research (2015)

Abstract c-MET is a receptor tyrosine kinase that is dysregulated in several types of maliganacies, including gastric, liver and lung cancers. Abnormal activation of c-MET could be caused by gene amplification, overexpression, or HGF aberrant expression. Activation of c-MET is involved in several cellular processes, including cell proliferation, cell migration, and angiogenesis. To explore c-MET targeted therapy, we discovered a small molecule that selectively inhibits c-MET activity with an IC50 of single digit nanomolar concentration across several cell lines. In xenograft tumor models from cell lines harboring cMET amplification including liver, gastric and lung cancer, tumor growth was significantly inhibited by this compound in a dose dependent manner. In addition, PD studies showed that c-MET and down-stream signaling pathways were blocked by the compound in the cMET amplified tumors. The compound also showed desirable PK and safety profiles. These data warrants further development of this compound for cancer therapy in cMET dysregulated cancers. Citation Format: Rudi Bao, Zhongzong Pan, Zhiming Zhao, Hongping Yu, Yaochang Xu. Discovery of a highly selective and potent small molecule inhibitor against c-MET for cancer therapy. [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 797. doi:10.1158/1538-7445.AM2015-797
143. Durable Expression of TT-034 in Cynomolgus Monkey Hepatic and Cardiac Tissues without Long-Term Adverse Effects on Endogenous MicroRNA Levels
Authors: Tin Mao, Shih-Chu Kao, David Suhy
Journal: Molecular Therapy (2016)

Background: The hepatitis C virus (HCV) is an attractive target for RNA interference (RNAi) based therapeutics because its genome consists of a single, positive stranded RNA and its replication occurs strictly within the cytoplasm. TT-034 is a DNA-directed RNAi (ddRNAi) based gene therapy product for the treatment of chronic HCV infection and is currently in a phase I/IIa clinical trial. TT-034 is comprised of a self-complementary recombinant adeno-associated virus (AAV) serotype 8 vector for transduction of hepatic tissues and is systemically administered as a single intravenous dose. Inside the hepatocyte, TT-034 uses the cell's own transcriptional machinery to continuously express three independent short hairpin RNAs (shRNAs) that simultaneously target the 5' UTR and NS5B regions of the HCV genome. Results: Following a single administration of up to 3.75E12 vg/kg of TT-034, biodistribution analyses demonstrated that greater than 90% of the quantified vector is found in the Cynomolgus monkey liver tissues. In situ hybridization analyses demonstrated almost 100% transduction of the hepatocytes when dosed at 1.25E12 vg/kg. Furthermore, qPCR data revealed that shRNA levels persisted for the duration of the 180-day experiment, demonstrating the durability of expression following a single injection. We examined the impact of continuous TT-034 expression on endogenous miRNAs in liver and cardiac tissues because previous reports have suggested that high expression of shRNA may cause global dysregulation of endogenous microRNA (miRNA) levels within cells. Non-human primates were dosed with saline control or either 1.00E11, 1.00E12, 1.00E13 vg/kg of TT-034. Expression profiles of mature miRNAs were generated from liver biopsies taken 15 days after TT-034 administration. Additionally, samples from liver and heart tissues were collected 60 and 180 days after administration. Approximately 260 different miRNAs were reliably detected in each sample type and used for the analyses. The day 15 liver samples showed significant differences in the expression levels of 27 miRNAs. When analyzing all 260 miRNAs, the day 60 and day 180 liver samples showed no significant statistical differences from the control group at any dose. In the heart tissues, no significant statistical differences between the TT-034 treated group and the control group were noted at any timepoint. Conclusions: These data suggest that a single, intravenous infusion of TT-034 results in almost complete transduction of Cynomolgus monkey hepatocytes. Furthermore, TT-034 results in durable expression of three anti-HCV shRNAs. These doses of TT-034 do not cause long-term perturbation of endogenous miRNA levels.
Alterations in the band3/Rh Protein Complex in Erythrocyte Membranes of Protein 4.2 (Chartres) deficient Cells Occur Late during Erythropoiesis
Authors: Emi le van den Akker, Timothy J Satchwell, Jo F Flatt, Stephanie Pellegrin, M. Maigre, Richard B Sessions, Geoff Daniels, Jean Delaunay, Lesley J Bruce, Ashley M Toye
Journal: Blood (2008)
Targeting of Aberrant αvβ6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells
Authors: Lynsey M Whilding, Ana C Parente-Pereira, Tomasz Zabinski, David M Davies, Roseanna M G Petrovic, Y Vincent Kao, Shobhit A Saxena, Alex Romain, Jose A Costa-Guerra, Shelia Violette, Hiroaki Itamochi, Sadaf Ghaem-Maghami, Sabari Vallath, John F Marshall, John Maher
Journal: Molecular Therapy (2017)

Expression of the αvβ6 integrin is upregulated in several solid tumors. In contrast, physiologic expression of this epithelial-specific integrin is restricted to development and epithelial re-modeling. Here, we describe, for the first time, the development of a chimeric antigen receptor (CAR) that couples the recognition of this integrin to the delivery of potent therapeutic activity in a diverse repertoire of solid tumor models. Highly selective targeting αvβ6 was achieved using a foot and mouth disease virus-derived A20 peptide, coupled to a fused CD28+CD3 endodomain. To achieve selective expansion of CAR T cells ex vivo, an IL-4-responsive fusion gene (4αβ) was co-expressed, which delivers a selective mitogenic signal to engineered T cells only. In vivo efficacy was demonstrated in mice with established ovarian, breast, and pancreatic tumor xenografts, all of which express αvβ6 at intermediate to high levels. SCID beige mice were used for these studies because they are susceptible to cytokine release syndrome, unlike more immune-compromised strains. Nonetheless, although the CAR also engages mouse αvβ6, mild and reversible toxicity was only observed when supra-therapeutic doses of CAR T cells were administered parenterally. These data support the clinical evaluation of αvβ6 re-targeted CAR T cell immunotherapy in solid tumors that express this integrin.
Akt-Mediated Phosphorylation of Bmi1 Regulates Its Chromatin Association and Growth Promoting Properties.
Authors: Yan Liu, Fan Liu, Xinyang Zhao, Goro Sashida, Anthony Deblasio, Zhenbang Chen, Hui-kuan Lin, Silvana Di Giandomenico, Shannon Elf, Youyang Yang, Yasuhiko Miyata, Gang Huang, Silvia Menendez, Ingo Mellinghoff, Pier Paolo Pandolfi, Cyrus V. Hedvat, Stephen D. Nimer
Journal: Blood (2009)
Doctors condemn need for Red Cross to step in to aid NHS in “humanitarian crisis”
Authors: Adrian O’Dowd
Journal: BMJ (2017)

Doctors’ leaders have attacked the government for allowing pressure on the NHS in England to grow to the extent that the volunteer charity the British Red Cross has stepped in to help the NHS, highlighting the urgency of need.

The British Red Cross said that several NHS trusts had called on it in recent weeks to help them cope with demand and described the situation as a “humanitarian crisis” in some areas. The charity said that it had deployed staff to help out in hospitals and had provided transport for discharged patients, in particular to support the East Midlands Ambulance Service on New Year’s day. It was also having talks with several hospitals about providing additional support, it said.

The charity has a longstanding arrangement to step in and help NHS providers and local authorities that come seeking help in particularly busy times, but it is unusual for it …
P2.05-013 Stereotactic Brain Radiosurgery in Lung Cancer Patients in the Era of Personalized Therapy: A Review of Outcomes and Prognostic Scores Evaluation
Authors: Florence Siu-Ting Mok, Michael K.M. Kam, Wai Kong Tsang, Darren Ming Chung Poon, Herbert H. Loong
Journal: Journal of Thoracic Oncology (2017)
OA22.02 Nintedanib plus Pemetrexed/Cisplatin in Patients with MPM: Phase II Findings from the Placebo-Controlled LUME-Meso Trial
Authors: Federica Grosso, Nicola Steele, Silvia Novello, Anna Nowak, Sanjay Popat, Laurent Greillier, Thomas John, Natasha Leighl, Martin Reck, Paul Taylor, Nick Pavlakis, Jens Benn Sørensen, David Planchard, Giovanni Ceresoli, Brett Hughes, Julien Mazieres, Mark Socinski, Martha Mueller, Ute Von Wangenheim, Arsene Bienvenu Loembe, Nassim Morsli, Jose Barrueco, Giorgio Scagliotti
Journal: Journal of Thoracic Oncology (2017)
P3.02b-071 First-Line Gefitinib for EGFR-Mutated Lung Adenocarcinoma Patients with Bone Metastases - A Single Institution Experience
Authors: Davorin Radosavljevic, Jelena Spasic, Nemanja Stanic, Marija Ristic, Milos Ratknic
Journal: Journal of Thoracic Oncology (2017)
P1.02-030 Performance Evaluation of ALK/ROS1 Dual Break Apart FISH Probe Kit (RUO) in Non-Small-Cell Lung Cancer
Authors: Hyun Chang, Sun Min Lim, Hye Ryun Kim, Yoon Jin Cha, Liang Shel, Gu Li, Yan Chin Tai, Ekaterina Pestova, Frank Polichit, Thomas Perez, Ross Soo, Won Young Park, Hyo Sup Shim, Byoung Chul Cho
Journal: Journal of Thoracic Oncology (2017)