tbuckley/cabot-search huggingface dataset:
Abstract 523: Decrease of ARNT promotes cancer metastasis by activating the fibronectin/integrin β1/FAK axis
Authors: Chi-Ruei Huang, Chung-Ta Lee, Kwang-Yu Chang, Wen-Chang Chang, Ben-Kuen Chen
Journal: Cancer Research (2015)

Abstract The aryl hydrocarbon receptor nuclear translocator (ARNT) is widely involved in regulating the tumorigenesis process by inducing genes that are involved in tumor growth and angiogenesis. Tumorigenesis usually involves normoxic conditions. However, the role of ARNT in tumor metastasis during normoxia remains unclear. Here, we demonstrated that ARNT protein levels were decreased in late stage human colorectal cancer using an immunohistochemical analysis. Stably silence of the ARNT protein promoted cancer cell migration and invasion, which was mediated by the activation of the fibronectin/integrin β1/FAK signaling axis. In addition, ARNT knockdown-induced migration and invasion was inhibited when ARNT was restored in cells. In a xenograft analysis of severe combined immunodeficiency mice, ARNT-knockdown inhibited tumor growth. However, when ARNT expression recovered, the tumor growth of ARNT-knockdown-induced metastatic lung colonies was significantly enhanced. Interestingly, chemotherapeutic drugs inhibited ARNT expression and promoted invasion of residual tumor cells. These results suggested that ARNT may play a positive role during tumor growth (either in early stage tumor growth or in metastatic organs), but plays a negative role in tumor migration and invasion. Therefore, the efficiency of ARNT-targeted therapy in different cancer stages should be carefully evaluated. Citation Format: Chi-Ruei Huang, Chung-Ta Lee, Kwang-Yu Chang, Wen-Chang Chang, Ben-Kuen Chen. Decrease of ARNT promotes cancer metastasis by activating the fibronectin/integrin β1/FAK axis. [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 523. doi:10.1158/1538-7445.AM2015-523
Abstract 5229: Disruption of the acetylcholine signaling pathway suppresses the growth and angiogenesis of human lung cancers
Authors: Piyali Dasgupta, Kathleen C. Brown, Jamie K. Lau, Aaron M. Dom, Brent A. Thornhill, Clayton M. Crabtree, Theodore R. Witte, W E. Hardman, Cody A. Stover, A B. Carpenter, Yi C. Chen
Journal: Cancer Research (2015)

Abstract Cigarette smoking bears a strong association with the development of lung cancer. Nicotine is the addictive component of cigarettes. Several convergent studies show that nicotine facilitates the growth and angiogenesis of human lung cancers. The biological activity of nicotine is mediated by nicotinic acetylcholine receptors (nAChRs). The endogenous ligand of nAChRs is acetylcholine (ACh). Data from our laboratory and other research groups show that lung cancers express all of the genes for synthesis, transport and degradation of ACh. These include nAChRs, choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), choline transporter (ChT1) and acetylcholinesterase (AChE). Nicotine upregulates the ACh-signaling loop in human lung cancer cells. Therefore, we conjectured that disruption of ACh-signaling pathway should suppress the growth of human cancers. We show that alpha7-nAChR antagonists robustly suppress angiogenesis in human lung and retinal microvascular endothelial cells. The anti-angiogenic activity of alpha7-nAChR antagonists was also observed in chicken chorioallantoic membrane (CAM) and nude mouse models. Similarly, vesamicol, a small molecule antagonist of VAChT, decreases nicotine-induced tumor growth in human NSCLCs. Our studies suggest that the acetylcholine signaling pathway may be have potential applications in the therapy of human lung cancers. Our results are also relevant to lung cancer patients who are exposed to nicotine via secondhand smoke, nicotine patches, gums or electronic cigarettes. Citation Format: Piyali Dasgupta, Kathleen C. Brown, Jamie K. Lau, Aaron M. Dom, Brent A. Thornhill, Clayton M. Crabtree, Theodore R. Witte, W E. Hardman, Cody A. Stover, A B. Carpenter, Yi C. Chen. Disruption of the acetylcholine signaling pathway suppresses the growth and angiogenesis of human lung cancers. [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 5229. doi:10.1158/1538-7445.AM2015-5229
214. Design of Multifunctional Chimeric Antigen Receptors for T Cell Cancer Immunotherapy
Authors: Lingfeng Liu, Alexandra Cabanov, Paula Kosasih, Daniel Sommermeyer, Stanley R. Riddell
Journal: Molecular Therapy (2015)

Adoptive therapy with T cells modified with synthetic chimeric antigen receptors (CAR-T cells) is emerging as an important and promising modality for hematologic malignancies, and has the potential for broad applications in cancer therapy. We have worked on novel CAR designs by incorporating strep-tag II in various locations in the extracellular domain of the CAR. We have shown that strep-tag II does not interfere with CAR function, provides an intrinsic marker for identification of CAR expression at the cell surface, and introduces flexibility in tailoring spacer length to optimize CAR function. Moreover, this CAR design can facilitate the application of time-saving and cost-efficient technologies for manufacturing of high-purity CAR T cell products either by using anti-strep-tag II plus anti-CD28 mAb coated microbeads to selectively expand CAR-T cells, or by rapidly enriching CAR-T cells using established Strep-Tactin purification systems. Using NSG mouse/human tumor xenograft models, we show that both strategies readily generate potent CAR T cell products for in vivo therapy. This innovation in CAR design can be universally applied for CARs with different scFv specificity (CD19, CD20, ROR1) and costimulatory domains (CD28, 4-1BB, CD28/4-1BB), and endows CAR-T cells with valuable properties for cGMP manufacturing of therapeutic CAR-T cell product with high efficiency.
Abstract 3986: Introduction of PTEN pseudogene in murine breast cancer upregulates PTEN, p53 and activating protein 2 gamma and delays tumor growth
Authors: Synnøve Yndestad, Eilin Austreid, Kai Ove Skaftnesmo, Per Eystein Lønning, Hans Petter Eikesdal
Journal: Cancer Research (2015)

Abstract Background: While PTEN is frequently downregulated in breast cancer, the mechanism remains obscure. PTEN pseudogene (PTENP1) is reported to function as a decoy adsorbing micro RNAs (miRNAs) targeting PTEN for degradation in prostate cancer cells. A potential role of PTENP1 in PTEN regulation in breast cancer has not been assessed systematically. Method: We transfected murine C3HBA breast cancer cells lacking endogenous PTENP1 with a lentiviral PTENP1 construct to investigate the influence of the pseudogene on PTEN and Akt-mTOR downstream signaling, global gene expression, as well as in vitro and in vivo tumor growth characteristics. Results: Upregulated PTENP1 3´UTR by lentiviral transfection increased PTEN protein levels and reduced cell cycle progression in vitro, but despite this increased Akt phosphorylation was observed. Similarily, PTENP1 transfection decreased tumor growth in C3HBA murine breast cancer in syngeneic, immunocompetent C3H mice, corresponding with upregulated PTEN, but without inhibition of Akt-mTOR signaling. In stead, increased protein levels of p53 and its downstream target activating protein-2 gamma (AP-2γ) was observed as possible tumor suppressors in this setting. Conclusion: In the murine C3HBA breast cancer cell line, PTENP1 transfection was associated with upregulated endogenous PTEN, p53 and AP-2γ protein levels and tumor growth inhibition. Citation Format: Synnøve Yndestad, Eilin Austreid, Kai Ove Skaftnesmo, Per Eystein Lønning, Hans Petter Eikesdal. Introduction of PTEN pseudogene in murine breast cancer upregulates PTEN, p53 and activating protein 2 gamma and delays tumor growth. [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 3986. doi:10.1158/1538-7445.AM2015-3986
PTU-050 Negative association between smoking and liver disease in heavy drinkers: a case control study: Abstract PTU-050
Authors: A Ali, J Jones, M Bradley, K McCormick, R Peck, D Gleeson
Journal: Gut (2010)

<h3>Introduction</h3> Only a minority of heavy drinkers develop alcoholic liver disease (ALD). A previous cohort study suggested an association between cigarette smoking and risk of alcoholic cirrhosis.1 Smoking has also been linked to disease severity in primary biliary cirrhosis.2 However, there is a negative association between smoking and other chronic inflammatory diseases such as PSC3 and ulcerative colitis.4 <h3>Methods</h3> To compare smoking behaviour between heavy drinkers with and without liver disease we recruited two cohorts of heavy alcohol drinkers (&gt;60 units/wk (men) and &gt;40 units/wk (women) for ≥5 years). Cases (n=284, 202 men (71%), age (mean±SD) 47±10 years) had decompensated ALD, defined as Child9s Grade B or C. Controls (n=199, 157 men (79%), age 48±9 years) had no clinical evidence of liver disease, persistently normal serum bilirubin, albumin and prothombin time, and ultrasound showing normal or echo-bright liver texture and no other abnormality. We collected data on smoking duration and the average number of cigarettes/day at different phases in life. Subjects were classified as current, past and never smokers. Comparison between groups was by Student t, χ<sup>2</sup> and Mann–Whitney U tests. Results were adjusted for age and gender using logistic linear regression analysis (*). <h3>Results</h3> All Subjects smoked cigarettes including 11(3.9%) cases and 4(2%) controls who also smoked rollups and cigars. There were significantly more “never smokers” among cases than controls (n=94 (33%) vs. 40(20%), p=0.002). However, the percentage of current smokers was not different (n=153 cases (54%) vs. n=109 controls (55%)). Case-control Comparisons are shown in Abstract 050. The differences were also significant when comparison was limited to:(1) Cases with Child9s grade C (n=123) vs. Controls (p=0.001–0.015) and (2) Cases vs Heath care seeking controls (n=137) (p=0.001–0.008). <h3>Conclusion</h3> These results show a significant negative association between smoking and ALD. This may be related to differences in the liver enzyme CYP2A6 responsible for nicotine metabolism, or confounding environmental factors associated with smoking behaviour. The data are also consistent with a protective effect of smoking against ALD in heavy drinkers.
Safety of lumen-apposing metal stents (LAMS) for pancreatic fluid collection drainage
Authors: Barbara M Ryan, Suresh Vasam Venkatachalapathy, Matthew T Huggett
Journal: Gut (2016)

Dear editor,

Bang et al 1 reported in Gut their recent experience with the Boston Scientific Hot AXIOS lumen-apposing metal stent (LAMS) in the treatment of walled-off necrosis (WON). They described a concerning 50% (6/12) rate of stent-related adverse events, in particular delayed bleeding (3/12) and buried stent syndrome (2/12). They postulated that rapid decompression of the WON facilitated by the wide-bore LAMS may lead to the LAMS impinging on the internal wall of the collection cavity resulting in damage to adjacent vasculature, causing haemorrhage, or inward migration of the outer flange of the stent causing buried stent …
EFFECTIVENESS OF THROMBUS ASPIRATION IN STEMI PATIENTS IN DAILY CLINICAL PRACTICE
Authors: Sinem Kilic, Jan Paul Ottervanger, Jan-Henk Dambrink, J Hoorntje, Marcel Gosselink, Evelien Kolkman, Harry Suryapranata, Arnoud van 't Hof
Journal: Journal of the American College of Cardiology (2012)
Dasatinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) In the DASISION Trial: 18-Month Follow-up
Authors: Neil Shah, Hagop Kantarjian, Andreas Hochhaus, Jorge E. Cortes, M. Brigid Bradley-Garelik, Chao Zhu, Michele Baccarani
Journal: Blood (2010)
Impact of 18 f-Fluoro-Deoxyglucose Positron Emission Tomography Imaging in the Management of Mantle Cell Lymphoma
Authors: Juliette Bouteloup, Salim Kanoun, Alina Berriolo-Riedinger, Hervé Ghesquières, Gilles A. Salles, Thérèse Gargi, Thomas Mognetti, Emmanuelle Nicolas-Virelizier, Amine Belhabri, Rey Philippe, Laurent Voillat, Cedric Rossi, Robin Noël, Jean-Noel M. Bastie, Olivier Casasnovas
Journal: Blood (2015)
Abstract LB-015: VAMP2-NRG1 fusion gene is a novel oncogenic driver of non-small cell lung adenocarcinoma
Authors: Yeonjoo Jung, Seunghui Yong, Pora Kim, Hee-Young Lee, Yeonhwa Jung, Juhee Keum, Suyeon Kim, Sanghyuk Lee, Jhingook Kim, Jaesang Kim
Journal: Cancer Research (2015)

Abstract Neuregulin 1 (NRG1) has been discovered as the tail moiety of fusion genes with several distinct partner head genes in lung cancers. These fusion genes activate ERBB2/ERBB3 receptor-mediated cell signaling and thereby function as oncogenic drivers. We have carried out whole-transcriptome sequencing of 100 non-small cell lung carcinoma (NSCLC) tumors and isolated a novel fusion gene consisting of Vesicle-Associated Membrane Protein 2 (VAMP2) and NRG1. RT-PCR and genomic DNA analysis were used to demonstrate inter-chromosomal translocation. Immunoblotting and soft agar assays were used to examine stimulating activity of the fusion gene through ERBB2/ERBB3 signaling pathway. The most highly expressed splice variant of VAMP2-NRG1 fusion gene was shown to be membrane-bound and display EGF-like domain of NRG1 extracellularly. VAMP2-NRG1 promotes anchorage-independent colony formation of H1568 lung adenocarcinoma cells. Ectopic expression of the fusion gene stimulates phosphorylation of ERBB2 and ERBB3 as well as down-stream targets, AKT and ERK, confirming activation of the signaling pathway. VAMP2-NRG1 is a novel oncogenic fusion gene representing a new addition to the list of NRG1 fusion genes which together may form an important diagnostic and clinical category of lung adenocarcinoma cases. Citation Format: Yeonjoo Jung, Seunghui Yong, Pora Kim, Hee-Young Lee, Yeonhwa Jung, Juhee Keum, Suyeon Kim, Sanghyuk Lee, Jhingook Kim, Jaesang Kim. VAMP2-NRG1 fusion gene is a novel oncogenic driver of non-small cell lung adenocarcinoma. [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 LB-015. doi:10.1158/1538-7445.AM2015-LB-015
Lung Cancer
Authors: Roy S. Herbst, John V. Heymach, Scott M. Lippman
Journal: New England Journal of Medicine (2008)

The Molecular Origins of Cancer series continues with this review of molecular and genetic mechanisms of lung cancer. The authors review genetic susceptibility to lung cancer and four genes of importance in the evolution of the disease: EGFR, KRAS, the PI3K–Akt–mTOR complex, and TITF1. They also discuss gene profiling and protein profiling, with emphasis on the clinical value of these methods.
Cardiac Safety Profile of Imatinib and Nilotinib In Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Results From ENESTnd
Authors: Richard A. Larson, Andreas Hochhaus, Giuseppe Saglio, Gianantonio Rosti, Jose L. Lopez, Leif Stenke, Hirohisa Nakamae, Stuart L. Goldberg, Ming-Chung Wang, Neil J. Gallagher, Albert Hoenekopp, Christine-Elke Ortmann, Timothy P. Hughes, Hagop M. Kantarjian
Journal: Blood (2010)
Abstract 524: Assessing the interaction between acetylenic tricyclic bis-(cyano enone) and cysteine residues of actin to inhibit non-small cell lung cancer cell migration
Authors: Eddie Chan, Akira Saito, Tadashi Honda, John Di Guglielmo
Journal: Cancer Research (2015)

Abstract During epithelial-to-mesenchymal transition (EMT), epithelial cells lose their cell-cell junctions, apical-basal polarity, and reorganize their actin cytoskeleton. These changes, among others, increase the motility of individual cells and promote a highly invasive phenotype. The actin cytoskeleton is also key in cell migration and invasion, as the polymerization of actin at the leading edge provides the necessary driving force for translocation and protrusions. Therefore, the actin cytoskeleton is a potential target for inhibiting tumour progression. In this study we characterized a novel tri-cyclic synthetic triterpenoid derivative, TBE-31, in its ability to associate with actin and inhibit cell migration. Using a pull-down approach, we demonstrate that TBE-31 binds directly to actin. Furthermore, TBE-31 inhibited branched and linear actin polymerization in vitro, and stress fibre formation in cultured cells. Actin cytoskeleton reorganization and stress fiber formation was also inhibited in TGFβ-dependent EMT of non-small cell lung cancer cells. We next used SwissDock software to investigate the potential molecular interaction between TBE-31 and actin. Swissdock predicted that TBE-31 would have a high affinity for binding to the same cleft as Cytochalasin D, a bona-fide actin polymerization inhibitor. As triterpenoids associate with cysteine residues in target proteins, we generated cysteine to alanine mutants of actin and verified TBE-31 binding using pull-down assays. Finally, we observed that TBE-31 inhibited fibroblast and non-small cell lung tumor cell migration with an IC50 of 1.0 and 2.5 μM, respectively. Taken together, our results suggest that TBE-31 targets actin polymerization to alter cell morphology and inhibit cell migration. Citation Format: Eddie Chan, Akira Saito, Tadashi Honda, John Di Guglielmo. Assessing the interaction between acetylenic tricyclic bis-(cyano enone) and cysteine residues of actin to inhibit non-small cell lung cancer cell migration. [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 524. doi:10.1158/1538-7445.AM2015-524
473. Qualification of a p24 ELISA Assay for Quantitation of Total Lentiviral Vector Concentration
Authors: Elisabeth Boucher, Pranali Buch, Melissa Buttimer, Josh Sorafine, Suzanna Melotti, Craig Fairchild, Mercedes Segura, James Warren
Journal: Molecular Therapy (2016)

Lentiviral vectors (LVV) are efficient gene transfer vehicles used in a growing list of gene therapy applications that are currently being evaluated clinically. We are conducting clinical trials in subjects with β-thalassemia major, severe sickle cell disease, and childhood cerebral adrenoleukodystrophy, which employ autologous CD34+ cells transduced with LVV encoding a corrective transgene, βA-T87Q-Globin or ABCD1. Essential to LVV process development is the availability of reliable analytical tools to characterize the purified LVV product and in-process samples. Total lentiviral vector particle titers can be estimated by quantitation of HIV-1 p24 antigen concentration using commercial ELISA kits. In support of late-stage process characterization, it is essential to qualify the assay and demonstrate its suitability to test in-process samples in different matrices. Following ICH Q2 R1 guidelines, assay accuracy, repeatability, intermediate precision, quantitation limit, linearity, and linear range were evaluated. Additionally, qualification tests for specificity and dilutional linearity were performed on in-process samples and buffers to assess potential matrix interference. The results of these tests were used to define appropriate dilutions and acceptance criteria for p24 ELISA in-process samples. The assay has shown to be linear between 400 pg/mL and 25 pg/mL, while maintaining accuracy for p24 detection with the limit of quantitation being 25 pg/mL. To demonstrate assay repeatability, various concentrations within the linear range were tested resulting in coefficients of variation below 5%. The coefficient of variation across different days and different operators was below 8% for all concentrations tested, indicating consistent assay precision. Spike recovery studies have shown consistent recovery of spiked p24 antigen (73-126%), demonstrating assay specificity and lack of matrix interference in all in-process matrices tested while maintaining dilutional linearity. To conclude, the p24 ELISA assay used for LVV quantitation has shown precision, repeatability, specificity and accuracy, within an established linear quantitation range, adequate to support late-stage process characterization activities.
766. Genetic Correction of Ifnγr1 Deficiency in Hematopoietic Cells Repairs the Cellular Phenotype of Mendelian Susceptibility to Mycobacterial Disease
Authors: Nico Lachmann, Adele Mucci, Miriam Hetzel, Robert Meineke, Olga K. Halle, Mark P. Kühnel, Ralph Goethe, Sebastian Brennig, Daniel Brand, Reinhold Förster, Axel Schambach, Thomas Moritz
Journal: Molecular Therapy (2016)

Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a rare primary immunodeficiency characterized by recurrent severe infections with otherwise only weakly virulent mycobacteria. MSMD is associated with mutations in different genes, all leading to an impaired activation of macrophages by T-cells and a defective innate immune response. Specifically mutations in the interferon-gamma (IFNγ)-receptor-1 or-2 (IFNγR1 /2) genes result in a life-threatening disease phenotype with most patients dying in early childhood. We here introduce a novel gene therapy approach for IFNγR1 deficiency. Thus, we have designed a 3rd generation SIN lentiviral vector expressing the murine cDNA of Ifnγr1 from a spleen focus forming virus (SFFV) promoter element coupled by an IRES to GFP (Lv.SFFV.Ifnyr1.iGFP). Transduction of hematopoietic stem/progenitor cells from Ifnγrl−/− mice showed expression of Ifnγr1 by FACS and qRT-PCR and no abnormalities in clonogenic growth when compared to WT control cells. Moreover, differentiation of transduced cells towards macrophages (MΦ) by M-CSF was normal as determined by morphology on cytospins and surface marker expression of CD11b, CD200R, CD115, CD45 and F4/80. When subjecting corrected MΦ to stimulation with IFNγ, corrected cells were able to build a functional IFNγR1-Ifnγ-IFNγR2 and internalize IFNγ as efficiently as WT cells, as suggested by the clearance of IFNγ from the medium within 24h of stimulation. Consequently, Lv. SFFV. Ifnγr1.iGFP corrected MΦ revealed restored up-regulation of HLA-DR and CD86 (B7.2) comparable to WT-MΦ. IFNγ dependent T-cell activation was evaluated using T cell receptor- transgenic T cells recognizing ovalbumin (OVA). Both WT and corrected MΦ were unable to activate T-cells in the presence of IFNγ and OVA, whereas MΦ from Ifnγr1−/− mice induced significantly stronger proliferation of T cells. This observation was accompanied by the induction of indoleamine 2,3-dioxygenase (IDO) in WT and corrected MΦ, suggesting that IDO enables MΦ to deplete tryptophan from the medium and interferes with T-cell proliferation. Finally, Ifnγrl downstream signaling showed restored phosphorylation of STAT1 in corrected MΦ, consistent with induction of iNos and Irf1 upon stimulation with IFNγ. Moreover, correction of Ifnγrl−/− MΦ led to a significantly improved anti-mycobacterial activity as measured by comparable killing of Mycobacterium Avium in corrected and WT MΦ. Thus, we here introduce a novel gene therapy approach for MSMD in the context of Ifnγr1 deficiency.