tbuckley/cabot-search huggingface dataset:
Development of nomograms for predicting survival in advanced gastric cancer
Authors: Yukiya Narita, Shigenori Kadowaki, Isao Oze, Hiroya Taniguchi, Takashi Ura, Masashi Ando, Seiji Ito, Yasushi Yatabe, Yasumasa Niwa, Kei Muro
Journal: Annals of Oncology (2015)
Abstract 5071: Inhibition of Porcupine reduces Wnt-dependent colony formation and/or proliferation in both autocrine and paracrine cell models
Authors: Ben A. Thompson, Kate J. Messenger, Emily Linnane, Sarah E. Coupland, Peter J. Calcraft
Journal: Cancer Research (2015)

Abstract Aberrant activation of the pro-survival Wnt signalling pathway is a key determinant in numerous cancers (Nusse and Varmus, 2012) and therefore constituents of this pathway are potentially promising therapeutic targets. The membrane-bound o-acyltransferase porcupine (PORCN) is required for post-translational modification of all Wnts, and is vital for Wnt secretion (Herr et. al., 2012). Due to the complex and varied oncogenic roles of the known Wnt ligands, prevention of active ligand secretion provides an effective mechanism for inhibiting canonical and non-canonical Wnt signalling in both paracrine and autocrine systems. Here we show that a novel inhibitor of porcupine potently inhibits both autocrine and paracrine models of Wnt/β-catenin signalling. Treatment of the pancreatic cancer cell line CAPAN-2 with REDX05562 resulted in a significant decrease of axin 2 mRNA expression by qPCR (10.4 fold, 10nM). This reduction in expression was partially reversed by the addition of recombinant human Wnt-3A (100ng.ml−1). The decrease in axin 2 expression was concomitant with an inhibition of CAPAN-2 proliferation (IC50 1.4nM +/- 0.8nM). Conversely treatment of MCF-7 mammospheres with REDX05562 did not inhibit sphere forming efficiency (SFE). However, when stimulated with recombinant Wnt-3A an increase in anoikis resistance was observed suggesting a potential paracrine influence. In vivo the presence of cancer associated fibroblasts (CAFs) are a likely source of paracrine Wnt (Green et. al., 2013). Indeed, conditioned media taken from primary CAFs (isolated from fresh mastectomies) increased anoikis resistance in MCF-7 cells without any discernible effect on CAF proliferation. This effect was significantly inhibited when MCF-7 cells were incubated with conditioned media taken from primary CAFs treated with REDX05562. Moreover, immunofluorescent labelling of PORCN revealed that PORCN expression is markedly higher in CAFs than in MCF-7s. This is consistent with the hypothesis that different mechanisms underpin Wnt-signalling in breast and pancreatic cancer. The above data show that the novel PORCN inhibitor REDX05562 effectively reduces the impact of pro-survival Wnt ligand-mediated signalling in both paracrine and autocrine models. This further emphasises the broad therapeutic potential of PORCN inhibition in Wnt-dependent cancers. Citation Format: Ben A. Thompson, Kate J. Messenger, Emily Linnane, Sarah E. Coupland, Peter J. Calcraft. Inhibition of Porcupine reduces Wnt-dependent colony formation and/or proliferation in both autocrine and paracrine cell models. [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 5071. doi:10.1158/1538-7445.AM2015-5071
Immunoproteasome-Selective Keto-Epoxide Inhibitors: Potential Therapeutic Agents for the Treatment of Hematological Disorders.
Authors: Francesco Parlati, Monette A. Aujay, Susan D. Demo, Eileen D. Goldstein, Jing Jiang, Christopher J. Kirk, Guy J. Laidig, Yan Lu, Tony Muchamuel, Kevin D. Shenk, Catherine Sylvain, Congcong M. Sun, Tina M. Woo, Han-Jie Zhou, Mark K. Bennett
Journal: Blood (2006)
357. A Mouse Model of Cobalamin A (cblA) Class Isolated Methymalonic Academy (MMA) Provides Unique Platform for Testing Gene and Cell Therapies
Authors: Madeline Epping, Irini Manoli, Cindy Wang, Pat Zerfas, Victoria Hoffmann, Gene Elliott, Lingli Li, Chuck Venditti
Journal: Molecular Therapy (2016)

Isolated Methylmalonic Acidemia (MMA) comprises a relatively common and heterogeneous group of inborn errors of metabolism. Most affected individuals display severe multisystemic disease with episodes of metabolic instability, chronic renal disease, and neurological complications. The most severe clinical presentations are typically associated with complete loss of methylmalonyl-CoA mutase (MUT) enzymatic activity. MUT converts methylmalonyl-CoA to succinyl-CoA within mitochondria but defects in the transport or synthesis of its cobalamin co-factor also variably impair MUT activity. Previous mouse models of Mut MMA generated by our group have been critical to developing gene therapy for MMA but have either displayed neonatal lethality or required concomitant transgenesis for viability. Thus, the need for ameliorated models to further investigate disease-associated pathophysiology and facilitate gene therapy studies exists. We have therefore constructed a mouse model of an attenuated form of isolated MMA, the cblA subtype, by using homologous recombination to create a deletion allele of Mmaa, the enzyme that performs the gated transfer of adenosylcobalamin to Mut and protects Mut from oxidative inactivation. Patients with the cblA subtype of MMA can have variable presentations, spanning the full spectrum of MMA associated symptoms and pathology, yet always harbor an element of clinical and biochemical responsiveness to injectable B12. Mmaa-/- mice were born in mendelian proportions, exhibited decreased survival after weaning (P<0.0001), weighed 50% less than littermates at 6 months (P<0.0001), lacked immunoreactive Mmaa and Mmaa mRNA in multiple tissues, including the liver, and manifested severe metabolic perturbations. Plasma methylmalonic acid concentrations ranged between 63.88-1641.91 µM, representing a 62-fold or more elevation over age matched littermates. Mmaa-/- mice also display diminished 1-C-13 propionate oxidative capacity (P<0.0001) and hepatic complex IV activity (P=0.002). Electron microscopy confirmed the presence of hepatic megamitochondria and abnormal proximal renal tubular mitochondria. The glomerular filtration rate, measured using FITC-sinistrin decay, showed that Mmaa-/- mice have diminished kidney function compared to heterozygous littermates. Following hydroxycobalamin administration, Mmaa-/- mice had improved survival and increased weight (P=0.0003), which was associated with improved 1-13C-propionate oxidative capacity. This new mouse model fully recapitulates the clinical and biochemical features seen in cblA patients, and provides a robust platform for testing gene and cell therapies for MMA because affected mice are relatively severe but survive until weaning. These animals also offer the opportunity to longitudinally examine disease biomarkers and more easily assay vectors across a wide age range.
Efficacy of Azacytidine (5-AC) Given as Maintenance or Salvage Therapy for Patients (pts) with Acute Leukemia Post Allogeneic Stem Cell Transplantation (HSCT).
Authors: Elias Jabbour, Sergio Giralt, Hagop Kantarjian, Guillermo Garcia-Manero, Elizabeth Shpall, Patrow Kebriaei, Leandro de Padua, Richard Champlin, Marcos de Lima
Journal: Blood (2007)
Reduced Intensity Conditioning with Thiotepa and Fludarabine for Allogeneic Transplantation: Evidence for Low Toxicity and Long-Lasting Disease Control in MDS with Low/Intermediate-1 IPSS Score and in AML from MDS in Complete Remission.
Authors: Emilio Paolo Alessandrino, Luca Malcovati, Giorgio La Nasa, Paolo de Fabritiis, Massimo Bernardi, Paolo Di Bartolomeo, Paolo Bernasconi, Anna A Colombo, Daniela Caldera, Cristiana Pascutto, Patrizio Mazza, Franco Narni, Rosanna Scime’, Attilio Olivieri, Marco Casini, Andrea Bacigalupo for GITMO
Journal: Blood (2008)
Abstract POSTER-BIOL-1318: Claudin 4 controls the receptor tyrosine kinase EphA2 pro-oncogenic switch through β-catenin
Authors: Xiying Shang, Xinjian Lin, Stephen B. Howell
Journal: Clinical Cancer Research (2015)

Abstract EphA2, which is expressed in ovarian cancer, is activated by two different mechanisms. Activation by engagement with one of its ephrin ligands is anti-oncogenic whereas activation by phosphorylation of S897 by AKT increases migration, invasion and metastasis. Down-regulation of claudin-4 (CLDN4) produces a loss of E-cadherin and increased β-catenin signaling and a phenotype similar to that produced by oncogenic activation of EphA2. We found that constitutive knockdown of CLDN4 was associated with a 4.5-fold increase in EphA2 mRNA and a 2.5-fold increase in EphA2 protein which was reversed by re-expression of CLDN4. Knockdown of EphA2 blocked the migratory phenotype induced by loss of CLDN4. Knockdown of CLDN4 resulted in a 5.8-fold increase in pEphA(S897), the oncogenic form of the receptor, as well as mislocalization of EphA2 to the interior of the cell. Forced expression of E-cadherin did not reduce total EphA2 or pEphA(S897) whereas re-expression of CLDN4 restored localization and reduced EphA2 and pEphA(S897) even in cells not expressing E-cadherin. Transient siRNA-mediated knockdown of EphA2 and β-catenin, and inhibition of PI3K by LY294002, demonstrated that increased pEphA(S897) in the CLDN4 knockdown cells was attributable to an increase in the level of active dephospho- β-catenin upstream of PI3K and AKT. We conclude that CLDN4 serves to restrain pro-oncogenic signaling from EphA2 by limiting the activity of β-catenin and PI3K and preventing phosphorylation of EphA2 on S897 by AKT. This suggests that interventions directed at enhancing the level or functional activity of CLDN4 may be of therapeutic interest. Citation Format: Xiying Shang, MD, PhD, Xinjian Lin, MD, Stephen B. Howell, MD. Claudin 4 controls the receptor tyrosine kinase EphA2 pro-oncogenic switch through β-catenin [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1318.
Gene Expression Changes In Patients with 5q- Syndrome Treated with Lenalidomide
Authors: Monika Belickova, Jaroslav Cermak, Kamila Fejglova, Michaela Dostalova Merkerova, Radana Neuwirtova, Miroslav Caniga, Magda Siskova, Libor Cervinek, Anna Jonasova
Journal: Blood (2010)
Minimal Residual Disease in Patients with Acute Myeloid Leukemia Quantified by Multiparameter Flow Cytomety and Quantitative RT-PCR Is an Independent Prognostic Parameter.
Authors: Wolfgang Kern, Claudia Schoch, Torsten Haferlach, Daniela Voskova, Wolfgang Hiddemann, Susanne Schnittger
Journal: Blood (2004)
117. Development of Novel Cancer Therapy Combination of Ad-SOCS Gene Therapy and LAK Cell Immunotherapy for the Treatment of Prostate Cancer
Authors: Hiroki Saito, Koichi Kitagawa, Tetsuji Naka, Satoshi Serada, Toshiro Shirakawa
Journal: Molecular Therapy (2016)

Background Suppressor of cytokine signaling 3 (SOCS3) is a promising molecule for cancer gene therapy. SOCS3 suppresses tumor growth through inhibition of mutiple signaling pathways including Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase (ERK), and focal adhesion kinase (FAK). The constitutive activation of JAK/STAT3 pathway is known to be involved in oncogenesis of various types of cancers including prostate cancer. We investigated the anti-tumor activity of Ad-SOCS, which is the recombinant adenovirus vectors carrying the SOCS3 gene, against prostate cancer cell line in vitro. Furthermore, to improve the antitumor effect against prostate cancer, we combined LAK (Lymphokine activated killer) cell immunotherapy with Ad-SOCS gene therapy. Materials and Methods LNCaP, human prostate cancer cell line was used in this study. The cytotoxicity of Ad-SOCS against LNCaP was measured by XTT assay. LAK cells were generated from PBMCs isolated from fresh blood by Ficoll-paque (GE Healthcare, Munich, Germany) density gradient centrifugation. PBMC were incubated in medium with interleukin (IL)-2 and anti CD3 antibody (OKT3) to generate LAK cells. The cytotoxicity of LAK cells against LNCaP cells infected with Ad-SOCS was investigated by the in vitro cytotoxicity assay. Expression level of SOCS3, STAT3 and ULBPs were measured by real-time PCR. Results Ad-SOCS showed the significantly higher cell growth inhibitory effect compared to Ad-LacZ and PBS controls in LNCaP cells. In real-time PCR, Ad-SOCS significantly increased the level of SOCS3 mRNA expression. Sequentially, the expression of STAT3 mRNA was decreased by Ad-SOCS infection. Upregulation of SOCS3 mRNA and downregulation of STAT3 mRNA were not observed in both Ad-LacZ and PBS infected LNCaP cells. In cytotoxicity assay, LAK cells exhibited the significantly higher cytotoxicity against LNCaP cells infected with Ad-SOCS at all effector: target cell ratios, 1:1,5:1, 10:1, compared with that of non-infected or Ad-LacZ infected cells. The mRNA expression levels of ULBP 1-5, which are NKG2D ligands to stimulate LAK cell activities, were measured and the mRNA expressions of ULBP 1, 3 and 4, in LNCaP infected with Ad-SOCS were significantly increased compared to the treatments. Conclusion In the present study, we demonstrated that Ad-SOCS could inhibit the cell growth of LNCaP cells and increased the sensitivity of LAK cell in vitro. These findings suggested that the Ad-SOCS and LAK cell combination therapy warranted the further development of novel therapeutic approach for advanced prostate cancer.
Factors Influencing Complete Remission (CR) Rate in Patients ≥ 60 Years with Acute Myeloid Leukemia (AML): Report From the German AML Intergroup Study
Authors: Dietger Niederwieser, Verena S Hoffmann, Rainer Krahl, Wolfgang E. Berdel, Maria Cristina Sauerland, Wolfgang Hiddemann, Ute Hegenbart, Bernhard Josef Woermann, U. Krug, Wolfram Pönisch, Vladan Vucinic, Karin Hebenstreit, Michael Cross, Christian Niederwieser, Markus Pfirrmann, A Schulze, Alwin Kraemer, Georg Maschmeyer, Mathias Freund, S Scholl, Thomas Heinicke, D Haehling, Hans-Heinrich Wolf, Thomas Büchner
Journal: Blood (2012)
240. Stable and Clinically Benign Clonal Dominance in an ADA-SCID Patient Treated With Retroviral Gene Therapy
Authors: Aaron R. Cooper, Kit L. Shaw, Georgia R. Lill, Robert Sokolic, Fabio Candotti, Donald B. Kohn
Journal: Molecular Therapy (2015)

To date, adverse events involving genotoxicity and oncogenic transformation have occurred in several gene therapy trials using oncoretroviral vectors. In striking and surprising contrast, insertional oncogenesis has not been observed in multiple trials treating SCID caused by adenosine deaminase deficiency (ADA-SCID), despite the use of very similar oncoretroviral vectors. In our trial for ADA-SCID, we employed non-restrictive LAM-PCR to monitor clonality and observed that one patient developed a marked clonal dominance that was stable over multiple years. Despite this, the patient has been clinically well up to present. The dominant clone was confirmed using an integration site-specific digital PCR assay, and it accounted for up to 85% of vector integrations in peripheral blood mononuclear cell (PBMC) DNA. The vector integration in the dominant clone is in a gene-poor region of chromosome 21, which is also a common insertion site observed in our cohort of patients. RNA-seq expression analysis of cells of this clone did not detect any dysregulation of nearby genes. Importantly, this analysis would have also detected unannotated non-coding RNAs or novel transcripts being produced from the vector, and we observed neither. The majority of vector copies detected in PBMC DNA were contributed by the NK lineage, and the clone was most dominant in NK cells. Compared to healthy donor NK cells, the patient's NK cells more highly expressed the NK receptor NKG2C. The beginning of the clonal expansion coincides with the onset of Epstein-Barr virus (EBV) viremia in the patient, which also correlates with the expansion of a potential EBV-reactive T-cell clone, as indicated by flow cytometric TCR beta family analysis. We hypothesize that NK cells expressing NKG2C and bearing the chr21 IS expanded in response to the EBV infection, which was not fully controlled by the patient's adaptive immune response.
Abstract 3482: Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide
Authors: Xiao-Han Tang, Lorraine J. Gudas
Journal: Cancer Research (2015)

Abstract We investigated the effects of bexarotene (a retinoid X receptor agonist), CD1530 (a retinoic acid receptor γ selective agonist), and the combination of these two drugs for the prevention of oral carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model of human oral-cavity and esophageal squamous-cell carcinoma previously generated in our laboratory. We observed decreased numbers of neoplastic tongue lesions and reduced lesion severity in the 4-NQO plus CD1530 (4N+C) and 4-NQO plus bexarotene plus CD1530 (4N+B+C) groups compared with the 4-NQO group. RNA-Seq analyses showed increases in transcripts in cell proliferation/cell cycle progression pathways in the 4-NQO vs. the untreated group. In addition, β-catenin and matrix metallopeptidase 9 (MMP9) protein levels and reactive oxygen species (ROS), as assessed by 4-hydroxynonenal (4-HNE) staining, were elevated in tongue tissues 17 wk after the termination of the 4-NQO treatment. The 4N+B, 4N+C, and 4N+B+C groups showed dramatically lower levels of β-catenin, MMP9, and 4-HNE staining compared with the 4-NQO group. The major reduction in 4-HNE staining in the retinoid treatment groups suggests a novel mechanism of action, reduction of ROS, by which bexarotene and CD1530 inhibit carcinogenesis. Citation Format: Xiao-Han Tang, Lorraine J. Gudas. Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide. [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 3482. doi:10.1158/1538-7445.AM2015-3482
Characteristics of Electronic Cigarette Use Among Middle and High School Students — United States, 2015
Authors: Tushar Singh, Sara Kennedy, Kristy Marynak, Alexander Persoskie, Paul Melstrom, Brian A. King
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Electronic cigarettes (e-cigarettes) are now the most commonly used tobacco product among U.S. youths (1,2); in 2015, 5.3% of middle school students and 16.0% of high school students reported using e-cigarettes in the past 30 days (1). However, limited information exists on the e-cigarette product types and brands used and the substances used in these products by youths. CDC and the Food and Drug Administration (FDA) analyzed data from the 2015 National Youth Tobacco Survey (NYTS) to examine the characteristics of e-cigarette use among U.S. middle (grades 6-8) and high (grades 9-12) school students in 2015, including types of products used, brands of products used, and whether substances other than nicotine were used with the products. Among respondents reporting ever having used an e-cigarette, 14.5% used only disposable e-cigarettes, 53.4% used only rechargeable/refillable e-cigarettes, and 32.1% used both types. Two of the most commonly used e-cigarette brands were blu (26.4%, 1.65 million youths) and VUSE (12.2%, 760,000 youths); half of students (50.7%, 3.18 million) did not know the brand of e-cigarette they used. One third (32.5%) of those who reported ever using an e-cigarette also reported having used e-cigarettes for substances other than nicotine. Preventing youths from beginning use of any tobacco product, including e-cigarettes, is critical to tobacco use prevention and control strategies in the United States (3). Monitoring the characteristics of e-cigarette use among youths, including product types, brands, and ingredients, is important to inform strategies to prevent and reduce e-cigarette use among youths.
Phase I/II Trial of Bortezomib Maintenance in Order To Prolong Remission-Duration Following Autologous Peripheral Blood Progenitor Cell Transplantation as Treatment for Intermediate- and Advanced-Stage Multiple Myeloma.
Authors: Gary J. Schiller, M. Liao, J.P. Sohn, R. Malone, K. Bartone, B. Habtemariam, R. Paquette, S. de Vos, M. Territo
Journal: Blood (2007)
Comparative Study of Post-Transplant Lymphoproliferative Disorders after Solid Organ Transplantation Versus Hematopoietic Stem Cell Transplantation
Authors: Samuel Romero, Juan Montoro, Jaime Sanz, Marta Guinot, Empar Mayordomo, Rafael López, Isabel Beneyto, Luis Almenar, Amparo Soler, Guillermo Sanz, Miguel Ángel Sanz
Journal: Blood (2015)
146. Regulation of Inflammation in Cystic Fibrosis Lung Epithelial Cells by miR-155
Authors: Motohiro Tsuchiya, Parameet Kumar, Sharmistha Bhattacharyya, Swathi Kalurupalle, Shobha Vasudevan, Jennifer Martindale, Myriam Gorospe, Roopa Biswas
Journal: Molecular Therapy (2016)

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, F508del, is associated with failure of the mutant CFTR to traffic to the plasma membrane, with concomitant loss of cAMP-activated chloride conductance, and hypersecretion of pro-inflammatory IL-8. Our data indicate that the mis-expression of microRNAs (miRNAs, miRs) in CF cells, both in culture and in ex vivo bronchial biopsies, contribute to the inflammatory disease phenotype of CF. Our studies have demonstrated that the aberrant up-regulation of miR-155, in CF cells compared to CFTR-repaired control cells, induces hyper-expression of IL-8 through reduction in AKT1 activation. Our data indicate that, in addition to regulation of IL-8 mRNA stability by targeting SHIP1 gene, miR-155 also promotes increased translation of IL-8 mRNA. Therefore, we have analyzed the role of pro-inflammatory RNA-binding proteins (RBPs) and RNAs in miR-155-mediated regulation of IL-8 expression in CF lung epithelial cells. We have employed an in vivo cross-linking and affinity purification strategy to isolate and identify proteins and RNA in the miR-155-induced IL-8-mRNP complexes that regulate IL-8 expression in CF cells. We have thus identified the antagonistic role of HuR and miR-16 in the regulation of IL-8 expression in CF. Additionally, we have also identified CF disease-specific inflammatory target genes of miR-155, viz. RPTOR, SIRT1 and NR2F2, in CF lung epithelial cells that regulate the CF disease phenotype. Understanding these mechanisms will ultimately lead to the development of novel miR-based anti-inflammatory therapeutics for CF and other pulmonary disorders.
High Resolution Array-CGH Provides New Insights Into the Prognosis of Chronic Lymphocytic Leukemia (CLL): Is 8p Loss Worse Than 17p Loss?.
Authors: Andrea Rinaldi, Michael Mian, Davide Rossi, Francesco Forconi, Clara Deambrogi, Valeria Spina, Emanuele Cencini, Elisa Sozzi, Daniela Drandi, Marco Ladetto, Rita Santachiara, Roberto Marasca, Ekaterina Chigrinova, Franco M.D. Cavalli, Valter Gattei, Emanuele Zucca, Gianluca Gaidano, Ivo Kwee, Francesco Bertoni
Journal: Blood (2009)