tbuckley/cabot-search huggingface dataset:
Abstract LB-099: A high-throughput screen of approved drugs uncovers a synergistic interaction targeting prostate cancer
Authors: Marco P. Licciardello, Patrick Markt, Freya Klepsch, Charles-Hugues Lardeau, Gerhard Dürnberger, Vladimir Ivanov, Jacques Colinge, Stefan Kubicek
Journal: Cancer Research (2015)

Abstract Libraries of approved drugs contain some of the best studied small molecules and represent invaluable resources for drug repurposing and chemical biology studies. Access to comprehensive libraries of clinical compounds is limited and these collections are otherwise difficult to arrange. Using cheminformatics approaches we have assembled a non-redundant set of representative FDA-approved small molecules that we call the CeMM Library of Unique Drugs (CLOUD). The CLOUD covers the chemical and biological space of approved drugs, contains active forms of prodrugs, and can be screened at clinically relevant concentrations. In a combinatorial viability screen of the CLOUD we uncovered a synergistic interaction between two approved drugs. We show that the concomitant administration of these two small molecules induces apoptosis in the androgen receptor (AR)-dependent prostate cancer cell line LNCaP. Mechanistically, the combination affects AR signaling and the stability of the receptor itself. We are currently dissecting further aspects of the mechanism of action and performing in vivo experiments. Altogether, our data suggest that the combination of these two drugs can be repurposed for the treatment of prostate cancer. Citation Format: Marco P. Licciardello, Patrick Markt, Freya Klepsch, Charles-Hugues Lardeau, Gerhard Dürnberger, Vladimir Ivanov, Jacques Colinge, Stefan Kubicek. A high-throughput screen of approved drugs uncovers a synergistic interaction targeting prostate 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 LB-099. doi:10.1158/1538-7445.AM2015-LB-099
Induction of Survivin-Specific, HLA-A24 Restricted Cytotoxic T Lymphocytes Using an Immunodominant Peptide; In-Vitro Feasibility Study and a Clinical Trial of Survivin Peptide Vaccination.
Authors: Masahiro Ogasawara, Misato Kikuchi, Satoru Kimura, Koichiro Kobayashi, Takayoshi Miyazono, Masanobu Nakata, Kiyotoshi Imai, Teiichi Hirano, Naoki Kobayashi, Yoshio Kiyama, Junji Tanaka, Masahiro Imamura, Masaharu Kasai
Journal: Blood (2006)
Abstract 5417: The identification of BMS-595, an orally active imidazo[1,2-b]pyridazine CK2 inhibitor with in vivo anti-tumor activity
Authors: Christine M. Tarby, Liqi He, Brian E. Fink, Andrew Nation, Yufen Zhao, Soong-Hoon Kim, Libing Chen, John S. Tokarski, Chiang Yu, Jonathan G. Pabalan, Urvashi V. Roongta, Jonathan Lippy, Mary Obermeier, Paul A. Elzinga, Aberra Fura, Benjamin Henley, Joseph J. Fargnoli, William R. Foster, Ashvinikumar V. Gavai, Tai W. Wong, John T. Hunt, Gregory D. Vite, Ashok V. Purandare, Brent A. Rupnow
Journal: Cancer Research (2015)

Abstract CK2 is a highly conserved, and constitutively active family of serine/threonine kinases abnormally elevated in a wide variety of cancers and linked to poor prognosis and disease progression. The enzymes form as hetero-tetrameric complexes comprised of two highly related catalytic subunits (α or α´) with two regulatory β subunits in various combinations and distributions, depending on cell type. While CK2 plays a role in normal growth and development, deregulation of the enzymes has been shown to promote and maintain a malignant phenotype through mechanisms in both the anti-apoptotic and the pro-proliferative signaling pathways. CK2 has been reported to modulate the activity of several oncogenic transcription factors including CREB, Myc, Jun and Fos. Studies with RNAi and small molecule compounds have demonstrated tumor cell dependence on CK2. We sought to identify potent CK2 inhibitors to probe the function of CK2 in cancer-linked pathways and for evaluation in CK2 dependent tumor xenograft models. Herein we report SAR studies in the imidazo[1,2-b]pyridazine chemotype leading to the discovery of BMS-595, a highly potent and selective ATP-competitive CK2 inhibitor with a commensurate level of cellular potency. BMS-595 demonstrates strong PK/PD correlations and robust, oral anti-tumor efficacy in CK2-driven xenograft models at tolerated doses. Citation Format: Christine M. Tarby, Liqi He, Brian E. Fink, Andrew Nation, Yufen Zhao, Soong-Hoon Kim, Libing Chen, John S. Tokarski, Chiang Yu, Jonathan G. Pabalan, Urvashi V. Roongta, Jonathan Lippy, Mary Obermeier, Paul A. Elzinga, Aberra Fura, Benjamin Henley, Joseph J. Fargnoli, William R. Foster, Ashvinikumar V. Gavai, Tai W. Wong, John T. Hunt, Gregory D. Vite, Ashok V. Purandare, Brent A. Rupnow. The identification of BMS-595, an orally active imidazo[1,2-b]pyridazine CK2 inhibitor with in vivo anti-tumor activity. [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 5417. doi:10.1158/1538-7445.AM2015-5417
Successful Pregnancy After Allogeneic Bone Marrow Transplantation Followed by Ovarian Tissue Autograft in a Sickle Cell Patient.
Authors: Christophe Roux, Clotilde Amiot, Germain Agnani, Francine Arbey-Gindre, Pascale Lagre, Yves Aubard, Eric Deconinck, Pascal Piver, Pierre-Simon Rohrlich
Journal: Blood (2009)
Abstract KP02: Functional genomics, cancer biology and targets
Authors: William C. Hahn
Journal: Clinical Cancer Research (2015)

Abstract Recent advances in genomics now make it possible to consider enumerating all of the genetic lesions in specific cancers. These approaches will yield critical information regarding the identification, number, and types of alterations found in human tumors and are increasingly being applied prospectively to patient samples in the clinic. At the same time, complementary approach to decipher the molecular basis of malignant transformation depends upon the application of genome scale tools to annotate the function of genes involved in cancer initiation and progression. Over the past several years, we have developed genome scale loss-of-function libraries and open reading frame expression libraries that permit a systematic evaluation of genes involved in cancer initiation and maintenance. Using these libraries, we have now performed screens in a panel of human ovarian cancer cell lines to systematically identify cancer vulnerabilities. By combining these functional approaches with information derived from mapping the structural abnormalities present in cancer genomes, we have identified several new oncogenes that contribute to cancer development. The ability to systematically manipulate gene expression at genome scale now provides opportunities to investigate the function of genes involved in cancer initiation and maintenance, which will provide a framework for therapeutic strategies. Citation Format: William C. Hahn. Functional genomics, cancer biology and targets [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 KP02.
Learning by Listening—Improving Health Care in the Era of Yelp
Authors: Raina M. Merchant, Kevin G. Volpp, David A. Asch
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
T1 Calcineurin inhibition impairs the dendritic cell transcriptional response to aspergillus fumigatus infection in lung transplant recipients
Authors: A Adlakha, DAJ Armstrong-James, B Lenhard
Journal: Thorax (2016)

<h3>Background</h3> Lung transplant recipients on calcineurin inhibitor immunosuppression have increased susceptibility to, and increased mortality from, invasive aspergillosis. Tacrolimus (FK506) diminishes the innate immune response to <i>Aspergillus fumigatus</i> infection partly by inhibition of the calcineurin-NFAT axis. We investigated the effects of FK506 on transcriptional regulation in dendritic cells (DC’s), and assessed interferon-gamma as a treatment, with a combination of RNA-Seq and histone modification ChIP-seq. <h3>Methods</h3> Healthy volunteer monocytes were negatively isolated from gradient-centrifugation-selected PBMC’s and differentiated into DC’s with GM-CSF and IL-4. DC’s were treated with FK506, interferon-gamma and/or inoculated with swollen conidia of <i>A.fumigatus </i>(MOI 1:1). For RNA-Seq, extracted mRNA was poly-A purified and reverse-transcribed to ds-DNA, and for ChIP-seq, DNA was cross-linked, sonicated, then immunoprecipitated with antibodies against histone marks H3k4me1 and H3k27ac. Resultant DNA was PCR-amplified to generate libraries for next generation sequencing on the Illumina HiSeq 2500. Computational sequencing analysis pipelines used open-source C++ and R-based packages (Bowtie, Kallisto, edgeR and MACS). <h3>Results</h3> <i>A.fumigatus </i>infection in DC’s elicited upregulation of genes belonging to two key groups of early-phase response transcription factors – the early growth response family (EGR1 – log fold-change 4.90, FDR p-value = 0.0003) and the nuclear receptor family (NR4A2 – logFC 6.96, p = 1.56 × 10<sup>–6</sup>). FK506 treatment ablated significant differential expression of these genes whilst subsequent interferon-gamma treatment restored their upregulation (EGR1 – logFC 4.43, p = 0.00093; NR4A2 – logFC 5.56, p = 0.00034). Active gene enhancers regions were identified by presence of significant peaks of H3k4me1 and H3k27ac antibody binding. Motif analysis of enhancers within regulatory domains around differentially-expressed genes identified enrichment of core binding motifs of NFAT (p = 7.8 × 10<sup>-9</sup>) and FOXF2 (p = 8.6 × 10<sup>–10</sup>) transcription factors, which was lost after FK506 treatment. <h3>Conclusions</h3> Transcriptome analysis has revealed the key genes involved in early dendritic cell responses to <i>A.fumigatus</i> infection, and their ablation by FK-506 treatment suggests a deleterious genome-level effect of calcineurin inhibitors in this context. Furthermore, interferon-gamma treatment restores a more favourable transcriptomic response to infection in FK506-treated DC’s. The condition-dependent differential enrichment of enhancer motifs suggests a role for both suspected (NFAT) and previously unidentified (FOXF2) transcription factors in the DC response to <i>A.fumigatus</i> infection.
Optimal Ex-Vivo Expansion (EvE) of Cord Blood (CB) Natural Killer (NK) Cells, NK Cytotoxicity and NK Receptor (NKR) Expression: Potential for CB Adoptive Cellular Immunotherapy (ACI).
Authors: Janet Ayello, Prakash Satwani, Carmella Van de Ven, Elizabeth Roman, Laxmi Baxi, Joanne Kurtzburg, Mitchell S. Cairo
Journal: Blood (2005)
Effect of sodium loading and depletion on vascular reactivity and prostacyclin generation.
Authors: Manabu Yoshimura, Isao Kaimasu, Teruo Kitani, Tsunehiro Kawamura, Kazuo Takeda, Susumu Sasaki, Yoshihiro Kajita, Masao Nakagawa, Hamao Ijichi
Journal: Circulation (1980)

In order to estimate the modulatory activity of Prostacyclin (PGI2 ) to the vascular reactivity, pressor responses to angiotensin II (A II) and noradrenaline (NA) and PGI2 generation of aorta were measured using the rats of sodium loading or of sodium depletion. On the sodium loading, the blood pressure increased gradually and plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were decreased. The pressor responses to A II and NA were enhanced by sodium loading. The PGI2 generation of aorta was enhanced at the initial stage of sodium loading and decreased thereafter. The increased generation of PGI2 may represent the adaptive mechanism for the attenuation of the sustained elevation in blood pressure. In sodium depletion, the pressor responses to A II and NA were decreased, and PRA and PAC were elevated. PGI2 generation of aorta was also increased. These findings suggested that PGI2 could participate in blood pressure control mechanism on sodium loading and depletion.
Delineation of a KIT-Independent Oncogenic Pathway in Neoplastic Mast Cells That Involves Lyn and Btk, and Can Be Disrupted by the KIT/Lyn/Btk-Targeting Drug Dasatinib
Authors: Karoline V. Gleixner, Matthias Mayerhofer, Uwe Rix, Gregor Hoermann, Alexander Gruze, Maria-Theresa Krauth, Winfried F. Pickl, Christian Sillaber, Giulio Superti-Furga, Peter Valent
Journal: Blood (2007)
Abstract 5166: THE WNT SIGNALING PATHWAY IN THE OVARIAN CARCINOMA
Authors: michal chehover, Claes Tropé, Reuven Reich, Ben Davidson
Journal: Cancer Research (2015)

Abstract Ovarian carcinoma is the most lethal gynecological cancer and currently ranks as the fifth in causing cancer-related deaths among women. This is attributed to frequent presentation at late stage, when the tumor has metastasized, as well as to development of chemotherapy resistance along tumor progression. Patients with advanced-stage ovarian carcinoma have widespread intraperitoneal metastases, including the formation of malignant serous effusions within the peritoneal cavity. Unlike the majority of solid tumors, particularly at the primary site, cancer cells in effusions are not amenable to surgical removal, and failure in their eradication is one of the main causes of treatment failure. Three WNT signaling pathways have been characterized: the canonical WNT pathway, the non-canonical planar cell polarity pathway, and the non-canonical WNT/calcium pathway. All three WNT signaling pathways are activated by the binding of a WNT-protein ligand to a Frizzled family receptor, which passes the biological signal inside the cell. Several lines of research indicate on the involvement of these pathways also in ovarian carcinomas. However, the specific pathway or their regulation in the process of tumor progression in this disease has not been elucidated, so far. The aim of the current study is to identify the acting components of these pathways during tumor progression namely, which receptors and which ligands are activated at the different stages of ovarian carcinoma. We have analyzed the expression 7 frizzle genes (fzd1, 2, 4, 5, 6, 7, 8, 10), 4 WNT genes (wnt 2,3,4,5a,7) and 2 co-receptors LRP (5,6) on 222 samples (143 effusions, 44 primary, and 35 metastatic lesions) using real-time PCR. All the tested genes were found to be expressed at all sites. FRZ5 (p = 0.002), FRZ6 (p&amp;lt;0.001), Wnt2 (p = 0.029), Wnt3 (p = 0.034) and Wnt6 (p = 0.022) were lower in effusion-derived cells compared to solids lesions. Further, Wnt2 expression was higher in pre-chemo (p = 0.037) samples compared to post-chemo ones. FRZ6 expression was higher in FIGO stage IV compared to stage III of the disease (p = 0.041), and FRZ4 expression was higher in cases with lower residual disease volume (p = 0.002). Wnt5a was higher in patients with better (complete) response (p = 0.019). FRZ6 expression was associated with poor overall survival (p = 0.045) and progression-free survival (p = 0.009). FRZ10 expression was associated with better overall survival (p = 0.005) and progression-free survival (p = 0.005). Citation Format: michal chehover, Claes Tropé, Reuven Reich, Ben Davidson. THE WNT SIGNALING PATHWAY IN THE OVARIAN CARCINOMA. [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 5166. doi:10.1158/1538-7445.AM2015-5166
Abstract 2048: Evidence that MTAP acts as a genetic switch to inhibit tumor formation
Authors: Baqing Tang, Warren Kruger
Journal: Cancer Research (2015)

Abstract Methylthioadenosine Phosphorylase (MTAP) deficiency is widely observed in a variety of human tumor and tumor derived cell lines, suggesting that MTAP may play a role in tumorigenesis. It is an enzyme that catalyzes phosphorylation of 5′deoxy-5′-methylthioadenosine (MTA), a byproduct of in vivo polyamine biosynthesis. To elucidate the mechanism by which MTAP inhibits tumor formation, we created a MCF-7 breast cancer derived cell line that expresses MTAP under a doxycycline (DOX) regulated promoter. In this cell line MTAP expression was undetectable in the absence of DOX and could be detected as early as 4 hours after DOX induction. MTAP expression caused a decrease in cell proliferation, soft-agar colony formation, and cell migration. Microarray studies revealed several genes that were regulated by MTAP. For two of the genes that were identified, AGPAT4 and IGFBP1, we examined the relationship between their mRNA levels and MTAP mRNA levels by qRT-PCR. Surprisingly, a brief pulse of MTAP expression was able to alter mRNA levels of these genes and this change in mRNA persisted even when MTAP RNA levels were no longer detectable. Our findings show that MTAP expression suppresses tumorigenesis and it may act as a genetic switch. Citation Format: Baqing Tang, Warren Kruger. Evidence that MTAP acts as a genetic switch to inhibit tumor formation. [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 2048. doi:10.1158/1538-7445.AM2015-2048
Abstract 218: PI3Kγ Regulates Age-Dependent Cardiac Hypertrophy Through Kinase-Independent GSK-3-PP2A Axis
Authors: Sathyamangla V Naga Prasad, Maradumane L Mohan, Elizabeth E Martelli, Manveen K Gupta, Neelakantan T Vasudevan
Journal: Circulation Research (2012)

Activation of phosphoinositide 3-kinase α (PI3Kα) by Receptor Tyrosine Kinase (RTK) or PI3Kγ by G-protein coupled receptor (GPCR) inhibits glycogen synthase kinase-3 (GSK-3) via protein kinase B (Akt). We show that in addition to promoting GSK-3 phosphorylation through Akt, PI3Kγ in parallel suppresses PP2A dependent GSK-3 dephosphorylation. This is evidenced by accelerated GSK-3 dephosphorylation in PI3Kγ knock out (PI3Kγ-KO) mice downstream of RTK-PI3Kα-Akt axis despite robust Akt activation by insulin. Confocal microscopy and immunoblotting show marked reduction of steady state GSK-3 phosphorylation in PI3Kγ-KO compared to littermate controls. Assessment of GSK-3 dephosphorylating enzyme protein phosphatase 2A (PP2A) showed significant elevation in PP2A and GSK-associated phosphatase activity in PI3Kγ-KO mice compared to controls. Mechanistically, we found that elevated PP2A activity in PI3Kγ-KO was due to PP2A methylation mediated by elevated PP2A methyl transferase (PPMT-1) activity. Consistent with the elevated anti-hypertrophic GSK-3 activity, we observed reduced heart size in PI3Kγ-KO mice at 6, 12, and 18 months compared to age matched littermate controls. To test in vivo whether PI3Kγ activity regulates cardiac GSK-3 function through PP2A, we bred transgenic mice with cardiac overexpression of inactive PI3Kγ (PI3Kγ inact ) with PI3Kγ-KO mice. Surprisingly, cardiac overexpression of PI3Kγ inact transgene in PI3Kγ-KO background completely normalized cardiac PPMT-1 activity resulting in reduced PP2A activity and increased GSK-3 phosphorylation. Expression of PI3Kγ inact transgene in PI3Kγ-KO resulted in normalization of heart size compared to PI3Kγ-KO littermates consistent with the increased GSK-3 phosphorylation and consequent inhibition of GSK-3 activity suggesting a novel kinase independent role of PI3Kγ downstream of growth factor receptor in regulating cardiac growth with age.
A New Rotary Powered Device for Bone Marrow Aspiration and Biopsy Yields Superior Specimens with Less Pain: Results of a Randomized Clinical Study
Authors: Ronan Swords, Javier Anguita, Russell A. Higgins, Andrea Yunes, Michael Naski, Swaminathan Padmanabhan, Kevin R Kelly, Devalingam Mahalingam, Thomas Philbeck, Larry Miller, Francis J. Giles, Marsha Kinney, Andrew Brenner
Journal: Blood (2010)
OC-016 Sequential activation of CXCR3 and CCR6 mediates recruitment and positioning of interleukin 17 producing T cells in the liver
Authors: Y H Oo, V M Banz, D Kavanagh, D R Withers, E Humphreys, L Lee-Turner, G Reynolds, N Kalia, S G Hubscher, B Eksteen, D H Adams
Journal: Gut (2010)

<h3>Introduction</h3> IL-17 secreting CD4 T cells (Th17) are a distinct lineage of pro-inflammatory lymphocytes that develop under control of the transcription factor RORγt. Th17 cells are pathogenic in models of autoimmunity and have been implicated in the pathogenesis of several forms of liver inflammation including primary biliary cirrhosis, alcoholic and viral hepatitis. Despite their importance in perpetuating inflammation, there is little known about the molecular basis for their recruitment and positioning to specific sites such as the liver. <h3>Methods</h3> Human intrahepatic Th17 cells were isolated from explanted liver tissue without cytokine expansion and analysed by multi colour flow cytometry. Murine liver injury models of Con A hepatitis, MCD Diet and repeated CCL4 injections were used for intravital microscopic assessment of Th17 cell recruitment to the liver. <h3>Results</h3> Less that 0.25% of T cells in normal human liver expressed IL-17 but we detected IL-17 secreting cells in inflamed human liver samples with the highest frequencies detected in patients with seronegative fulminant hepatitis (median 3.7%; IQR 3.4–3.9) non-alcoholic steatohepatitis (median 3.3%; IQR 2.7–3.5%) and auto-immune hepatitis (median 2.8%; IQR 2.6–3.3%). Intrahepatic IL-17+ cells expressed RORγt and the IL-23 receptor consistent with a Th17 lineage. They secreted IL-22 and IFNγ in addition to IL-17 and expressed high levels of the chemokine receptors CCR5, CCR6, CXCR3 and CXCR6. Intravital microscopy in murine models of acute liver injury (con-A hepatitis), steatohepatitis (MCD) and chronic liver injury (CCl4) demonstrated enhanced recruitment of adoptively transferred Th17 cells to the hepatic parenchyma via the sinusoids. Recruitment was significantly reduced by a blocking the CXCR3 ligand CXCL10 which also ameliorated liver injury. The CCR6 ligand, CCL20, was restricted to biliary epithelium and secreted by cholangiocytes in vitro suggesting a further recruitment signal positions Th17 cells near bile ducts in portal tracts. <h3>Conclusion</h3> Th17 cells are recruited to sites of inflammation in the liver by sequential interactions in which the CXCR3 ligand, CXCL10 promotes recruitment into the parenchyma from blood via the sinusoids and the CCR6 ligand, CCL20 positions cells at the biliary epithelium.