tbuckley/cabot-search huggingface dataset:
658. Bortezomib Treatment Sensitizes Oncolytic Virus Treated Tumors to NK Cell Immunotherapy
Authors: Ji Young Yoo
Journal: Molecular Therapy (2016)

Background: Bortezomib, a proteasome inhibitor and oncolytic herpes simplex virus-1 (oHSV) are currently FDA-approved and continue to be evaluated in several human cancers. Various combinatorial treatment modalities are being investigated to enhance the efficacy of each treatment. In this study, bortezomib-mediated oHSV killing sensitization and anti-tumor immunity were evaluated. Experimental Design: The synergistic interaction between oHSV and bortezomib was calculated using Chou-Talalay analysis. Western blot, flow cytometry, and caspase 3/7 activity assays were used to evaluate the induction of necroptotic cell death, JNK activation, and apoptosis. Production of reactive oxygen species (ROS) was measured. Inhibitors/shRNA targeting ROS, JNK and RIP1 kinase (RIPK1) were utilized to investigate the mechanism of cell killing. Natural killer (NK) cells isolated from normal human blood and co-cultured with tumor cells at an Effect/Target ratio of 2:1. Q-PCR, ELISA, and FACS analysis were used to evaluate NK cell activation. Intracranial tumor xenografts were utilized to evaluate anti-tumor efficacy. Results: Combination treatment with bortezomib and oHSV induced necroptotic cell death with increased production of mitochondrial ROS and phosphorylation of JNK. Inhibitors/shRNA of RIPK1 and JNK rescued synergistic cell killing. Combination treatment also increased HMGB1 and IL-1α secretion and significantly enhanced NK cell activation and tumor cell killing. Moreover, combinatorial therapy enhanced NK cell therapy. Conclusions: This study provides a significant rationale for triple combination therapy of bortezomib, oHSV, and NK cells to achieve synergistic efficacy, leading to future clinical testing of oHSV with bortezomib in patients.
Abstract LB-001: Development and evaluation of a fluorescent antibody-drug conjugate for molecular imaging and targeted therapy of pancreatic cancer
Authors: Steve Knutson, Erum Raja, Ryan Bomgarden, Marie Nlend, Aoshuang Chen, Ramaswamy Kalyanasundaram, Surbhi Desai
Journal: Cancer Research (2015)

Abstract Developing new strategies to effectively diagnose and treat various types of cancer is paramount to increasing patient survival rates. Although chemotherapeutic small molecules are effective for some cancer types, they often have harmful side effects, resulting in significant damage to healthy tissue. Targeted therapy, where anti-cancer drugs are more precisely delivered to specific cells, has the potential to revolutionize chemotherapy, through increased localized effective doses with minimized systemic toxicity. Antibody-drug conjugates (ADCs) are one such class of targeted therapy biopharmaceuticals, employing the inherent specificity of antibodies as a targeting mechanism to yield a potent drug delivery system. In addition to being used as ADCs, antibody-conjugates are also commonly used as a highly effective tool for cancer typing and longitudinal treatment monitoring by immunohistochemistry staining or diagnostic imaging. However, antibody-conjugates used for tumor diagnosis and treatment are different molecules. Fluorescent dye labeling of therapeutic antibodies has been previously demonstrated for cancer imaging. However, therapeutic antibodies dual-labeled with both chemotherapeutic small molecules and fluorescent dyes has not been reported. Here, we demonstrate the development of a directly-labeled, fluorescent antibody-drug conjugate for simultaneous targeted drug delivery and in vivo molecular imaging of cancer. Our novel biopharmaceutical entity is a monoclonal antibody specific for a carcinoembryonic antigen (CEA) biomarker conjugated to an average of one molecule of paclitaxel and two molecules of a near-infrared fluorophore (DyLight 680-4xPEG). Preliminary data show that this fluorescent ADC selectively binds CEA positive cells and is cytotoxic using in vitro model systems. Ongoing studies using an in vivo mouse xenograft cancer model will demonstrate the utility of this fluorescent ADC as a new concurrent pancreatic cancer detection, monitoring and treatment technology. Citation Format: Steve Knutson, Erum Raja, Ryan Bomgarden, Marie Nlend, Aoshuang Chen, Ramaswamy Kalyanasundaram, Surbhi Desai. Development and evaluation of a fluorescent antibody-drug conjugate for molecular imaging and targeted therapy of pancreatic 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-001. doi:10.1158/1538-7445.AM2015-LB-001
Abstract IA23: Integrating chemical and functional genomics for leukemia discovery.
Authors: Kimberly Stegmaier
Journal: Clinical Cancer Research (2015)

Abstract Characterization of the genomic landscapes of cancer with new technologies, such as massively parallel sequencing, has catapulted our understanding of human malignancies. However, many questions remain about the true genetic dependencies in human cancer, and for most malignancies, therapeutic impact has lagged behind the unraveling of the DNA code. In principle, the integration of functional and chemical genomics offers a powerful approach to decipher the mechanisms of cancer and inform therapeutics. We have applied such as integrative approach to the identification of new targeted strategies to induce the differentiation of acute myeloid leukemia (AML) cells. Targeting PML-RARα, the fusion protein present in the majority of patients diagnosed with acute promyelocytic leukemia (APL), demonstrated feasible the use of targeted differentiation therapy in this AML subtype. Emerging data support a role not only for transcription factor-directed therapy, but also for kinase-directed therapy, to induce AML differentiation. In a recent clinical trial the FMS-like tyrosine kinase 3 (FLT3) inhibitor quizartinib induced differentiation in patients with FLT3-ITD-positive AML, leading to responses in the majority of patients receiving the drug. Moreover, newer agents targeting chromatin regulators (e.g., DOT1L and BRD4) have been demonstrated to induce AML differentiation in vitro and in vivo, lending additional support to the potential of differentiation therapy for this disease. We have applied chemical and functional genomic screens for small-molecule and shRNA inducers of a complex gene expression signature of differentiation. Two high priority metabolic targets emerged at the intersection of these screens and have been validated in AML cells in vitro and in vivo with chemical and genetic perturbagens. Citation Format: Kimberly Stegmaier. Integrating chemical and functional genomics for leukemia discovery. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA23.
PWE-094 Patient selection for magnetic resonance cholangiopancreatography in management of common bile duct stones
Authors: D M L Tse, P Trivedi, I Al-Bakir, H D'Costa
Journal: Gut (2010)

<h3>Introduction</h3> Magnetic resonance cholangiopancreatography (MRCP) is highly sensitive and specific for detection of common bile duct (CBD) stones. The British Society of Gastroenterology guidelines on the management of suspected CBD stones recommend its use in patients with intermediate to high-risk as a non-invasive test to confirm the presence of ductal stones prior to therapy. Clinical, biochemical and ultrasound findings in isolation all suffer from low sensitivity, thus it is recommended that these variables be considered in combination. This study aims to identify the combination of clinical, biochemical or ultrasound findings that allow effective risk stratification in selecting patients for MRCP. <h3>Methods</h3> A retrospective analysis of 231 consecutive patients undergoing laparoscopic cholecystectomy was conducted. Clinical presentation, liver function tests (LFTs), and abdominal ultrasound findings were recorded, as well as findings from preoperative MRCP (if performed) and the eventual presence or absence of CBD stones at perioperative ERCP or on table cholangiogram. Multivariate logistic regression analysis was performed to investigate the relationship between clinical, biochemical and sonographic variables and the presence of CBD stone. <h3>Results</h3> 24 of 231 patients (10.4%) had CBD stones diagnosed intraoperatively or perioperatively. Raised LFTs (any of bilirubin, ALT or ALP) demonstrated significant odds ratio (OR) of 24.3 (95% CI 3.1 to 191.0), while clinical risk factors (history of jaundice, pancreatitis, cholangitis) or a dilated CBD on ultrasound showed increased but non-significant OR of 1.47 (95% CI 0.56 to 3.87) and 2.18 (95% CI 0.84 to 5.65), respectively. Combining LFTs and ultrasound findings to define a high-risk group, with abnormal LFT and/or abnormal CBD on ultrasound, yielded OR of 29.3 (95% CI 3.89 to 221.2). The combined high-risk group contained 114 patients (49%), with a sensitivity of 96% for presence of CBD stones, and positive predictive value of 20%. In the low risk group with normal LFTs and normal ultrasound, one out of 117 patients (0.85%) had a CBD stone. MRCP performed preoperatively in 74 (65%) of the high-risk group detected CBD stones in 14 patients (19%) with a negative predictive value of 98%. MRCP was performed on 10 (9%) of the low risk group: none showed CBD stones. <h3>Conclusion</h3> Patients with any abnormal LFT or abnormal CBD on ultrasound are at a significantly increased risk of CBD stones. Combining these biochemical and ultrasound features would enable efficient selection of high-risk patients to undergo MRCP prior to invasive therapy, and minimise the use of MRCP in low risk patients.
P62 Avoiding inappropriate prescribing of high dose inhaled corticosteroid combination inhalers – is the message getting through?
Authors: V Mak, G D’Ancona
Journal: Thorax (2016)

<h3>Introduction</h3> In the UK, over a third of asthma patients are treated at BTS step 4 or 5<sup>1</sup> with similar suggestions of over use of high dose inhaled corticosteroids (ICS), equivalent to ≥1000 micrograms beclomethasone dipropionate, in patients with COPD.<sup>2</sup> This has resulted in the highest dose ICS (HDICS-licensed daily dose equivalent to 2000micrograms beclomethasone dipropionate) with long-acting Beta<sub>2</sub>-agonist combination inhalers consistently appearing in the top five costliest drugs to the NHS. The London Respiratory Team have shared their concerns regarding the potential harm and waste associated with this practice; hence, many prescribing initiatives have been implemented to optimise ICS use through appropriate step down or ICS withdrawal. However cost-saving interventions such as generic prescribing have also been implemented. <h3>Aims</h3> To ascertain whether any reduction in spend on HDICS combinations is due to treatment optimisation or generic switches. <h3>Methods</h3> Monthly prescription cost analysis data available from the NHSBSA website (http://www.nhsbsa.nhs.uk) for the latest 15 months were analysed for the quantities prescribed and associated cost (Net Ingredient Cost) of all of the HDICS combination inhalers currently available. <h3>Results</h3> In 2015–16, the monthly spend on all HDICS combination inhalers fell from around £20million/month to £18million/month, and number of items fell from around 400,000/month to 365,000/month. By the last quarter, the switch from high cost HDICS combinations to lower cost ones accounted for 15% of all HDICS combinations, saving around £0.75million/month. <h3>Conclusion</h3> The message around inappropriate use of high dose ICS is beginning to filter through. Savings have been made from both switching to lower cost HDICS combination products and reduction in total numbers prescribed. Some of these saving will be offset by some patients being prescribed lower cost, lowerz’ dose ICS combinations. However the reduction in high dose prescribing is less than 10% of the total number prescribed. Given the extent of overuse, further harm and waste reduction can be made by reviewing the appropriateness of high dose ICS combinations prescribing in asthma and COPD with can lead to significant cost savings and improve value. <h3>References</h3> Covvey J, <i>et al</i>. Is the BTS/SIGN guideline confusing? A retrospective database analysis of asthma therapy. <i>Prim Care Respir J</i> 2013;<b>22</b>(3):290–5. White P, <i>et al</i>. Overtreatment of COPD with inhaled corticosteroids-implications for safety and costs: cross-sectional observational study. <i>PLoS One</i> 2013;<b>8</b>(10):e75221.
Abstract 227: Characterization of single cells from dissociated solid tumors
Authors: Aaron J. Middlebrook, Shahryar Niknam, Joyce Ruitenberg, Albert J. Mach, Maria Suni, Warren Porter, Friedrich Hahn, Eileen Snowden, Rainer Blaesius, Smita Ghanekar
Journal: Cancer Research (2015)

Abstract The heterogeneous nature of solid tumors, coupled with the relatively small sample size of available biopsies, has led to an emerging need to glean as much information as possible from these valuable specimens. Current approaches to solid tumor analysis fail to completely reveal the diverse range of cellular compartments that comprise the tumor microenvironment. A comprehensive approach to tumor interrogation requires efficient tissue dissociation to facilitate analysis at the single-cell level. In contrast to current methods, single-cell analysis of tumor derived cell suspensions by flow cytometry has the potential to provide a more complete understanding of the many subpopulations within the tumor microenvironment and the cell to cell interactions that govern this space. Here we demonstrate an efficient workflow that enables comprehensive single-cell analysis of solid tumors from breast cancers. Using tumors from clinical samples and mouse models, we evaluated different dissociation and processing techniques for their effects on cellular viability and surface marker expression. Solid tumors were dissociated into single-cell suspensions using a combination of mechanical dissociation and enzymatic digestion. Phenotypic distribution and morphology of cells within the tumor microenvironment was evaluated using flow cytometry. As this approach evolves, and a knowledge base of relevant surface markers is established, this technology has the potential to significantly impact how tumor biopsies are processed to get multiparametric information at a single cell level. Citation Format: Aaron J. Middlebrook, Shahryar Niknam, Joyce Ruitenberg, Albert J. Mach, Maria Suni, Warren Porter, Friedrich Hahn, Eileen Snowden, Rainer Blaesius, Smita Ghanekar. Characterization of single cells from dissociated solid tumors. [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 227. doi:10.1158/1538-7445.AM2015-227
Abstract 5323: Targeting PIM1 and CDK4/6 kinases in renal cell carcinoma
Authors: Jeffery S. Small, Sheldon L. Holder
Journal: Cancer Research (2015)

Abstract In this study we examine the hypothesis that combination therapy targeting the VEGFR, PIM1, and CDK4/6 kinases improves the efficacy of VEGFR-directed monotherapy in renal cell carcinoma (RCC). Two RCC cell lines, 786-O and Caki-1 (chosen for differences in VHL), were evaluated and the ED50s of SGI-1776 (PIM1 inhibitor), PD0332991 (CDK4/6 inhibitor), and LY2835219 (dual PIM1 and CDK4/6 inhibitor) assessed with an MTT assay. Cell Titer-Glo® was used to determine the effects of each of the inhibitors on cellular viability alone and in combination with sunitinib (VEFGR tyrosine kinase inhibitor). The effect of LY2835219 on phosphorylation of BAD, a PIM1 substrate, was assessed by Western blot. PIM1 and dual PIM1-CDK4/6 inhibition showed more potent effects on cellular viability than CDK4/6 inhibition. ED50 values of each inhibitor for RCC cells are reported in Table 1. Further assays showed greater decreased cellular viability in cells treated with the combination of a PIM1 inhibitor and sunitinib than in cells treated with either a PIM1 inhibitor or sunitinib alone. When combined with sunitinib, dual PIM1-CDK4/6 inhibition was more effective than PIM1 inhibition in 786-O cells. Sunitinib in combination with a CDK4/6 inhibitor was not as effective as in combination with either a PIM1 inhibitor or a dual PIM1-CDK4/6 inhibitor. Western blot analysis showed a decrease in phospho-BAD in cells treated with a dual PIM1-CDK4/6 inhibitor. Table 1.Potency of Kinase Inhibitors Against RCC Cell LinesInhibitorED50 (786-O; uM)ED50 (Caki-1; uM)SGI-17768.67 (8.13 - 9.25)6.94 (5.05 - 9.53)PD0332991Indeterminate*Indeterminate*LY28352197.46 (6.32 - 8.81)1.18 (1.02 - 1.36)95% confidence intervals are presented in parenthesis. *Highest dose level did not result in a sufficient response to allow for reliable curve fitting to determine the ED50 Our data reveal that targeting PIM1 in combination with sunitinib is superior to sunitinib alone in RCC cell lines. Additionally, in 786-O cells, added CDK4/6 inhibition further improves the efficacy of the combination therapy. Dual PIM1-CDK4/6 kinase targeted therapy in combination with sunitinib is an attractive therapeutic regimen with good potential for translation to the clinic. Ongoing studies include further characterization of the molecular events involved including apoptosis, cell cycle regulation, PIM1 kinase and CDK4/6 kinase activity, and evaluation of the combination therapy in a mouse xenograft model of RCC. Citation Format: Jeffery S. Small, Sheldon L. Holder. Targeting PIM1 and CDK4/6 kinases in renal cell 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 5323. doi:10.1158/1538-7445.AM2015-5323
Studies on the Cerebral Vascular Lesions in the Aged by Cerebral Arteriography
Authors: Norikazu Nakazawa
Journal: Circulation (1961)

The term  vascular lesions in this report includes cerebral arteriosclerosis and cerebral apoplexy. The cerebral arteriosclerosis is not only the cause of various cerebral symptoms, but important as the basis of cerebral vascular accidents. The cerebral arteriography is an excellent method for the diagnosis of cerebral atherosclerosis as well as for the etiologic and differential diagnosis of cerebral stroke. There have hitherto been many angiographic studies of cerebral stroke, but few attentions have been paid to the angiographic study of cerebral atherosclerosis. The author has performed arteriography on 60 cases of the aged with cerebral vascular lesions, the results of which are reported here. Method 1. The arteriography and observation of eyegrounds were performed on 60 cases, and mesurement of cerebral circulation on 24 cases, with cerebral vascular lesions, aging 50 to 80. 2. The arteriography was performed transcutaneously, using 60% Urographin or 50% Hypaque as contrast medium. The patients were injected with 40% papaverinum hydrochloricum for safety 30 minutes before arteriography. For the prevention of complications, general anesthesia was applied using thiopental sodium. In each arteriography, 10cc. of Urografin or Hypaque was used. 3. The cerebral circulation was measured by the N2O-method of Kety & Schmidt. 4. The observation of eyegrounds was made according to the Keith-Wagener classification. Results A. Cerebral arteriosclerosis The arteriographic grades of sclerosis, classified according chiefly to Brobeil and Riischede, were compared to retinal vascular changes, subjective symptoms, and cerebral hemodynamics values. 1. A rough relation was found between retinal findings (KW) and the grade of arteriographic sclerosis. 2. There was a tendency for the subjective symptoms, such as headache, drumming in the ear, and vertigo to increase with the arteriographic grade of sclerosis. 3. The comparison of cerebral circulation to arteriographic grade of sclerosis and retinal findings (KW) is as follows :
Salvage Therapy with the Combination of ARA-C and Gemtuzumab Ozogamicin in Post-Allo-SCT High Risk AML Patients Is Feasible and Results in Modest Responses.
Authors: Maya Koren-Michowitz, Hannah Maayaan, Ronit Yerushalmi, Noga Shem-Tov, Yulia Volchek, Abraham Avigdor, Avichai Shimoni, Arnon Nagler
Journal: Blood (2012)
Ponatinib As Frontline Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)
Authors: Preetesh Jain, Hagop M. Kantarjian, Elias Jabbour, Gautam Borthakur, Naveen Pemmaraju, Naval Daver, Evguenia Gachimova, Alessandra Ferrajoli, Steven M. Kornblau, Farhad Ravandi, Susan O'Brien, Jorge E. Cortes
Journal: Blood (2014)
Co-Existance of JAKV617F and PIG-A mutations in Primary Budd-Chiari Syndrome.
Authors: Chiharu Sugimori, Kenneth H Shain, Gisela Caceres, Lubomir Sokol, David Araten, Jaroslaw P. Maciejewski, JianXiang Zou, P.K. Epling-Burnette, Alan F List
Journal: Blood (2009)
Abstract 3279: Expression of chemerin and chemerin receptors in neuroblastoma: implications in tumorigenesis
Authors: Conny Tuemmler, Igor Snapkov, Ugo L. Moens, Per Kogner, John Inge Johnsen, Baldur Sveinbjørnsson
Journal: Cancer Research (2015)

Abstract Chemerin is an adipokine and immunomodulating factor that promotes chemotaxis of immature dendritic cells, natural killer cells, macrophages and endothelial cells. Secreted as prochemerin with low activity, it can be C-terminally processed by different proteases expressed by a broad range of cell types and tissues. The resulting isoforms vary in receptor affinity and biological activity and are natural ligands for the G protein-coupled receptors (GPCRs) CMKLR1, GPR1 and CCLR2. To date, the activation of CMKLR1 (chemokine-like receptor 1) by chemerin and its role in metabolism and metabolic disorders as well as inflammation is best understood. Neuroblastoma (NB) is a malignancy of the sympathetic nervous system and the most common extracranial solid pediatric tumor. Several chemoattractant GPCRs have been suggested to promote tumor progression, angiogenesis and metastasis in NB. Although for some cancers a potential function has been suggested, the role of chemerin and its receptors in the NB tumor microenvironment remains unknown. In our study, the screening of microarray databases and analysis of neuroblastoma expression data showed a correlation between high CMKLR1, GPR1 and CCLR2 expression and a reduction in the overall survival probability. Expression of CMKLR1, GPR1, and chemerin was shown in nine neuroblastoma cell lines using RT-PCR, Western blot and immunocytochemistry. Furthermore, chemerin and CMKLR1 were also detected in neuroblastoma tumor tissue by immunohistochemistry. Stimulation of NB cell lines with active chemerin induced calcium mobilization and increased phosphorylation of MEK1/2 and ERK1/2 indicating an activation of the MAPK signaling pathway. Furthermore, chemerin stimulation led to increased NF-κB phosphorylation and translocation to the nucleus. The induction of NF-κB mediated signaling was observed by luciferase reporter assay. TNFα, IL-1β or serum stimulation increased chemerin protein expression and secretion in neuroblastoma cells. To assess the functional significance of chemerin and its receptors in neuroblastoma tumorigenesis, cell clones overexpressing or silenced for CMKLR1/ Chemerin/ GPR1 are used in NB animal models. Citation Format: Conny Tuemmler, Igor Snapkov, Ugo L. Moens, Per Kogner, John Inge Johnsen, Baldur Sveinbjørnsson. Expression of chemerin and chemerin receptors in neuroblastoma: implications in tumorigenesis. [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 3279. doi:10.1158/1538-7445.AM2015-3279