tbuckley/cabot-search huggingface dataset:
Abstract 2733: Developing novel anti-OX40 antibodies on Biocytogen's in vivo drug screening platform
Authors: Chaoshe Guo, Yanan Guo, Yuelei Shen, Benny Yang
Journal: Cancer Research (2018)

Abstract OX40, also known as CD134 or TNFRSF4, is a member of the TNFR superfamily of receptors. OX40 is a co-stimulatory receptor, and it interacts with its ligand to providepositive signal for T cell activation. OX40 is not expressed on resting naïve T cells, however its expression goes up after 24 to 72 hours following activation. Disruption of OX40 pathway led to defective T cell responses and overexpression of OX40 caused massive immune activation. Due to its importance in keeping immune homeostasis, strategies modulating the OX40 pathway hold great promise in fighting against cancer and autoimmune diseases. We have interests in developing novel OX40 antibodies for boosting cancer patients' own immunityinlight of other successful immune checkpoint modulators. We developed a cohort of OX40 specific antibodies using the classic hybridoma technology. In order to screen their efficacy to stimulate anti-tumor activity in live animals, we managed to rank these antibodies using Biocytogen'shumanized mouse platform of immune checkpoints. Specifically, we utilized humanized OX40 mice (h-OX40) and implanted syngeneic tumors subcutaneously, followed by treating mice with purified testing antibodies. Via this approach, we are able to discern several lead antibodies that effectively inhibited tumor growth without prior knowledge of their in vitro activities. Furthermore, we identified that one clone works in concert with Keytruda in the dual humanized model of h-OX40 and h-PD1. We are currently investigating the mechanisms of action underlying these potentially useful antibodies. Citation Format: Chaoshe Guo, Yanan Guo, Yuelei Shen, Benny Yang. Developing novel anti-OX40 antibodies on Biocytogen's in vivo drug screening platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2733.
Copper Chelation as Targeted Therapy in a Mouse Model of Oncogenic BRAF-Driven Papillary Thyroid Cancer
Authors: MengMeng Xu, Michael Casio, Danielle E. Range, Julie A. Sosa, Christopher M. Counter
Journal: Clinical Cancer Research (2018)

Purpose: Sixty percent of papillary thyroid cancers (PTC) have an oncogenic (V600E) BRAF mutation. Inhibitors of BRAF and its substrates MEK1/2 are showing clinical promise in BRAFV600E PTC. PTC progression can be decades long, which is challenging in terms of toxicity and cost. We previously found that MEK1/2 require copper (Cu) for kinase activity and can be inhibited with the well-tolerated and economical Cu chelator tetrathiomolybdate (TM). We therefore tested TM for antineoplastic activity in BRAFV600E -positive PTC.Experimental Design: The efficacy of TM alone and in combination with current standard-of-care lenvatinib and sorafenib or BRAF and MEK1/2 inhibitors vemurafenib and trametinib was examined in BRAFV600E-positive human PTC cell lines and a genetically engineered mouse PTC model.Results: TM inhibited MEK1/2 kinase activity and transformed growth of PTC cells. TM was as or more potent than lenvatinib and sorafenib and enhanced the antineoplastic activity of sorafenib and vemurafenib. Activated ERK2, a substrate of MEK1/2, overcame this effect, consistent with TM deriving its antineoplastic activity by inhibiting MEK1/2. Oral TM reduced tumor burden and vemurafenib in a BrafV600E -positive mouse model of PTC. This effect was ascribed to a reduction of Cu in the tumors. TM reduced P-Erk1/2 in mouse PTC tumors, whereas genetic reduction of Cu in developing tumors trended towards a survival advantage. Finally, TM as a maintenance therapy after cessation of vemurafenib reduced tumor volume in the aforementioned PTC mouse model.Conclusions: TM inhibits BRAFV600E -driven PTC through inhibition of MEK1/2, supporting clinical evaluation of chronic TM therapy for this disease. Clin Cancer Res; 24(17); 4271-81. ©2018 AACR.
Abstract 478: Regulation ofMUC13by microRNA in colorectal cancer
Authors: Linda Bartu, Alena Opattova, Pavel Vodicka, Veronika Vymetalkova
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) represents a serious health problem with high incidence and mortality worldwide. The main reason of high mortality is the late diagnosis. For the Duke stage I, the average 5-years survival rate is 90%. In comparison to patients diagnosed at IV stage, the 5-years survival rate decreases to 3%. Mucinous CRC is generally defined as having greater than 50 % of the tumor area with a mucinous differentiation by histological examination. The increased incidence occurs in proximal colon and among younger patients, as compared to nonmucinous adenocarcinoma. Mucinous CRCs have been found to have a higher Duke stage at diagnosis, and, consequently a poorer prognosis. Mucines are surface or secreted glycoproteins with high molecular weight. Dysregulation of their expression may lead to malignant transformation. MUC13 overexpression influences colon cancer tumorigenesis and metastasis via multiple oncogenic proteins. Recently, we have observed that rs1532602 polymorphism in microRNA (miRNA) binding sites in MUC13 gene was associated with significantly decreased risk of CRC. The aim of the present study is to investigate regulation in vitro by miRNAs as a potential mechanism for increased MUC13 expression in CRC. Two different miRNAs were selected in this investigation. MiRNA-4647 is predicted to bind to the rs1532602 in MUC13. MiRNA-137 functions as a tumour suppressor in colon. Additionally, we investigated the impact of miRNAs mentioned above on regulation of MUC13 in a cohort of 113 patients with sporadic CRC. The present work provides important insights into role of miRNAs which bind to MUC13. Definition of functions, mechanisms of MUC13 regulation and its impact on CRC may contribute to better prediction and individual treatment of CRC. Acknowledgement: Grant Agency of the Ministry of Health of the Czech Republic (AZV MZ 15-26535A) and Grant Agency of the Czech Republic GACR 17-16857S. Citation Format: Linda Bartu, Alena Opattova, Pavel Vodicka, Veronika Vymetalkova. Regulation of MUC13 by microRNA in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 478.
Promoting Scientist–Advocate Collaborations in Cancer Research: Why and How
Authors: Jeannine M. Salamone, Wanda Lucas, Shelley B. Brundage, Jamie N. Holloway, Sherri M. Stahl, Nora E. Carbine, Margery London, Naomi Greenwood, Rosa Goyes, Deborah Charles Chisholm, Erin Price, Roberta Carlin, Susan Winarsky, Kirsten B. Baker, Julia Maues, Ayesha N. Shajahan-Haq
Journal: Cancer Research (2018)

Advocates bring unique and important viewpoints to the cancer research process, ensuring that scientific and medical advances are patient-centered and relevant. In this article, we discuss the benefits of engaging advocates in cancer research and underscore ways in which both the scientific and patient communities can facilitate this mutually beneficial collaboration. We discuss how to establish and nurture successful scientist-advocate relationships throughout the research process. We review opportunities that are available to advocates who want to obtain training in the evaluation of cancer research. We also suggest practical solutions that can strengthen communication between scientists and advocates, such as introducing scientist-advocate interactions at the trainee level. Finally, we highlight the essential role social media can play in disseminating patient-supported cancer research findings to the patient community and in raising awareness of the importance of promoting cancer research. Our perspective offers a model that Georgetown Breast Cancer Advocates have found effective and which could be one option for those interested in developing productive, successful, and sustainable collaborations between advocates and scientists in cancer research. Cancer Res; 78(20); 5723-8. ©2018 AACR.
Minimum important difference of the Epworth Sleepiness Scale in obstructive sleep apnoea: estimation from three randomised controlled trials
Authors: Sarah Crook, Noriane A Sievi, Konrad E Bloch, John R Stradling, Anja Frei, Milo A Puhan, Malcolm Kohler
Journal: Thorax (2018)

The Epworth Sleepiness Scale (ESS) is a widely used tool for assessing sleepiness in patients with obstructive sleep apnoea (OSA). We aimed to estimate the minimal important difference (MID) in patients with OSA.We used individual data from three randomised controlled trials (RCTs) in patients with OSA where the preintervention to postintervention change in ESS was used as a primary outcome. We used anchor-based linear regression and responder analysis approaches to estimate the MID. For anchors, we used the change in domains of the Functional Outcomes of Sleep Questionnaire and 36-Item Short Form Health Survey. We also used the distribution-based approaches Cohen's effect size, SE of measurement and empirical rule effect size to support the anchor-based estimates. The final MID was determined by triangulating all estimates to a single MID.A total of 639 patients with OSA were included in our analyses across the three RCTs with a median (IQR) baseline ESS score of 10 (6-13). The median (IQR) ESS change score overall was -2 (-5 to 1). The anchor-based estimates of the MID were between -1.74 and -4.21 points and estimates from the responder analysis were between -1 and -3 points. Distribution-based estimates were smaller, ranging from -1.46 to -2.36.We propose an MID for the ESS of 2 points in patients with OSA with a disease severity from mild to severe. This estimate provides the means to plan trials and interpret the clinical relevance of changes in ESS.Provent, NCT01332175; autoCPAP trial, NCT00280800; MOSAIC,ISRCTN (3416388).
Abstract 1849: Determining the molecular requirements for paclitaxel-induced spindle multipolarity
Authors: Christina Scribano
Journal: Cancer Research (2018)

Abstract Paclitaxel (TaxolTM) and other microtubule poisons are standard chemotherapy agents used in the treatment of breast cancer. However, only a subset of patients experience positive therapeutic effects from these drugs, underscoring the importance of further mechanistic study. Recently we showed that paclitaxel does not accumulate in primary breast cancers at sufficient concentrations to cause mitotic arrest, as it does at typically used concentrations in cell culture. Instead, paclitaxel therapy induces multipolar spindles in breast cancers. Breast cancer cell lines treated with low nanomolar, clinically relevant doses of paclitaxel exhibit chromosome missegregation due to multipolar divisions. We have now extended this to demonstrate that low nanomolar concentrations of other clinically used microtubule poisons (including ixabepilone, vinorelbine, and eribulin) also induce multipolarity in breast cancer cells, suggesting that multipolar mitotic divisions may be a common mechanism of cytotoxicity for microtubule-targeted drugs. Importantly, supernumerary centrosomes are not required for microtubule poison-induced multipolar spindles. To gain mechanistic insight into the formation of paclitaxel-induced multipolar spindles, a variety of mitotic regulators were tested for their ability to affect spindle multipolarity in breast cancer cells treated with clinically relevant concentrations of paclitaxel. Our results demonstrate that the mitotic kinesin Eg5 and the kinase Plk1 promote both the formation and the maintenance of paclitaxel-induced spindle multipolarity, while the mitotic kinesin CENP-E and the kinase Mps1 do not. Interestingly, we found that decreasing the time to anaphase onset decreases the number of multipolar divisions in paclitaxel, resulting in reduced cytotoxicity. Previous studies have shown that Mps1 inhibition sensitizes cells to paclitaxel, and this combination therapy has entered clinical trials (NCT02138812 and NCT02366949). However, our evidence suggests that Mps1 inhibition reduces the efficacy of paclitaxel as a result of decreased time to anaphase onset and fewer multipolar divisions. Additionally, our results suggest that inhibitors of spindle pole clustering increase the number of paclitaxel-induced multipolar divisions and therefore have the potential to increase its efficacy. Identification of the cellular requirements for multipolarity induced by paclitaxel, and of agents that drive the metaphase-to-anaphase transition in the presence of multipolar spindles, may improve the clinical utility of paclitaxel and other microtubule poisons. Citation Format: Christina Scribano. Determining the molecular requirements for paclitaxel-induced spindle multipolarity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1849.
Abstract 23: Overexpression Of Tbx20 In Adult Cardiomyocytes Promotes Cardiomyocyte Proliferation And Improves Cardiac Function Post Myocardial Infarction
Authors: Fu-liXiang, KatherineYutzey
Journal: Circulation Research (2014)

Background: Adult mammalian cardiomyocytes (CM) have the potential to proliferate, but this is not sufficient to compensate for the massive loss of functional CMs after myocardial infarction (MI), which remains a leading cause of death in the US. During embryonic heart development, the transcription factor Tbx20 is required for CM proliferation, and Tbx20 overexpression promotes fetal characteristics in adult CMs when initiated before birth in mice. We hypothesize that Tbx20 overexpression (Tbx20OE), when induced in adult CMs after injury, improves cardiac function and repair via dedifferentiation of CMs, thus promoting cell cycle re-entry and repair in mice post-MI. Methods and Results: αMHCMerCreMer (STG) and the inducible cardiomyocyte-specific Tbx20 transgenic (αMHCMerCreMer/CAG-CAT-Tbx20, DTG) mice were subjected to MI or sham surgeries. Tbx20OE was induced 3 days post-surgery via tamoxifen to specifically target cardiac repair post-MI. In sham-operated mice, no difference in cardiac function or morp...
Dual Pathways for Nuclear Factor κB Activation by Angiotensin II in Vascular Smooth Muscle
Authors: LipingZhang, JizhongCheng, YeweiMa, WalterThomas, JiqiangZhang, JieDu
Journal: Circulation Research (2005)

Activation of nuclear factor (NF)-κB by angiotensin II (Ang II) plays an essential role in stimulating expression of vascular adhesion molecules, which are essential for vascular inflammation. We report that Ang II activates NF-κB by phosphorylating its p65 subunit via a pathway mediated partially by ribosomal S6 kinase (RSK). In investigating other pathway(s) that may be involved, we found that the ability of Ang II to activate NF-κB in mouse embryonic fibroblast is suppressed (&70%) either by deletion of IκB Kinase (IKK) or by inhibiting or knocking down IKK in vascular smooth muscle cells using a dominant-negative IKK adenovirus or small interference RNA to IKKβ. Thus, Ang II also stimulates NF-κB via IKK. In vitro, we found that Ang II stimulates IKK to phosphorylate myelin basic protein and the p65 subunit of NF-κB. The mechanism by which Ang II activates IKK is to increase phosphorylation of IKKβ in its activation loop (Ser181) rather than IκB phosphorylation. Inhibiting both the RSK and IKK pathway...
Angiotensin-Converting Enzyme Inhibitor Helps Prevent Late Remodeling After Left Ventricular Aneurysm Repair in Rats
Authors: TakuyaNomoto, TakeshiNishina, SenriMiwa, HiroshiTsuneyoshi, IzumiMaruyama, KazunobuNishimura, MasashiKomeda
Journal: Circulation (2002)

Background We reported in a previous study that the initial effects of left ventricular (LV) repair (LVR) for LV aneurysm were not long lasting. Angiotensin-converting enzyme inhibitor (ACE-I) is known to attenuate remodeling after myocardial infarction, and could be effective after LVR. Methods and Results Left ventricular aneurysms were developed in rats after left anterior descending artery ligation. Rats were divided into 3 groups: sham operation with ACE-I (lisinopril 10 mg/kg/d) (n=10; group A), LVR (by plicating the LV aneurysm) with placebo (n=8; group R), and LVR with ACE-I (n=10; group RA). LV function was evaluated by echocardiography and catheterization. Oxidative stress in the myocardium was estimated by immunohistochemistry for 8-hydroxy-2′-deoxyguanosine. One week after LVR, LV end-diastolic area was smaller and fractional area change was better in the 2 LVR groups. Four weeks after LVR, LV end-diastolic area, and fractional area change deteriorated in group R but not so much in group RA; E...
Platelet Protease Nexin-1, a Serpin That Strongly Influences Fibrinolysis and Thrombolysis
Authors: YacineBoulaftali, BenoitHo-Tin-Noe, AnaPena, StéphaneLoyau, LaurenceVenisse, DéborahFrançois, BenjaminRichard, VéroniqueArocas, Jean-PhilippeCollet, MartineJandrot-Perrus, Marie-ChristineBouton
Journal: Circulation (2011)

Background—Protease nexin-1 (PN-1) is a serpin that inhibits plasminogen activators, plasmin, and thrombin. PN-1 is barely detectable in plasma, but we have shown recently that PN-1 is present within the α-granules of platelets. Methods and Results—In this study, the role of platelet PN-1 in fibrinolysis was investigated with the use of human platelets incubated with a blocking antibody and platelets from PN-1–deficient mice. We showed by using fibrin-agar zymography and fibrin matrix that platelet PN-1 inhibited both the generation of plasmin by fibrin-bound tissue plasminogen activator and the activity of fibrin-bound plasmin itself. Rotational thromboelastometry and laser scanning confocal microscopy were used to demonstrate that PN-1 blockade or deficiency resulted in increased clot lysis and in an acceleration of the lysis front. Protease nexin-1 is thus a major determinant of the lysis resistance of platelet-rich clots. Moreover, in an original murine model in which thrombolysis induced by tissue pl...
Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis
Authors: Samuele Cortese, Nicoletta Adamo, Cinzia Del Giovane, Christina Mohr-Jensen, Adrian J Hayes, Sara Carucci, Lauren Z Atkinson, Luca Tessari, Tobias Banaschewski, David Coghill, Chris Hollis, Emily Simonoff, Alessandro Zuddas, Corrado Barbui, Marianna Purgato, Hans-Christoph Steinhausen, Farhad Shokraneh, Jun Xia, Andrea Cipriani
Journal: The Lancet Psychiatry (2018)

The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults.
Systemic Effects of Radiotherapy in Ductal Carcinoma In Situ
Authors: Mira Goldberg, Timothy J. Whelan
Journal: JAMA Network Open (2018)

Giannakeas and colleagues 1 report results of a cohort study of more than 140 000 women with primary ductal carcinoma in situ (DCIS) treated by lumpectomy alone, lumpectomy plus radiation, or mastectomy enrolled in the Surveillance, Epidemiology, and End Results (SEER) database from 1998 to 2014.Using a matched-pair design with propensity weighting, the 15-year breast cancer mortality rates were reduced in patients treated with lumpectomy plus radiation compared with lumpectomy alone (1.78% vs 2.05%; hazard ratio [HR], 0.77; 95% CI, 0.67-0.88).Breast cancer mortality was also reduced in patients treated with lumpectomy plus radiation compared with mastectomy (HR, 0.75; 95% CI, 0.65-0.87),but no difference was detected when mastectomy was compared with lumpectomy alone (HR, 0.91; 95% CI, 0.78-1.05).The methods used in this epidemiologic database analysis were rigorous.Investigators were careful to match for year and age at diagnosis, tumor grade, estrogen receptor status, and propensity score, taking into account ethnicity, household income, tumor size, and progesterone receptor status.Cumulative breast cancer mortality rates were determined using the Kaplan-Meier method, and groups were compared using the Cox proportional hazards model.Results were similar when
Transcutaneously refillable nanofluidic implant achieves sustained level of tenofovir diphosphate for HIV pre-exposure prophylaxis
Authors: Corrine Ying Xuan Chua, Priya Jain, Andrea Ballerini, Giacomo Bruno, R. Lyle Hood, Manas Gupte, Song Gao, Nicola Di Trani, Antonia Susnjar, Kathryn Shelton, Lane R. Bushman, Marco Folci, Carly S. Filgueira, Mark A. Marzinke, Peter L. Anderson, Ming Hu, Pramod Nehete, Roberto C. Arduino, Jagannadha K. Sastry, Alessandro Grattoni
Journal: Journal of Controlled Release (2018)
Abstract 3342: Truncated glioma-associated oncogene homolog 1 (tGLI1) is a novel mediator of mesenchymal subtype of glioblastoma and a novel transcriptional activator of CD44
Authors: Tadas K. Rimkus
Journal: Cancer Research (2018)

Abstract The subpopulation of stem-like cells, or glioma stem cells (GSCs), is a key driver of tumor initiation, recurrence, and chemoresistance. Recently, patient-derived GSC lines were identified to contain two mutually exclusive subtypes termed proneural and mesenchymal. Mesenchymal GBM and GSCs were found to be more aggressive and radioresistant; however, the molecular pathways supporting mesenchymal GBM and mesenchymal GSCs are not well understood. To address this knowledge gap, we examined truncated glioma-associated oncogene homolog 1 (tGLI1) for its role in mesenchymal subtypes of GBM and GSCs. Discovered in our laboratory, tGLI1 is a novel alternatively spliced, gain-of-function variant of GLI1 zinc-finger transcription factor with an in-frame deletion of 41 codons retains all of the known functional domains of GLI1, but gains the ability to activate genes not regulated by GLI1. In this study, we report for the first time that tGLI1 is a tumor-specific transcription factor that facilitates GBM growth, enriches in the mesenchymal subtype of GBM and GSCs, and promotes mesenchymal GSCs via transcriptionally activating CD44 expression. Using an orthotopic GBM xenograft mouse model, we observed that tGLI1-overexpressing tumors grew more aggressively, with increased proliferation and angiogenesis, compared to control and GLI1-overexpressing xenografts. IHC analysis using tGLI1- and GLI1-selective antibodies we developed showed that tGLI1 was significantly expressed in GBM specimens but undetectable in normal brains whereas GLI1 was expressed in both tissues. Datamining further showed that tGLI1 activation signature (tGAS) was correlated with glioma grade, tumor angiogenesis, and poor overall survival, and that GBMs with high tGAS were enriched with mesenchymal GBM and GSC gene signatures. Neurospheres contained increased levels of tGLI1, but not GLI1, compared to the monolayer culture. Mesenchymal GSCs expressed more tGLI1 than proneural GSCs. Ectopic tGLI1 expression significantly enhanced the ability of GSCs to yield neurospheres in vitro and form aggressive tumors in mouse brains. Finally, we examined the ability of tGLI1 to regulate stemness genes and found that tGLI1 binds to and transactivates the promoter of the CD44 gene, a marker and mediator for mesenchymal GSCs. Collectively, these findings advanced our understanding of GBM biology by establishing tGLI1 as a novel transcriptional activator of CD44 and a novel mediator of mesenchymal GBM and GSCs. Citation Format: Tadas K. Rimkus. Truncated glioma-associated oncogene homolog 1 (tGLI1) is a novel mediator of mesenchymal subtype of glioblastoma and a novel transcriptional activator of CD44 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3342.