tbuckley/cabot-search huggingface dataset:
Abstract 1119: Quaking (Qki) loss enhances stemness of glioma stem cells through regulating intracellular vesicle trafficking system
Authors: Jian Hu, Takashi Shingu
Journal: Cancer Research (2018)

Abstract Glioma stem cells (GSCs) have higher self-renewal capacity than neural stem cells (NSCs), yet the underlying molecular mechanism is less clear. Here we report the generation of a novel conditional KO allele of Quaking (Qki), a tumor suppressor in glioblastoma with RNA binding activity. When Qki was deleted in Nestin-CreERT2;QkiL/L mice, the NSC population, which is characterized by long-term BrdU retention and GFAP+/Nestin+ double positive staining, was greatly increased, indicating that Qki deletion enhances NSC self-renewal. To determine whether Qki deletion promotes gliomagenesis, we generated a Nestin-CreERT2;QkiL/L;PtenL/L;p53L/L cohort, in which 92% of the mice developed glioblastoma with a median survival of 105 days. However, the Nestin-CreERT2;PtenL/L;p53L/L cohort did not develop any glioma up to a year; therefore Qki deletion greatly promotes gliomagenesis. Transcriptomic and proteomic profiling coupled with PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) analyses revealed that genes involved in intracellular vesicle trafficking were greatly enriched by Qki deletion. Specifically, 34% of the genes up-regulated by Qki deletion are involved in receptor delivery, and 39% of the genes down-regulated by Qki deletion are subunits of receptor degradation machineries such as endosomes and lysosomes. High level of receptor delivery and low level of receptor degradation concomitantly enrich receptors on the membrane and enhance the activity of the receptors that are involved in maintaining stemness, including RTK, Notch1 and Frizzled. Lower lysosomal activity induced by Qki deletion also leads to defective mitophagy, which consequently leads to accumulation of damaged mitochondria, high level of ROS, and genomic instability in Qki-deficient NSCs. We identified that genomic instability induced by Qki deletion led to accumulation of classical glioblastoma-associated mutations such as copy number gains of PDGFRa, Cyclin D1 and Cyclin D3. Taken together, our data suggest that Qki loss-induced endolysosomal defects promotes gliomagenesis through both reducing receptor degradation and inducing genomic instability. Citation Format: Jian Hu, Takashi Shingu. Quaking (Qki) loss enhances stemness of glioma stem cells through regulating intracellular vesicle trafficking system [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 1119.
Echocardiography Screening for Rheumatic Heart Disease in Ugandan Schoolchildren
Authors: AndreaBeaton, EmmyOkello, PeterLwabi, CharlesMondo, RobertMcCarter, CraigSable
Journal: Circulation (2012)

Background—Historically, sub-Saharan Africa has had the highest prevalence rates of clinically detected rheumatic heart disease (RHD). Echocardiography-based screening improves detection of RHD in endemic regions. The newest screening guidelines (2006 World Health Organization/National Institutes of Health) have been tested across India and the Pacific Islands, but application in sub-Saharan Africa has, thus far, been limited to Mozambique. We used these guidelines to determine RHD prevalence in a large cohort of Ugandan school children, to identify risk factors for occult disease, and to assess the value of laboratory testing. Methods and Results—Auscultation and portable echocardiography were used to screen randomly selected schoolchildren, 5 to 16 years of age, in Kampala, Uganda. Disease likelihood was defined as definite, probable, or possible in accordance with the 2006 National Institutes of Health/World Health Organization guidelines. Ninety-seven percent of eligible students received screening (4...
Abstract 113: Gemcitabine treatment induces immunosuppressive microenvironment in pancreatic cancer by promoting the infiltration, growth, and polarization of macrophages
Authors: Sachin Kumar Deshmukh, Arun Bhardwaj, Nikhil Tyagi, Mohammad Aslam Khan, Sanjeev K. Srivastava, Ahmed AL-Ghadhban, Kari Dugger, James E. Carter, Ajay P. Singh, Seema Singh
Journal: Cancer Research (2018)

Abstract Resistance to chemotherapeutic drugs remains a major cause of therapeutic failure in pancreatic cancer (PC) patients. Efficacy of chemotherapy is further limited by its debilitating effects on immune system. Apart from genetic abnormalities in tumor cells, the tumor immune- microenvironment plays a crucial role in PC chemoresistance. However, it is unclear how chemotherapy affects the cancer immunity or how it affects the tumor microenvironment (TME). In the present study, we demonstrate gemcitabine induces an increased infiltration of CD68+ M2 macrophages in pancreatic tumors isolated from an orthotopic xenograft murine model. Moreover, the conditioned media from PC cell lines cultured with gemcitabine (Gem-CM) promotes migration, invasion, and growth of RAW264.7 macrophage. Interestingly, Gem-CM induces an upregulation of tumor-associated or M2-polarized macrophage markers, arginase-1 and TGF-β1. Additionally, gemcitabine treatment of PC cell lines induces the expression of M2-polarization associated cytokines, growth factors and chemokines, including IL-8. IL-8 exhibits the greatest upregulation after culture with Gemcitabine. Further, IL-8 neutralization in Gem-CM diminished its ability to induce growth, migration, and invasion of RAW264.7 macrophages. Together, these findings suggest an indirect effect of gemcitabine on increasing macrophage trafficking and M2-polarization that potentially supports a pro-tumor microenvironment. These actions may contribute to the chemoresistance of PC. Prevention of gemcitabine-induced macrophage infiltration, growth and M2-polarization will offer a better strategy to counter chemotherapy-induced immunosuppression in PC. Citation Format: Sachin Kumar Deshmukh, Arun Bhardwaj, Nikhil Tyagi, Mohammad Aslam Khan, Sanjeev K. Srivastava, Ahmed AL-Ghadhban, Kari Dugger, James E. Carter, Ajay P. Singh, Seema Singh. Gemcitabine treatment induces immunosuppressive microenvironment in pancreatic cancer by promoting the infiltration, growth, and polarization of macrophages [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 113.
Abstract 169: Identification of RNA aptamers selectively recognizing and affecting glioblastoma stem cells
Authors: Alessandra Affinito, Cristina Quintavalle, Maurizio Albero, Claudia Vilardo, Francesco Palma, Giuseppina Roscigno, Lucia Ricci Vitiani, Roberto Pallini, Carla Lucia Esposito, Vittorio de Franciscis, Gerolama Condorelli
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM) is the most frequent and aggressive primary brain tumour in adults. Despite advances in surgical and medical neuro oncology, prognosis for GBM patients remains dismal, with a median survival of about 15 months. It has been demonstrated that the modest benefit of conventional therapies depends on a small population of cancer stem cells within the tumor, named Glioma Stem Cells (GSCs) that cause tumor relapse and chemoresistance and therefore could play a key role in GBM recurrence. Thus, the identification of new specific ligands for GSCs could be a fundamental challenge for the development of effective glioma therapies. Here, we developed an in vitro evolution based approach, named differential whole cellSELEX; it is used to generate nucleic acid ligands, named aptamers, with high affinity and specificity for GSCs. Aptamers, were obtained through the iterative evolution of a random pool of sequences using human primary GSCs as target. Among different potential candidates we focused on one sequence, named 40L. The 40L aptamer and its truncated form, 40S, were selective for human GSCs distinguishing them from tumor differentiated cells, obtained from the stem cells induced to differentiate. 40L revealed to be functionally active on target cells and able to inhibit stemness, cell growth and migration. 40s preserves binding ability of 40L sequence and it has further proven to strongly reduce tumor proliferation in in vivo experiment. Moreover, both 40L and 40s were able to rapidly internalize upon target binding and therefore may serve as selective vehicle for therapeutics.In conclusion, our results indicate that 40L and its short form 40s can selectively target GSCs both in vitro and in vivo. Given the crucial role of these cells in GBM recurrence and therapy resistance, 40L and 40s represent innovative drug candidates with a great potential in the GBM treatment. Citation Format: Alessandra Affinito, Cristina Quintavalle, Maurizio Albero, Claudia Vilardo, Francesco Palma, Giuseppina Roscigno, Lucia Ricci Vitiani, Roberto Pallini, Carla Lucia Esposito, Vittorio de Franciscis, Gerolama Condorelli. Identification of RNA aptamers selectively recognizing and affecting glioblastoma stem cells [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 169.
Abstract 3728: α-Mangostin-encapsulated PLGA nanoparticles inhibit pancreatic carcinogenesis by targeting cancer stem cells in KC and KPC mice
Authors: Raj K. Verma, Wei Yu, Anju Shrivastava, Rakesh K. Srivastava, Sharmila Shankar
Journal: Cancer Research (2018)

Abstract Activation of sonic Hedgehog (Shh) in cancer stem cell (CSC) has been demonstrated with aggressiveness of pancreatic cancer. In order to enhance the biologic activity of α-mangostin, we formulated mangostin-encapsulated PLGA nanoparticles (Mang-NPs) and examined the molecular mechanisms by which they inhibit human and KC mice (PdxCre;LSL-KrasG12D) pancreatic CSC characteristics in vitro, and pancreatic carcinogenesis in KPC (PdxCre;LSLKrasG12D;LSL-Trp53R172H) mice. Mang-NPs inhibited human and KrasG12D mice pancreatic CSC characteristics in vitro. Mang-NPs also inhibited EMT by upregulating E-cadherin and inhibiting N-cadherin and transcription factors Slug, and pluripotency maintaining factors Nanog, c-Myc, and Oct4. Furthermore, Mang-NPs inhibited the components of Shh pathway and Gli targets. In vivo, Mang-NPs inhibited the progression of pancreatic intraneoplasia to pancreatic ductal adenocarcinoma and liver metastasis in KPC mice. The inhibitory effects of Mang-NPs on carcinogenesis in KPC mice were associated with downregulation of pluripotency-maintaining factors (c-Myc, Nanog and Oct4), stem cell markers (CD24 and CD133), components of Shh pathway (Gli1, Gli2, Patched1/2, and Smoothened), Gli targets (Bcl-2, XIAP and Cyclin D1), and EMT markers and transcription factors (N-cadherin, Slug, Snail and Zeb1), and upregulation of E-cadherin. Overall, our data suggest that Mang-NPs can inhibit pancreatic cancer growth, development and metastasis by targeting Shh pathway. Citation Format: Raj K. Verma, Wei Yu, Anju Shrivastava, Rakesh K. Srivastava, Sharmila Shankar. α-Mangostin-encapsulated PLGA nanoparticles inhibit pancreatic carcinogenesis by targeting cancer stem cells in KC and KPC mice [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 3728.
Abstract 4086: Efficient primary culture model of patient-derived epithelial cells from colorectal cancer using a ROCK inhibitor and feeder cells
Authors: Hyekyung Hong, Nakhyeon Yun, Taewon Kim, Yeosong Lee, Sujeong Song, Jaemoon Bae, Wooyong Lee, Yongbeom Cho
Journal: Cancer Research (2018)

Abstract In vitro culture for patient-derived cells offers many advances in the development of novel therapies for colorectal cancer. Although various culture systems have been developed, experimental systems in which the long-term expansion of patient-derived epithelial cells still remained difficult. Here, we demonstrated that epithelial cells isolated from colorectal cancer patient-derived xenograft can be efficiently immortalized in conditioned medium from irradiated feeder cells containing a Rho kinase inhibitor Y-27632. Patient-derived tumor cells were rapidly proliferated to reach confluence in approximately 6 days. Short tandem repeat (STR) analysis of tumor tissue and cultured cells demonstrate that they have 13 identical STR loci and Amelogenin, Penta E, Penta D, D2S1338 and D19S433. The epithelial character was confirmed by staining for EpCAM, cytokeratin 20 and vimentin as a mesenchymal marker. Cells were continued to proliferate and formed well-defined tumor spheroids when transferred to 3D culture. To study the mechanism for promoting unrestricted cell proliferation, we investigated the expression of several cellular genes that fall into two designated pathways, induction of telomerase and cytoskeletal remodeling/p16 pathway. Moreover, patient-derived tumor cells were utilized for high-throughput screening of FDA approved drugs allowing detection of gene-drug associations. Collectively, we demonstrate that the long-term expansion of patient-derived tumor epithelial cells and these cells could be a useful tool in order to investigate a personalized treatment approach. Citation Format: Hyekyung Hong, Nakhyeon Yun, Taewon Kim, Yeosong Lee, Sujeong Song, Jaemoon Bae, Wooyong Lee, Yongbeom Cho. Efficient primary culture model of patient-derived epithelial cells from colorectal cancer using a ROCK inhibitor and feeder cells [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 4086.
Effects of the Diuretic Agent Indapamide on Na+, Transient Outward, and Delayed Rectifier Currents in Canine Atrial Myocytes
Authors: YanjieLu, LixiaYue, ZhiguoWang, StanleyNattel
Journal: Circulation Research (1998)

Abstract—The diuretic agent indapamide has been reported to block the slow component of the delayed rectifier K+ current (IKs) without altering the rapid component (IKr) or the inward rectifier current and has been used as a pharmacological probe for IKs; however, the effects of indapamide on Na+ (INa), L-type Ca2+ (ICa), and transient outward K+ (Ito) currents have not been determined. We applied tight-seal, whole-cell, patch-clamp techniques to assess the effects of indapamide on INa, Ito, ICa, and IKs in canine atrial myocytes. Indapamide inhibited INa, Ito, and IKs in a concentration-dependent and reversible way, without altering ICa. Block increased with depolarization, with the 50% blocking concentration (EC50) decreasing from 129±26 μmol/L (at −60 mV) to 79±17 μmol/L (at −10 mV) for INa, from 174±19 μmol/L (at +10 mV) to 98±7 μmol/L (at +60 mV) for Ito, and from 148±28 μmol/L (at +10 mV) to 86±18 μmol/L (at +60 mV) for IKs. Significant inhibition was seen at concentrations as low as 10 μmol/L for a...
Publisher Correction: Visual perception: Sensory category learning
Authors: Stefan Pollmann
Journal: Nature Human Behaviour (2018)

In the version of this News & Views originally published, the following sentence was mistakenly omitted from the Fig. 1 caption: 'Gabor patches generated from https://www.cogsci.nl/gabor-generator under a Creative Commons licence CC BY 4.0.' This has now been corrected.
Abstract 19387: Angioplasty of Chronic Total Coronary Occlusions is Not Associated with Improved Survival Compared With Elective Medical Therapy: a Propensity Matched Retrospective Cohort Study
Authors: AndrewLadwiniec, VictoriaAllgar, SimonThackray, FarquadAlamgir, AngelaHoye
Journal: Circulation (2014)

Introduction: Although an association between improved survival and successful PCI of chronic total coronary occlusions (CTO) compared with failed PCI has been widely reported, there is little published data reporting outcomes for those found to have a CTO which is electively treated medically versus those treated by PCI; a comparison which is more pertinent to clinical decision making. Our aim was to compare long-term clinical outcomes in a cohort of patients with an identified CTO on angiography between these two treatment groups. We hypothesised there would be a significant difference in all-cause mortality at 5 year follow-up. Methods: Patients found to have a CTO on angiography between 2002 and 2008, without prior CABG or important structural heart disease in a single tertiary centre were identified using a dedicated database. Patients undergoing CTO PCI and elective medical therapy to the CTO were propensity matched to adjust for baseline clinical and angiographic differences. Events at follow-up we...
Abstract 5365: Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies
Authors: Matthew Alderdice, Susan D. Richman, Simon Gollins, Peter Stewart, Chris Hurt, Richard Adams, Amy M. McCorry, Aideen Roddy, Dale Vimalachandran, Claudio Isella, Enzo Medico, Tim Maughan, Darrgh G. McArt, Mark Lawler, Philip D. Dunne
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) biopsies underpin accurate diagnosis, but are also relevant for patient stratification in molecularly-guided clinical trials. The consensus molecular subtypes (CMS) and colorectal cancer intrinsic subtypes (CRIS) transcriptional signatures have potential clinical utility for improving prognostic/predictive patient assignment. However, their ability to provide robust classification, in pre-treatment biopsies from multiple regions or at different time points remains untested. In this study, we undertook a comprehensive assessment of the robustness of CRC transcriptional signatures, including CRIS and CMS, using a range of tumour sampling methodologies currently employed in clinical and translational research. These include analyses using (i) laser-capture microdissected CRC tissue, (ii) eight publically available rectal cancer biopsy data sets (n=543), (iii) serial biopsies (from AXEBeam trial, NCT00828672; n=10), (iv) multi-regional biopsies from colon tumours (n=29 biopsies, n=7 tumours) and (v) pre-treatment biopsies from the phase II rectal cancer trial COPERNCIUS (NCT01263171; n=44). Compared to previous results obtained using CRC resection material, we now demonstrate that CMS classification in biopsy tissue is significantly less capable of reliably classifying patient subtype (43% unknown in biopsy versus 13% unknown in resections, p=0.0001). In contrast, there was no significant difference in classification rate between biopsies and resections when using the CRIS classifier. Additionally, we demonstrated that CRIS provides significantly better spatially- and temporally- robust classification of molecular subtypes in CRC primary tumour tissue compared to CMS (p= 0.003 and p=0.02, respectively). These findings may have potential to inform ongoing biopsy-based patient stratification in CRC, enabling robust and stable assignment of patients into clinically-informative arms of prospective multi-arm, multi-stage clinical trials. Citation Format: Matthew Alderdice, Susan D. Richman, Simon Gollins, Peter Stewart, Chris Hurt, Richard Adams, Amy M. McCorry, Aideen Roddy, Dale Vimalachandran, Claudio Isella, Enzo Medico, Tim Maughan, Darrgh G. McArt, Mark Lawler, Philip D. Dunne. Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies [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 5365.
Abstract 3774: BGB324, a selective small-molecule inhibitor of receptor tyrosine kinase AXL, targets tumor immune suppression and enhances immune checkpoint inhibitor efficacy
Authors: Kjersti Davidsen, Katarzyna Wnuk-Lipinska, Wenting Du, Magnus Blø, Agnete Engelsen, Stephane Terry, Stacey D´mello, Maria Lie, Jing Kang, Linn Hodneland, Sebastien Bougnaud, Kristina Aguilera, Oddbjørn Straume, Salem Chouaib, Rolf A. Brekken, Gro Gausdal, James B. Lorens
Journal: Cancer Research (2018)

Abstract The AXL receptor tyrosine kinase is associated with poor overall survival in a wide spectrum of cancers. AXL signaling is important for tumor cell plasticity related to epithelial-to-mesenchymal transition (EMT), immune escape and intrinsic resistance to cytotoxic lymphocytes. AXL is expressed on several cells associated with the tumor immune microenvironment, including natural killer (NK) cells, dendritic cells and a subset of tumor-associated myeloid cells. AXL signaling enhances secretion of immune-suppressive cytokines from innate immune cells that limit antitumor immunity. Hence AXL resides uniquely at the nexus between tumor and microenvironmental antitumor immune suppression mechanisms. BGB324, a selective clinical-stage small-molecule Axl kinase inhibitor, is currently being evaluated in combination with pembrolizumab in three phase II clinical trials in patients with TNBC (NCT03184558), NSCLC (NCT03184571) and melanoma (NCT02872259). We show that BGB324 targets immune suppression mechanisms in the tumor microenvironment that improve immunotherapy in different murine tumor models. BGB324 treatment reduces myeloid-derived suppressor cells and tumor-associated macrophages, and lowers CCL11, IL-7, IL-1β, and IL-6 in murine pancreatic cancer models. This altered immune landscape is associated with increased tumor infiltration of NK and CD8+ T cells and enhanced therapy responses. Further, BGB324 targets tumor intrinsic immune resistance and enhances human CD8+ T cell and NK-cell mediated NSCLC tumor cell lysis. We are currently using high-dimensional mass cytometry analysis (CyTOF) to map adaptive Axl-dependent immune suppression during immune checkpoint blockade. Collectively these results highlight a prominent function for AXL in resistance to immune therapy and support continued clinical translation of combining BGB324 with immune checkpoint inhibitors to improve cancer treatment. Citation Format: Kjersti Davidsen, Katarzyna Wnuk-Lipinska, Wenting Du, Magnus Blø, Agnete Engelsen, Stephane Terry, Stacey D´mello, Maria Lie, Jing Kang, Linn Hodneland, Sebastien Bougnaud, Kristina Aguilera, Oddbjørn Straume, Salem Chouaib, Rolf A. Brekken, Gro Gausdal, James B. Lorens. BGB324, a selective small-molecule inhibitor of receptor tyrosine kinase AXL, targets tumor immune suppression and enhances immune checkpoint inhibitor efficacy [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 3774.
Characterization of the Endothelium-Specific Murine Vascular Endothelial Growth Factor Receptor-2 (Flk-1) Promoter
Authors: VolkerRönicke, WernerRisau, GeorgBreier
Journal: Circulation Research (1996)

Flk-1, a high-affinity signaling receptor for vascular endothelial growth factor (VEGF), is strongly and specifically expressed on endothelial cells during embryonic development of the vascular system and during tumor angiogenesis. Disruption of Flk-1 gene function has recently been shown to prevent completely endothelial cell differentiation during murine embryonic development. To gain insights into the mechanisms that regulate the endothelium-specific Flk-1 expression, we have isolated the 5′-flanking region of the murine Flk-1 gene. RNase protection and primer extension analyses revealed a single transcriptional start site located 299 bp upstream from the translational start site in an initiator-like pyrimidine-rich sequence. The 5′-flanking region is rich in GC residues and lacks a typical TATA or CAAT box. A luciferase reporter construct containing a fragment from nucleotides −1900 to +299 showed strong endothelium-specific activity in transfected bovine aortic endothelial cells. Deletion analyses re...