tbuckley/cabot-search huggingface dataset:
Abstract 2474: Identification of lncRNAs involved in regulation of chromosome instability-associated genes in a prostate cancer model
Authors: Rogelio Montiel Manriquez, Cristian Gabriel Oliverio Arriaga Canon, Fernanda Cisneros Soberanis, Carlo César Cortés, Inti Alberto De La Rosa Velazquez, Luis Alonso Herrera Montalvo
Journal: Cancer Research (2018)

Abstract In this study we aim to identify new lncRNAs, using RNA-seq data, and study whether those transcripts could be involved in chromosomal instability in prostate cancer and propose new possible RNA-based biomarkers. Using RNA-seq data from two prostate cell lines, neoplastic and non-neoplastic, we have identified a new lncRNA adjacent to CEP55, a gene associated with chromosomal instability. This lncRNA, which we have named lncRNA-CEP55, is 1.6 kb long and it is downregulated in the neoplastic cell line; this is also seen in the adjacent coding gene, CEP55, where the expression decreases in the neoplastic line, suggesting an important role of this transcript in carcinogenesis. This new lncRNA could be regulating CEP55 expression in these cell lines. Changes in expression of CEP55 have been associated to chromosomal instability and cancer development in colon cancer cell lines. Another lncRNA with differential expression in both cell lines has been identified, lncRNA-RFC4. This lncRNA has been reported before; it is an annotated gene in the human genome GRCh38/hg38, but it has not been studied in cancer. This lncRNA is highly expressed in the neoplastic cell line whereas its expression is very low in the non-neoplastic cell line. This lncRNA is 4.3 kb away from RFC4 (Replication Factor C Subunit 4), a protein coding gene related to mismatch repair and DNA double-strand break repair, which has been associated with chromosomal instability. lncRNA-RFC4 could be playing an important role in the cis regulation of RFC4 gene. lncRNA-CEP55 and lncRNA-RFC4 are important targets of study because of their differential expression in prostate cell lines (neoplastic and non-neoplastic). These lncRNAs could be playing an essential role in regulating the expression of the adjacent genes related to chromosomal instability, a enabling characteristic that facilitates the acquisition of the hallmarks of cancer. Citation Format: Rogelio Montiel Manriquez, Cristian Gabriel Oliverio Arriaga Canon, Fernanda Cisneros Soberanis, Carlo César Cortés, Inti Alberto De La Rosa Velazquez, Luis Alonso Herrera Montalvo. Identification of lncRNAs involved in regulation of chromosome instability-associated genes in a prostate cancer model [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 2474.
Abstract 5338: Comprehensive pan-cancer genomic analysis reveals link between 3'UTR DNA methylation and increased gene expression
Authors: Michael H. McGuire
Journal: Cancer Research (2018)

Abstract Investigations into the function of non-promoter DNA methylation have yielded new insights into epigenetic regulation of gene expression. Previous studies have highlighted the importance of distinguishing between DNA methylation in discrete functional regions (e.g. promoter, gene body, enhancer); however, the relationship between DNA methylation outside of the promoter region and gene expression in cancer requires further exploration. Through integrated analysis of gene expression and DNA methylation profiles (&amp;gt;3,000 samples across multiple cancer types and corresponding normal tissues), we uncovered an enrichment of DNA methylation sites within the 3'UTR in which DNA methylation is strongly positively correlated with gene expression. In 5 of 10 tumor types examined, DNA methylation of the 3'UTR is associated with patient survival in a significant number of genes. Filtering for genes in which 3'UTR DNA methylation, relative to gene body DNA methylation, is more strongly correlated with gene expression yields a list of genes enriched for functions involving T cell activation. The immune checkpoint gene HAVCR2 (TIM-3) shows a substantial increase in 3'UTR DNA methylation, but not adjacent exonic/intronic, or promoter DNA methylation, upon T cell stimulation and upregulation of gene expression. Furthermore, this increase in HAVCR2 gene expression can be abrogated by treatment with demethylating agents. These findings implicate the 3'UTR as a functionally relevant DNA methylation site, particularly in regard to T cell activity. Additionally, they reveal a novel mechanism by which HAVCR2 is upregulated in T cells, providing a new means of targeting immune checkpoint blockade. Finally, these data offer a selective marker for choosing patients that could respond to the combination therapy of PD-1/PD-L1 inhibition and demethylating agents. Citation Format: Michael H. McGuire. Comprehensive pan-cancer genomic analysis reveals link between 3'UTR DNA methylation and increased gene expression [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 5338.
Abstract LB-301: Inhibition of the co-inhibitory receptor KLRG1 reduces murine 4T1 breast cancer metastasis and MC38 colon cancer primary tumor growth and mortality
Authors: Steven A. Greenberg, Stefano V. Gulla, Evan Thompson
Journal: Cancer Research (2018)

Abstract Introduction Targeting of lymphocyte co-inhibitory receptors, such as CTLA-4, PD-1, Lag-3, and Tim-3, has gained intense interest for treatment of cancer. KLRG1 is also a lymphocyte co-inhibitory receptor, expressed predominantly on effector memory CD8+ T cells and NK cells, whose ligands E- and N-cadherin are differentially expressed during epithelial-mesenchymal transition. Targeting of KLRG1 in murine cancer models has not previously been published. Methods We constructed an anti-mouse KLRG1 antibody that neutralized the interaction of KLRG1 with its ligands. Anti-KLRG1 antibody was administered as a monotherapy in a murine metastatic tumor model (4T1 murine breast cancer) and as combination therapy with anti-PD-1 (clone RMP1-14) in a murine primary tumor growth model (MC38 murine colon cancer). Results In the 4T1 murine breast cancer model, anti-KLRG1 antibody reduced lung metastases compared to control antibody as measured by mean lung weights (0.28 g vs. 0.47 g; p=0.04) and nodule count (10.7 vs. 30.1; p=0.002). In the MC38 model, primary tumor growth was inhibited by anti-KLRG1 + anti-PD-1 antibody greater than anti-KLRG1 antibody or anti-PD-1 antibody or control antibody (day 13 tumor volume 582 vs. 1259 vs. 1279 vs. 1461 mm3, respectively). Combination therapy anti-KLRG1 + anti-PD-1 produced synergistic benefit significantly greater than that of anti-PD-1 alone for tumor volume (p=0.01) and survival (p=0.02; day 18 survival 60% of mice alive treated with combination therapy compared to 0% alive treated with anti-PD-1 alone). Ex vivo KLRG1 blockade with anti-human KLRG1 antibodies resulted in human CD8+ T cell proliferation and proinflammatory cytokine secretion. Conclusions Anti-KLRG1 neutralizing antibody demonstrates efficacy in inhibiting metastases in the murine 4T1 breast cancer model and reducing primary tumor volume and improving survival as synergistic combination therapy with anti-PD-1 in the murine MC38 colon cancer model. Anti-KLRG1 blockade with anti-human KLRG1 antibodies results in activation of CD8+ T cells. These data suggest that anti-KLRG1 treatment is a promising new approach for cancer immunotherapy. Citation Format: Steven A. Greenberg, Stefano V. Gulla, Evan Thompson. Inhibition of the co-inhibitory receptor KLRG1 reduces murine 4T1 breast cancer metastasis and MC38 colon cancer primary tumor growth and mortality [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 LB-301.
Macrophage-targeted drugamers with enzyme-cleavable linkers deliver high intracellular drug dosing and sustained drug pharmacokinetics against alveolar pulmonary infections
Authors: Fang-Yi Su, Selvi Srinivasan, Brian Lee, Jasmin Chen, Anthony J. Convertine, Timothy Eoin West, Daniel M. Ratner, Shawn J. Skerrett, Patrick S. Stayton
Journal: Journal of Controlled Release (2018)
miR-22 suppresses DNA ligase III addiction in multiple myeloma
Authors: Daniele Caracciolo, Maria Teresa Di Martino, Nicola Amodio, Eugenio Morelli, Martina Montesano, Cirino Botta, Francesca Scionti, Daniela Talarico, Emanuela Altomare, Maria Eugenia Gallo Cantafio, Valeria Zuccalà, Lorenza Maltese, Katia Todoerti, Marco Rossi, Mariamena Arbitrio, Antonino Neri, Pierosandro Tagliaferri, Pierfrancesco Tassone
Journal: Leukemia (2018)

Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability. Here we provide evidence that hyper-activation of DNA ligase III (LIG3) is crucial for genomic instability and survival of MM cells. LIG3 mRNA expression in MM patients correlates with shorter survival and even increases with more advanced stage of disease. Knockdown of LIG3 impairs MM cells viability in vitro and in vivo, suggesting that neoplastic plasmacells are dependent on LIG3-driven repair. To investigate the mechanisms involved in LIG3 expression, we investigated the post-transcriptional regulation. We identified miR-22-3p as effective negative regulator of LIG3 in MM. Enforced expression of miR-22 in MM cells downregulated LIG3 protein, which in turn increased DNA damage inhibiting in vitro and in vivo cell growth. Taken together, our findings demonstrate that myeloma cells are addicted to LIG3, which can be effectively inhibited by miR-22, promoting a novel axis of genome stability regulation.
Abstract 1124: Wnt-producing niche cells support cancer stem-like cells in pancreatic ductal adenocarcinoma
Authors: Katherine Wu, Olivera Grbovic-Huezo, Griffin Hartmann, Tyler Jacks, Tuomas Tammela
Journal: Cancer Research (2018)

Abstract Despite modern advances in cancer therapy, the prognosis for pancreatic ductal adenocarcinoma (PDAC) remains dismal, highlighting the need for better understanding of the biologic underpinnings of the disease. Well established as a pathway for growth and regeneration, Wnt signaling maintains subpopulations of cancer cells in a stem-like state, contributing to the heterogeneous composition of tumors. Our previous work demonstrated that Porcupine, an essential enzyme for secretion of paracrine Wnt signals, can be used to mark Wnt-producing cells in normal and tumor tissues. We detected the presence of nuclear beta-catenin, a biomarker of active Wnt-signaling, in a subpopulation of cancer cells adjacent to Porcupine+ niche cells in murine PDAC tissue. Furthermore, genetic inactivation of Porcupine translated to a 25% increase in survival in PDAC-bearing mice. In vitro, we see a marked increase in spheroid formation and proliferation of the stem-like subpopulation over the rest of the primary tumor cells. Ongoing lineage-tracing experiments in an autochthonous murine model of PDAC will determine whether these cancer stem cells are able to produce their Wnt-secreting niche in vivo. Our current efforts are focused on the preclinical evaluation of Wnt inhibitors in the treatment of mouse and human PDAC as single agents or in combination with chemotherapy. Such findings open the door for interrogation of the Wnt pathway as a possible target for improving the clinical outcome of pancreatic cancer. Citation Format: Katherine Wu, Olivera Grbovic-Huezo, Griffin Hartmann, Tyler Jacks, Tuomas Tammela. Wnt-producing niche cells support cancer stem-like cells in pancreatic ductal adenocarcinoma [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 1124.
Effects of DNA Damage in Smooth Muscle Cells in Atherosclerosis
Authors: KellyGray, SheetalKumar, NicholaFigg, JamesHarrison, LaurenBaker, JohnMercer, TrevorLittlewood, MartinBennett
Journal: Circulation Research (2015)

Rationale:DNA damage and the DNA damage response have been identified in human atherosclerosis, including in vascular smooth muscle cells (VSMCs). However, although double-stranded breaks (DSBs) are hypothesized to promote plaque progression and instability, in part, by promoting cell senescence, apoptosis, and inflammation, the direct effects of DSBs in VSMCs seen in atherogenesis are unknown. Objective:To determine the presence and effect of endogenous levels of DSBs in VSMCs on atherosclerosis. Methods and Results:Human atherosclerotic plaque VSMCs showed increased expression of multiple DNA damage response proteins in vitro and in vivo, particularly the MRE11/RAD50/NBS1 complex that senses DSB repair. Oxidative stress–induced DSBs were increased in plaque VSMCs, but DSB repair was maintained. To determine the effect of DSBs on atherosclerosis, we generated 2 novel transgenic mice lines expressing NBS1 or C-terminal deleted NBS1 only in VSMCs, and crossed them with apolipoprotein E−/− mice. SM22α-NBS1/...
Relationship of Platelet Serotonin to Disturbances of Clotting and Hemostasis
Authors: Murrayweiner, Sidneyudenfriend
Journal: Circulation (1957)

The presence of serotonin (5-hydroxytryptamine) in high concentration in platelets and its absence from normal platelet-free plasma suggest the possibility that this vasoconstrictor substance may play a role in hemostatic mechanisms. Platelet serotonin content measured by a fluorometric method in 94 patients showed an average content of 0.22 µg./ml. blood. In none of the disease groups studied, including hypertension, was a significant alteration found in platelet serotonin. However, the administration of reserpine resulted in a marked and prolonged depletion of platelet serotonin that was not accompanied by any significant change in any of the clotting factors. The in vitro addition of serotonin in amounts up to 50 µg./ml. also failed to alter any of the clotting factors studied. Platelet serotonin did not correlate with diagnosis, age, weight, blood pressure, cephalin-fluocculation, or capillary fragility. However, markedly anemic patients (below 10 Gm. per cent hemoglobin) and patients whose blood urea...
Evidence in Support of Hypoxia but Against High Potassium and Hyperosmolarity as Possible Mediators of Sustained Vasodilation in Rabbit Cardiac and Skeletal Muscle
Authors: MiklosGellai, ReedDetar
Journal: Circulation Research (1974)

The vasoactive properties of hypoxia, elevated extracellular potassium concentration ([K]o), and hyperosmolarity were studied in helical strip preparations of small coronary and deep femoral arteries (260-700 µm, o.d.) equilibrated in a physiological salt solution with an oxygen tension (Po2) of 100 mm Hg, [K]o of 3.18 mM, and an osmolarity of 304 milliosmoles/liter. Increasing [K]o (2-6 mM) or osmolarity (30-50 milliosmoles/liter) produced relaxation of resting tension in 50% of the coronary strips but had no effect on resting tension in deep femoral strips. Sustained increments in [K]o or osmolarity produced concentration-dependent, transient relaxation of aganist-induced contractile tension in both coronary and deep femoral arterial strips: a potassium increment of 4 mM produced 40% relaxation with 100% recovery within 5-6 minutes, an osmotic increment of 30 milliosmoles/liter caused 20-40% relaxation with 100% recovery within 15-60 minutes, and simultaneous potassium (4 mM) and osmotic (30 milliosmole...
Noninvasive Creation of an Atrial Septal Defect by Histotripsy in a Canine Model
Authors: ZhenXu, GabeOwens, DavidGordon, CharlesCain, AchiLudomirsky
Journal: Circulation (2010)

Background— The primary objective of this study was to develop an image-guided, noninvasive procedure to create or enlarge an atrial septal defect for the treatment of neonates with hypoplastic left heart syndrome and an intact or restrictive atrial septum. Histotripsy is an innovative ultrasonic technique that produces nonthermal, mechanical tissue fractionation through the use of high-intensity ultrasound pulses. This article reports the pilot in vivo study to create an atrial septal defect through the use of extracardiac application of histotripsy in an open-chest canine model. Methods and Results— In 10 canines, the atrial septum was exposed to histotripsy by an ultrasound transducer positioned outside the heart. Ultrasound pulses of 6-microsecond duration at a peak negative pressure of 15 MPa and a pulse repetition frequency of 3.3 kHz were generated by a 1-MHz focused transducer. The procedure was guided and monitored by real-time ultrasound imaging. In 9 of 10 canines, an atrial septal defect was p...
Abstract 17182: Long-term Prognosis in Patients with Type 1 and Type 2 Diabetes Mellitus after Coronary Artery Bypass Grafting
Authors: MartinHolzmann, BjörnRathsman, JeanetteKuhl, ThomasNyström, UlrikSartipy
Journal: Circulation (2014)

Introduction: Patients with diabetes mellitus (DM) have an increased risk of adverse outcomes after coronary artery bypass grafting (CABG). Prior studies in patients with DM have reported prognosis in relation to treatment with insulin or not, and not in relation to type of DM. The prognosis after CABG in patients with type 1 or type 2 diabetes mellitus (DM1 or DM2) is not known. Methods: We included all patients who underwent primary isolated CABG in Sweden during 2003 through 2013 from the SWEDEHEART register, and the Swedish National Diabetes Register identified patients with DM1 or DM2. Cox proportional hazards regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI) for all-cause mortality in patients with DM1 or DM2 compared with no diabetes mellitus. Results: In total 36 035 patients underwent primary isolated CABG during the study period, of whom 628 (1.7%) had DM1, and 7544 (21%) had DM2. Patients with DM1 were younger (59 vs. 67 years), and had reduced kidney functi...
Pharmacological Evidence for the Importance of Catecholamines in Cardiac Rhythmicity
Authors: Jayroberts, Waltermodell
Journal: Circulation Research (1961)

Dogs with complete heart block were used to explore the dependence of the intrinsic rhythmicity of the heart on catecholamine activity. By the use of reserpine, hexamethonium, and surgical sympathectomy, it was demonstrated that, while reduction in catecholamine activity slows both the atrial and the ventricular rates, the ventricular pace maker was always affected to a greater degree. The effect of a combination of reserpine and hexamethonium on the ventricle was greater than when either agent was administered alone, suggesting that the greater the sympathetic blockade, the greater the depression in pacemaker rhythmicity. Since the course of its action on the heart paralleled that of catecholamine depletion, it seems probable that the effect of reserpine on rhythmicity was due to its catecholamine depleting action. It was thought unlikely that prolonged hypotension contributed to the reserpine action on the heart. It is indicated that disturbances in electrolyte balance and blood pH did not play a role i...
Abstract 3456: Molecular mechanisms of RSK2-ELK3 signaling axis in neoplastic cell transformation
Authors: Seon-Yeon Cho, Cheol-Jung Lee, Sun-Mi Yoo, Seung-Min Kim, Juhee Park, Yong-Yeon Cho
Journal: Cancer Research (2018)

Abstract Constitutive active Ras mutation (RasG12V) plays a key role in cell proliferation and transformation in many solid human cancers. RSK2, a member of p90RSK superfamily, controlled by ERKs is an intermediate signaling molecule transducing Ras activation signal to downstream substrates including transcription factors, epigenetic factors and some kinases. Since RSK2 shows wide range of substrate spectrum, identification of RSK2's novel substrates is important to understand the role of RSK2 in cancer. We found that ELKs including ELK1, ELK3 and ELK4 are novel interaction partners of RSK2 by mammalian two-hybrid assay. In vitro kinase assay and immunoprecipitation assay indicated that ELK3 is a major binding partner of RSK2. Luciferase reporter assay demonstrated that ELK3 transactivation activity was increased by RSK2, resulted in the increase of c-fos promoter activity. Importantly, constitutive active (CA)-RasG12V-mediated foci formation in NIH3T3 cells were more increased by ectopic co-expression of CA-RasG12V and RSK2. Additionally, signaling blockage of the CA-RasG12V/ELK3 by RSK2 knockdown suppressed foci formation. These results demonstrated that RSK2-ELK3 signaling axis plays an important role in RasG12V-mediated neoplastic cell transformation. Key words : MAPK, RSK2, ELKs, cell proliferation, cell transformation Citation Format: Seon-Yeon Cho, Cheol-Jung Lee, Sun-Mi Yoo, Seung-Min Kim, Juhee Park, Yong-Yeon Cho. Molecular mechanisms of RSK2-ELK3 signaling axis in neoplastic cell transformation [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 3456.
Abstract A50: EP4 receptor antagonism in paclitaxel-resistant ovarian clear cell carcinomas
Authors: Cong Fan, Jocelyn Reader, Gautam Rao, Paul Staats, Mc Millan Ching, Amy Fulton, Dana Roque
Journal: Clinical Cancer Research (2018)

Abstract Advanced ovarian clear cell carcinoma (OCCC) is associated with a survival disadvantage relative to ovarian serous carcinoma following platinum/taxane-based chemotherapy and optimal cytoreduction. Prostaglandin E2 (PGE2) contributes to disease progression through modulation of several G-protein coupled receptors (EP1-4). Selective EP4 antagonism is preferred over global COX inhibition due to concerns over cardiotoxicity and compensatory upregulation of COX isoenzymes. Class III β-tubulin is a marker for paclitaxel resistance and is widely overexpressed in OCCC. The purpose of this study is to demonstrate that EP4 inhibition may overcome paclitaxel resistance in OCCC that overexpress class III β-tubulin. Expression of EP4 receptor and class III β-tubulin was quantified using immunohistochemistry and Western blot in solid tissues and cell lines. OCCC overexpress class IIIβ-tubulin/EP4 relative to normal ovary. EP4 staining intensity was 2+ in 100% OCCC using an ovarian cancer tissue microarray (62 cores, 13% OCCC); this rate was only 26-56% among other histologies. Standard metabolic growth and migration assays were employed to test the effects of drug treatment and EP4 inhibition. EP4 inhibition reduces growth of paclitaxel resistant cells. Likewise, treatment with EP inhibitors and silencing of EP4 resulted in reduced migration. Selective antagonism of PGE2 through EP4 receptor inhibition may represent a powerful targeted therapy for paclitaxel-resistant OCCC. Further study including simultaneous treatment (EP4 inhibitor + paclitaxel) and larger samples sizes is required. Citation Format: Cong Fan, Jocelyn Reader, Gautam Rao, Paul Staats, Mc Millan Ching, Amy Fulton, Dana Roque. EP4 receptor antagonism in paclitaxel-resistant ovarian clear cell carcinomas. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A50.