tbuckley/cabot-search huggingface dataset:
Abstract 354: Haploinsufficiency Of Sam68 Attenuates Vascular Inflammation And Atherosclerosis In Apoe-deficient Mice
Authors: ShulingHan, JunlanZhou, GangjianQin
Journal: Circulation Research (2014)

Background: Chronic inflammation in the arterial wall is a major drive of atherosclerosis and is largely mediated by the NF-kappaB signaling pathway in the vascular and pro-inflammatory cells, notably macrophages. Recently, Sam68, an adaptor protein and Src kinase substrate, has been shown to promote NF-kappaB signaling in mouse embryonic fibroblasts (MEFs). However, whether Sam68 plays a role in the development of atherosclerosis is currently unknown. Methods and Results: To evaluate the role of Sam68 in atherosclerosis, we crossed Sam68(+/-)mice (Sam68-/- mice are sterile) with ApoE(-/-)mice and obtained ApoE(-/-)Sam68(+/-)and ApoE(-/-)sam68(+/+)mice, which are both grossly normal. Fed on a regular chow, time-course analyses of atherosclerotic lesions were performed histologically throughout the aortas in these mice. ApoE(-/-)Sam68(+/-) mice displayed a significantly delayed development of atheromatous plaques as compared to ApoE(-/-)sam68(+/+)mice at 5, 7, and 10 months of age. The expression levels of...
The microRNA-342-5p Fosters Inflammatory Macrophage Activation Through an Akt1- and microRNA-155–Dependent Pathway During Atherosclerosis
Authors: YuanyuanWei, MalihehNazari-Jahantigh, LilyChan, MengyuZhu, KathrinHeyll, JuditCorbalán-Campos, PetraHartmann, AnnaThiemann, ChristianWeber, AndreasSchober
Journal: Circulation (2013)

Background—Atherosclerosis is a chronic inflammatory vascular disease driven by the subendothelial accumulation of macrophages. The mechanism regulating the inflammatory response in macrophages during atherogenesis remains unclear. Because microRNAs (miRNAs) play a crucial role in cellular signaling by posttranscriptional regulation of gene expression, we studied the miRNA expression profiles during the progression of atherosclerosis. Methods and Results—Using an miRNA real-time polymerase chain reaction array, we found that macrophage-derived miR-342-5p and miR-155 are selectively upregulated in early atherosclerotic lesions in Apoe−/− mice. miR-342-5p directly targets Akt1 through its 3′-untranslated region. Akt1 suppression by miR-342-5p induces proinflammatory mediators such as Nos2 and II6 in macrophages via the upregulation of miR-155. The local application of an miR-342-5p antagomir inhibits the development of atherosclerosis in partially ligated carotid arteries. In atherosclerotic lesions, the mi...
Abstract 210: Thioredoxin-2 Inhibits Mitochondrial Ros Generation And Ask1 Activity To Maintain Cardiac Function
Authors: WangMin, QunhuaHuang
Journal: Circulation Research (2013)

Background: Increasing evidence indicates that mitochondrial-derived reactive oxygen species (ROS) and cellular apoptosis contribute to the pathogenesis of cardiac dysfunction. Mitochondrial thioredoxin (Trx2) is a key protein regulating cellular redox and survival, However, but its role in normal cardiac growth has not been determined. Methods and Results: We have generated cardiac-specific Trx2 knockout mice (Trx2-cKO) to determine the physiological importance of the Trx2 system in the heart. Trx2-cKO mice developed a spontaneous dilated cardiomyopathy at 1 month of age with increased heart size, fibrosis, reduced ventricular wall thickness, and progressive contractile dysfunction, resulting in death due to heart failure by 4 months of age. Cardiac changes in Trx2-cKO mice were accompanied by disruption of mitochondrial integrity and function, as evident by alterations in mitochondrial number, ultrastructure, membrane potential and ATP production. Increases in ASK1 signaling and ROS production preceded ...
Abstract 2464: Divergent lncRNA <i>MYMLR</i> regulates MYC by eliciting DNA looping and promoter-enhancer interaction
Authors: Taisuke Kajino, Teppei Shimamura, Shuyi Gong, Kiyoshi Yanagisawa, Masahiro Nakatochi, Sebastian Griesing, Yukako Shimada, Keiko Kano, Motoshi Suzuki, Satoru Miyano, Takashi Takahashi
Journal: Cancer Research (2018)

Abstract Long non-coding RNAs (lncRNAs), longer than 200 nucleotides in length, function in a wide range of processes by diverse mechanisms. lncRNAs are attracting research interest in the field of cancer research though their roles in regulation of oncogenes and/or tumor suppressors remain rather elusive. In order to search for MYC-modulating lncRNA, we performed a global search for lncRNAs affecting MYC activity using a systems biology-based approach with a K supercomputer and the GIMLET algorism based on local distance correlations. Consequently, MYMLR was identified and experimentally shown to maintain MYC transcriptional activity despite its low levels of expression and cell cycle progression. A proteomic search for MYMLR-binding proteins identified PCBP2, which transcriptionally regulates MYC expression in cooperation with MYMLR. Mechanistically, MYMLR places a 557-kb upstream enhancer region to make the MYC promoter and enhancer regions reside in the proximity. These findings implicate a crucial role for MYMLR in regulation of the archetypical oncogene MYC, and warrant future studies regarding the involvement of low copy number lncRNAs in regulation of other crucial oncogenes and tumor suppressor genes in cancer development. Citation Format: Taisuke Kajino, Teppei Shimamura, Shuyi Gong, Kiyoshi Yanagisawa, Masahiro Nakatochi, Sebastian Griesing, Yukako Shimada, Keiko Kano, Motoshi Suzuki, Satoru Miyano, Takashi Takahashi. Divergent lncRNA MYMLR regulates MYC by eliciting DNA looping and promoter-enhancer interaction [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 2464.
Phenotypic profile of Ile68Leu transthyretin amyloidosis: an underdiagnosed cause of heart failure
Authors: Christian Gagliardi, Federico Perfetto, Massimiliano Lorenzini, Alessandra Ferlini, Fabrizio Salvi, Agnese Milandri, Cristina Candida Quarta, Giulia Taborchi, Simone Bartolini, Sabrina Frusconi, Raffaele Martone, Michele Mario Cinelli, Serena Foffi, Maria Letizia Bacchi Reggiani, Gioele Fabbri, Paolo Cataldo, Francesco Cappelli, Claudio Rapezzi
Journal: European Journal of Heart Failure (2018)
Relaxin, a Pregnancy Hormone, Is a Functional Endothelin-1 Antagonist
Authors: ThomasDschietzig, CorneliaBartsch, ChristophRichter, MichaelLaule, GertBaumann, KarlStangl
Journal: Circulation Research (2003)

We have recently demonstrated that relaxin (RLX) acts as compensatory mediator in human heart failure. RLX inhibits the stimulation of endothelin-1, the most potent vasoconstrictor in heart failure. Upregulation of the endothelin type-B receptor (ETB), which mediates endothelin-1 clearance and endothelial release of NO, represents a pivotal mode of RLX action. However, signal transduction and abundance of this phenomenon are unknown. Therefore, we investigated RLX-induced regulation of ETB in human umbilical vein endothelial, epithelial (HeLa), and vascular smooth muscle cells. In human umbilical vein endothelial cells and HeLa cells, but not in human vascular smooth muscle cells, RLX upregulated ETB expression and activated extracellular signal–regulated kinase-1/2 (ERK-1/2) and nuclear factor-κB (NF-κB), a transcription factor. PD-98059, a selective inhibitor of the mitogen-activated protein kinase kinase-1 (MEK-1)–ERK-1/2 pathway, abolished ERK-1/2 and NF-κB activation and ETB upregulation. NF-κB inhib...
Polyglutamine Repeats in Neurodegenerative Diseases
Authors: Andrew P. Lieberman, Vikram G. Shakkottai, Roger L. Albin
Journal: Annual Review of Pathology Mechanisms of Disease (2018)

Among the age-dependent protein aggregation disorders, nine neurodegenerative diseases are caused by expansions of CAG repeats encoding polyglutamine (polyQ) tracts. We review the clinical, pathological, and biological features of these inherited disorders. We discuss insights into pathogenesis gleaned from studies of model systems and patients, highlighting work that informs efforts to develop effective therapies. An important conclusion from these analyses is that expanded CAG/polyQ domains are the primary drivers of neurodegeneration, with the biology of carrier proteins influencing disease-specific manifestations. Additionally, it has become apparent that CAG/polyQ repeat expansions produce neurodegeneration via multiple downstream mechanisms, involving both gain- and loss-of-function effects. This conclusion indicates that the likelihood of developing effective therapies targeting single nodes is reduced. The evaluation of treatments for premanifest disease will likely require new investigational approaches. We highlight the opportunities and challenges underlying ongoing work and provide recommendations related to the development of symptomatic and disease-modifying therapies and biomarkers that could inform future research.
Transient Outward Currents in Subendocardial Purkinje Myocytes Surviving in the Infarcted Heart
Authors: CynthiaJeck, JudithPinto, PenelopeBoyden
Journal: Circulation (1995)

Background Altered electrical activity of subendocardial Purkinje fibers contributes to arrhythmias in the 48-hour infarcted canine heart. Changes in the transmembrane action potentials of these fibers include marked action potential prolongation. The ionic basis for these changes is unknown. Methods and Results We used whole-cell voltage-clamp techniques to study 4-aminopyridine (4-AP)–sensitive voltage-dependent transient outward currents (Ito1) in Purkinje myocytes isolated from LV subendocardial (n=14) and free-running (n=15) bundles of the normal canine heart. Ito1 in these two groups of control cells (normal-zone Purkinje cells [NZPCS]) did not differ. NZPCS Ito1 was then compared with Ito1 of Purkinje myocytes dispersed from subendocardium of infarcted hearts 48 hours after total coronary artery occlusion (IZPC48, n=14). Ito1 amplitude and current density were significantly reduced (P<.01) in IZPC48s (1650±389 pA, 9±2 pA/pF) compared with NZPCS (2917±267 pA, 20.2±2 pA/pF) at Vt=+55 mV, Vh=−60 mV, w...
Abstract 2722: Investigation of the expression profile and functional role of PD-1, TIM-3 and LAG-3 in human tumors
Authors: Srimoyee Ghosh, Jon Travers, Kristen McEachern, Sujatha Kumar, Sridhar Ramaswamy, David Jenkins
Journal: Cancer Research (2018)

Abstract While immunotherapies directed against PD-1 and PD-L1 have proven effective across multiple indications, there is still a large unmet medical need for therapies for patients who do not respond or who develop acquired resistance during the course of treatment. There are several emerging hypotheses to explain the lack of response, one of which is the upregulated expression of additional checkpoint receptors, such as TIM-3 and LAG-3, that limit the ability of PD-1 pathway blockade to re-establish effective anti-tumor immunity. To investigate the potential role of TIM-3 and LAG-3 relative to PD-1, we set out to evaluate the expression and function of these receptors in several systems. Firstly, we used a flow cytometry approach to enumerate immune cell populations in a panel of human tumor samples, including non-small cell lung cancer (NSCLC). In these samples, PD-1, TIM-3 and LAG-3 expression was observed in both T-cell and non-T-cell populations. PD-1 was found to be co-expressed with TIM-3 and LAG-3 in CD8+ T-cells and we also found expression of TIM-3 and LAG-3 in other cell types, including regulatory T-cells and myeloid cells. Building on the expression data, we explored the functional effects of targeting these receptors, evaluating the effect of single agent and combination effects of anti-PD-1, anti-TIM-3 and anti-LAG-3 antibodies in mouse models. In these studies, we found not only that dual-blockade of PD-1 with either anti-TIM-3 or anti-LAG-3 resulted in improvements in efficacy over monotherapy, but also that the triple combination of all 3 inhibitors was associated with further anti-tumor activity. In a humanized mouse model of NSCLC, the triple combination was associated with pharmacodynamic effects not only in T-cells, but also reductions in Tregs and macrophages. Taken together, these studies provide further evidence to suggest that in addition to PD-1, LAG-3 and TIM-3 are important emerging immunotherapy targets and provide rationale for not only doublet but also triplet combinations as an approach to cancer therapy. Citation Format: Srimoyee Ghosh, Jon Travers, Kristen McEachern, Sujatha Kumar, Sridhar Ramaswamy, David Jenkins. Investigation of the expression profile and functional role of PD-1, TIM-3 and LAG-3 in human tumors [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 2722.
Abstract 4857: Discovery of PF-06855800, a SAM competitive PRMT5 inhibitor with potent antitumor activity
Authors: Indrawan J. Mcalpine, John Tatlock, Joseph Billitti, John Braganza, Alexei Brooun, Deng Ya-Li, Brad Hirakawa, Kristen Jensen-Pergakes, Robert Kumpf, Wei Liu, Karen Maegley, Michele McTigue, Ryan Patman, Eugene Rui, Stephanie Scales, Noah Spiegel, Michelle Tran-Dubé, Fen Wang, Zhenxiong Wang, Shinji Yamazaki, Tao Zhang, Martin Wythes
Journal: Cancer Research (2018)

Abstract Protein arginine methyltransferase 5 (PRMT5) is the primary type II arginine methyltransferase responsible for symmetric dimethylation of protein arginine residues. PRMT5 utilizes S-adenosylmethionine (SAM) to methylate a number of cytoplasmic and nuclear substrates that are involved in tumorigenesis. A number of these substrates affect a variety of biologic functions including RNA splicing, transcriptional regulation and translation, all of which are dysregulated in cancer. The discovery of adenosine as an efficient inhibitor of PRMT5 catalyzed a medicinal chemistry effort aimed at nucleoside optimization. Protein structure-based and ligand property-based design were combined to deliver molecules with desirable potency, selectivity and ADME properties. Here we will describe a series of deazapurine nucleoside analogues that culminate in the identification of PF-06855800, a SAM competitive PRMT5 inhibitor with antiproliferative activity in both in vitro and in vivo models. Citation Format: Indrawan J. Mcalpine, John Tatlock, Joseph Billitti, John Braganza, Alexei Brooun, Deng Ya-Li, Brad Hirakawa, Kristen Jensen-Pergakes, Robert Kumpf, Wei Liu, Karen Maegley, Michele McTigue, Ryan Patman, Eugene Rui, Stephanie Scales, Noah Spiegel, Michelle Tran-Dubé, Fen Wang, Zhenxiong Wang, Shinji Yamazaki, Tao Zhang, Martin Wythes. Discovery of PF-06855800, a SAM competitive PRMT5 inhibitor with potent antitumor activity [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 4857.
Abstract 1982: Obesity reversibly enhances mammary epithelial estrogen receptor alpha expression and progenitor activity
Authors: Tamara Chamberlin, Joseph V. D'Amato, Lisa M. Arendt
Journal: Cancer Research (2018)

Abstract Obesity has been identified as an important risk factor for breast cancer in post-menopausal women and is significantly correlated with poor prognosis in breast cancer patients. Women with an increasing body mass index (BMI) are more likely to develop estrogen receptor alpha (ERα) positive tumors that are larger at the time of diagnosis and demonstrate an increased risk for metastasis. Given that obesity is becoming a global epidemic, understanding how obesity alters the biology of the normal breast is of significant clinical relevance. To examine the effects of obesity on mammary tissue, mice were fed a high fat diet to induce obesity and compared with mice fed a control diet. We also examined reduction mammoplasty tissue from women with a known BMI. In both obese female mice and women, mammary epithelial cell populations demonstrated significant decreases in basal/myoepithelial cells, when examined using either flow cytometry or cell type-specific markers (SMA and p63) in tissue. ERα expression was significantly increased in luminal cells in obese mammary tissue, compared with control mice or breast tissue from lean women. Functional assays demonstrated significantly enhanced mammary epithelial progenitor activity in obese mammary epithelial cells as well as elevated numbers of ERα positive epithelial cells that were co-labeled with markers of proliferation. Weight loss in a group of obese mice reversed increases in progenitor activity and ERα expression observed in obese mammary tissue. Obesity enhances the percentage of ERα positive epithelial cells and reduces the number of basal/myoepithelial cells within normal mammary tissue in both women and female mice. Both aspects of this phenotype have been linked to breast tumor susceptibility. These changes may contribute to lifetime risk for the development of ERα positive tumors in postmenopausal women. However, the changes in epithelial cell populations induced by obesity are reversible with weight loss, suggesting that weight loss interventions in obese women may effectively reduce breast cancer risk by decreasing the number of potential tumor progenitor cells in the breast epithelium. Citation Format: Tamara Chamberlin, Joseph V. D'Amato, Lisa M. Arendt. Obesity reversibly enhances mammary epithelial estrogen receptor alpha expression and progenitor activity [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 1982.
The Tyrosine Kinase Receptor RON Is Phosphorylated upon Epo-Receptor Activation, Mediates Expansion and Inhibits Differentiation of Erythroid Progenitors
Authors: E. V. n Den Akker, T. B. Van Dijk, M. V. n Parren Amelsvoort, B. Lowenberg, M. V. n Lindern
Journal: Blood (2002)
Abstract 4145: Characterization of the ODZ receptor family in neuroblastoma
Authors: Teodora Andonova, Per Kogner, John Inge Johnsen, Malin Wickström
Journal: Cancer Research (2018)

Abstract Neuroblastoma is the most common extracranial solid tumor of childhood, causing 6% of all childhood cancers but 9% of deaths from malignant tumors in children. It is a tumor with highly heterogeneous clinical behavior, believed to originate from undifferentiated neural crest cells that form the sympathetic nervous system. Neuritogenesis is the process during embryonic development when neural crest cells migrate and differentiate into multiple cell types. The Rho/Rac signaling cascade is fundamental for this process. We performed whole genome sequencing of 40 neuroblastoma tumor samples, 32.5% of the samples contained a mutation in a gene associated with Rho/Rac signaling. The most frequently mutated receptor family among the Rho/Rac associated genes was the tenuerins (ODZ1-4). The ODZ genes were mutated in three out of 40 patients, i.e. 7.5%. The ODZ proteins are not fully characterized, however it is known they are highly expressed during the development of the central nervous system and play role in differentiation of the drosophila fly. Evidence suggests a function for dysregulated expression of the ODZs in human tumors, but investigations of a deeper cellular and molecular understanding in neuroblastoma are missing. The aim of this study is to investigate the ODZ receptors to determine the role and function of these proteins in neuroblastoma tumor development, progression and metastasis. When investigated in publically available and validated neuroblastoma cohorts, low expression levels of ODZ1, ODZ2 and ODZ3 were associated with poor overall survival, while low ODZ4 expression correlated with high overall survival. Our data demonstrated that the ODZ receptors were differently expressed in neuroblastoma cell lines. Preliminary results also showed that siRNA knockdown of ODZ4 in a neuroblastoma cell line led to a 50% decrease in cell viability compared to control, together with morphological changes such as more neurite extensions, suggesting that an inhibition of ODZ4 may result in differentiation. Knockout of the four different ODZ transcripts also showed that the ODZ receptors might have compensatory mechanisms for each other. Our data suggest that activity of the ODZ receptors may be important for neuroblastoma development and that manipulation could offer a possible therapy for neuroblastoma. Citation Format: Teodora Andonova, Per Kogner, John Inge Johnsen, Malin Wickström. Characterization of the ODZ receptor family in neuroblastoma [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 4145.
Abstract 4288: The cell cycle gene regulatory DREAM complex is disrupted by oncogenic B-Myb
Authors: Audra N. Iness, Varsha Ananthapadmanabhan, Fatmata Sesay, Mikhail Dozmorov, Larisa Litovchick
Journal: Cancer Research (2018)

Abstract The oncogene MYBL2 (encoding B-Myb) is a poor prognostic biomarker in many cancers. B-Myb interacts with the MuvB core of five proteins (LIN9, LIN37, LIN52, LIN53/RBBP4, and LIN54) to form the MMB (Myb-MuvB) complex and promotes expression of late cell cycle genes necessary for progression through mitosis. Both MYBL2 amplification and over-expression are associated with deregulation of the cell cycle and increased cell proliferation. Alternatively, by interacting with E2F4-DP1 and p130/p107, the MuvB core becomes part of the DREAM complex (DP, RB-like, E2F, and MuvB). The DREAM complex opposes MMB by globally repressing cell cycle genes in G0/G1, maintaining the cell in a quiescent state. However, the specific mechanism by which B-Myb alters the cell cycle is not well understood. Herein, we show that B-Myb disrupts the DREAM complex by sequestration and stabilization of LIN52. Analysis of The Cancer Genome Atlas data revealed significant upregulation of DREAM and MMB target genes in breast and ovarian cancer with MYBL2 gain. Given that most of the DREAM target genes are not directly regulated by B-Myb, we investigated the effects of B-Myb on DREAM formation. We found that depletion of B-Myb results in increased DREAM formation in cancer cell lines, while its overexpression inhibits DREAM formation in non-transformed cells. Since the MuvB core subunit LIN52 is essential for assembly of both the DREAM and MMB complexes, we tested whether B-Myb disrupts DREAM by sequestering LIN52. Overexpression of LIN52 did not increase either DREAM or MMB formation, but instead increased the turnover rate of the endogenous LIN52 protein. Interestingly, co-expression of B-Myb increased the expression of both endogenous and overexpressed LIN52 while knockdown of B-Myb had an opposite effect. We found that regulation of LIN52 occurs at the protein level, and that activity of DYRK1A kinase, the enzyme that triggers DREAM complex formation by phosphorylating LIN52, is required for this regulation. These findings are the first to implicate B-Myb in the disassembly of the DREAM complex and offer further mechanistic insights for cancers with MYBL2 amplification. We conclude that B-Myb's oncogenic effects are not only secondary to increased mitotic gene expression by the MMB complex, but also broad disruption of cell cycle gene regulatory programs through compromised DREAM formation. Citation Format: Audra N. Iness, Varsha Ananthapadmanabhan, Fatmata Sesay, Mikhail Dozmorov, Larisa Litovchick. The cell cycle gene regulatory DREAM complex is disrupted by oncogenic B-Myb [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 4288.