tbuckley/cabot-search huggingface dataset:
Abstract A09: ErbB3/ErbB2 complexes as a therapeutic target in a subset of wild-type BRAF/NRAS cutaneous melanomas
Authors: Claudia Capparelli, Sheera Rosenbaum, Lisa D. Berman-Booty, Nadège Gaborit, Tingting Zhan, Michael A. Davies, Yulius Y. Setiady, Yosef Yarden, Andrew E. Aplin
Journal: Cancer Research (2015)

Abstract The treatment options remain poor for melanoma patients who are wild-type for both BRAF and NRAS (WT/WT). ErbB3 regulates melanocyte homeostasis and elevated ErbB3 expression in malignant melanomas correlates with reduced patient survival; however, the effect of selectively targeting ErbB3 in melanoma remains poorly characterized. We demonstrate that a subgroup of WT/WT melanomas display high basal phosphorylation of ErbB3 that is associated with autocrine production of the ErbB3 ligand, neuregulin-1 (NRG1). In phospho-ErbB3-high WT/WT cell lines, knockdown of NRG1 reduced cell viability that was associated with decreased phosphorylation of ErbB3, its co-receptor ErbB2 and its downstream target, AKT. Analogous effects were obtained targeting ErbB3 with either small interfering RNAs or the neutralizing ErbB3 monoclonal antibodies, huHER3-8 and NG33. Additionally, pertuzumab-mediated inhibition of ErbB2 heterodimerization decreased AKT phosphorylation, cell growth in vitro and xenograft growth in vivo. Our study demonstrates that targeting ErbB3-ErbB2 signaling in a cohort WT/WT melanomas leads to tumor growth reduction. These findings are supportive of targeting the NRG1-ErbB3-ErbB2 axis as a novel treatment strategy in a subset of malignant cutaneous melanoma. Citation Format: Claudia Capparelli, Sheera Rosenbaum, Lisa D. Berman-Booty, Nadège Gaborit, Tingting Zhan, Michael A. Davies, Yulius Y. Setiady, Yosef Yarden, Andrew E. Aplin. ErbB3/ErbB2 complexes as a therapeutic target in a subset of wild-type BRAF/NRAS cutaneous melanomas. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A09.
Role for Tissue Factor Pathway in Murine Model of Vascular Remodeling
Authors: Ripudamanjit Singh, Shuchong Pan, Cheryl S. Mueske, Tyra Witt, Laurel S. Kleppe, Timothy E. Peterson, Adriana Slobodova, Jen-Yea Chang, Noel M. Caplice, Robert D. Simari
Journal: Circulation Research (2001)

Abstract —Tissue factor (TF) is a low-molecular-weight glycoprotein that initiates the extrinsic clotting cascade and is considered a major regulator of arterial thrombogenicity. TF pathway inhibitor (TFPI) is a major physiological inhibitor of TF-initiated coagulation. The aim of this study was to define the complex interplay between TF and TFPI and the regulation of vascular thrombogenicity in a model of vascular remodeling. To determine the levels and pattern of vascular expression of TF and TFPI associated with vascular remodeling, a murine model of flow cessation was studied. TF activity of the arteries increased after ligation ( P &lt;0.05). Quantitative analysis of homogenates of remodeled carotid arteries revealed increased TF expression but unchanged TFPI expression compared with normal carotid arteries, resulting in enhanced TF activity. To determine the potential therapeutic role of TFPI in this thrombogenic state, mice were treated with intravascular adenoviral delivery of either murine TFPI (Ad-mTFPImyc) or a control adenovirus (Ad-ΔE1). Overexpression of TFPI decreased vascular TF activity compared with viral control ( P &lt;0.01). Overexpression of TFPI inhibited neointimal formation ( P =0.038), resulting in enhanced luminal area ( P =0.001) 4 weeks after flow cessation. In this murine model of vascular remodeling, an imbalance between TF and TFPI expression is generated, resulting in increased TF activity. Overexpression of TFPI in this model inhibits vascular TF activity and results in attenuation of vascular remodeling associated with flow interruption.
Oncogenic <i>NRAS, KRAS</i>, and <i>HRAS</i> Exhibit Different Leukemogenic Potentials in Mice
Authors: Chaitali Parikh, Ramesh Subrahmanyam, Ruibao Ren
Journal: Cancer Research (2007)

Abstract RAS proteins are small GTPases that play a central role in transducing signals that regulate cell proliferation, survival, and differentiation. The RAS proteins interact with a common set of activators and effectors; however, they associate with different microdomains of the plasma membrane as well as other endomembranes and are capable of generating distinct signal outputs. Mutations that result in constitutive activation of RAS proteins are associated with ∼30% of all human cancers; however, different RAS oncogenes are preferentially associated with different types of human cancer. In myeloid malignancies, NRAS mutations are more frequent than KRAS mutations, whereas HRAS mutations are rare. The mechanism underlying the different frequencies of RAS isoforms mutated in myeloid leukemia is not known. In this study, we compared the leukemogenic potential of activated NRAS, KRAS, and HRAS in the same bone marrow transduction/transplantation model system. We found that all three RAS oncogenes have the ability to induce myeloid leukemias, yet have distinct leukemogenic strengths and phenotypes. The models established here provide a system for further studying the molecular mechanisms in the pathogenesis of myeloid malignancies and for testing targeted therapies. [Cancer Res 2007;67(15):7139–46]
Mechanisms of transactivation by nuclear factor of activated T cells-1.
Authors: C Luo, E Burgeon, A Rao
Journal: The Journal of Experimental Medicine (1996)

Nuclear factor of activated T cells-family proteins (NFAT1/NFATp, NFATc, NFAT3, and NFAT4/NFATx/NFATc3) play a key role in the transcription of cytokine genes and other genes during the immune response. We have defined the mechanisms of transactivation by NFAT1. NFAT1 possesses two transactivation domains whose sequences are not conserved in the other NFAT-family proteins, and a conserved DNA-binding domain that mediates the recruitment of cooperating nuclear transcription factors even when it is expressed in the absence of other regions of the protein. The activity of the NH2-terminal transactivation domain is modulated by an adjacent regulatory region that contains several conserved sequence motifs represented only in the NFAT family. Our results emphasize the multiple levels at which NFAT-dependent transactivation is regulated, and predict significant differences in the architecture of cooperative transcription complexes containing different NFAT-family proteins.
Extraction of Gross Surface Antigens From AKR Mouse Lymphoma Cells With Potassium Chloride2
Authors: Phyllis B. Brandchaft, Charles W. Boone
Journal: JNCI Journal of the National Cancer Institute (1974)

Approximately 47% of the surface antigen activity present on Gross virus-infected AKR mouse lymphoma cells was extracted in soluble form with 3M potassium chloride, as measured by inhibition of radioiodinated antibody binding to surface antigens. After precipitation with 60% ammonium sulfate and Sephadex chromatography, the soluble antigen was purified 6.4-fold, with a total recovery of 13% of the activity initially detected on the whole cells. The antigen elicited productiol of antibodies against Gross surface antigens in allogeneic mice.
Adrenomedullin, a Multifunctional Regulatory Peptide*
Authors: Joy Patricia Hinson, Supriya Kapas, David Michael Smith
Journal: Endocrine Reviews (2000)

Since the discovery of adrenomedullin in 1993 several hundred papers have been published regarding the regulation of its secretion and the multiplicity of its actions. It has been shown to be an almost ubiquitous peptide, with the number of tissues and cell types synthesizing adrenomedullin far exceeding those that do not. In Section II of this paper we give a comprehensive review both of tissues and cell lines secreting adrenomedullin and of the mechanisms regulating gene expression. The data on circulating adrenomedullin, obtained with the various assays available, are also reviewed, and the disease states in which plasma adrenomedullin is elevated are listed. In Section III the pharmacology and biochemistry of adrenomedullin binding sites, both specific sites and calcitonin gene-related peptide (CGRP) receptors, are discussed. In particular, the putative adrenomedullin receptor clones and signal transduction pathways are described. In Section IV the various actions of adrenomedullin are discussed: its actions on cellular growth, the cardiovascular system, the central nervous system, and the endocrine system are all considered. Finally, in Section V, we consider some unresolved issues and propose future areas for research.
Gynaecological Illness after Sterilization
Authors: M. J. Muldoon
Journal: BMJ (1972)

A total of 374 patients were followed up for at least 10 years after tubal ligation, and 43% required further gynaecological treatment. Major gynaecological surgery was needed by 25%. There seems a good case for the selective use of hysterectomy as a method of sterilization.
<i>Neisseria gonorrhoeae </i>Epithelial Cell Interaction Leads to the Activation of the Transcription Factors Nuclear Factor κB and Activator Protein 1 and the Induction of Inflammatory Cytokines
Authors: Michael Naumann, Silja Weßler, Cornelia Bartsch, Björn Wieland, Thomas F. Meyer
Journal: The Journal of Experimental Medicine (1997)

We have studied the effect of human bacterial pathogen Neisseria gonorrhoeae (Ngo) on the activation of nuclear factor (NF)-κB and the transcriptional activation of inflammatory cytokine genes upon infection of epithelial cells. During the course of infection, Ngo, the etiologic agent of gonorrhea, adheres to and penetrates mucosal epithelial cells. In vivo, localized gonococcal infections are often associated with a massive inflammatory response. We observed upregulation of several inflammatory cytokine messenger RNAs (mRNAs) and the release of the proteins in Ngo-infected epithelial cells. Moreover, infection with Ngo induced the formation of a NF-κB DNA–protein complex and, with a delay in time, the activation of activator protein 1, whereas basic leucine zipper transcription factors binding to the cAMP-responsive element or CAAT/enhancer-binding protein DNA-binding sites were not activated. In supershift assays using NF-κB–specific antibodies, we identified a NF-κB p50/p65 heterodimer. The NF-κB complex was formed within 10 min after infection and decreased 90 min after infection. Synthesis of tumor necrosis factor α and interluekin (IL)-1β occurred at later times and therefore did not account for NF-κB activation. An analysis of transiently transfected IL-6 promoter deletion constructs suggests that NF-κB plays a crucial role for the transcriptional activation of the IL-6 promoter upon Ngo infection. Inactivation of NF-κB conferred by the protease inhibitor N-tosyl-l-phenylalanine chloromethyl ketone inhibited mRNA upregulation of most, but not all, studied cyctokine genes. Activation of NF-κB and cytokine mRNA upregulation also occur in Ngo-infected epithelial cells that were treated with cytochalasin D, indicating an extracellular signaling induced before invasion.
Inhibition of MicroRNA-17 Improves Lung and Heart Function in Experimental Pulmonary Hypertension
Authors: Soni S. Pullamsetti, Carmen Doebele, Ariane Fischer, Rajkumar Savai, Baktybek Kojonazarov, Bhola K. Dahal, Hossein A. Ghofrani, Norbert Weissmann, Friedrich Grimminger, Angelika Bonauer, Werner Seeger, Andreas M. Zeiher, Stefanie Dimmeler, Ralph T. Schermuly
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17-92 cluster was significantly altered in experimental pulmonary hypertension (PH).To evaluate the therapeutic efficacy and antiremodeling potential of miR inhibitors in the pathogenesis of PH.We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), miR-21 (A-21), and miR-92a (A-92a) in chronic hypoxia-induced PH in mice and A-17 in monocrotaline-induced PH in rats. Moreover, biological function of miR-17 was analyzed in cultured pulmonary artery smooth muscle cells.In the PH mouse model, A-17 and A-21 reduced right ventricular systolic pressure, and all antagomirs decreased pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced right ventricular hypertrophy and improved pulmonary artery acceleration time. In the monocrotaline-induced PH rat model, A-17 treatment significantly decreased right ventricular systolic pressure and total pulmonary vascular resistance index, increased pulmonary artery acceleration time, normalized cardiac output, and decreased pulmonary vascular remodeling. Among the tested miR-17 targets, the cyclin-dependent kinase inhibitor 1A (p21) was up-regulated in lungs undergoing A-17 treatment. Likewise, in human pulmonary artery smooth muscle cells, A-17 increased p21. Overexpression of miR-17 significantly reduced p21 expression and increased proliferation of smooth muscle cells.Our data demonstrate that A-17 improves heart and lung function in experimental PH by interfering with lung vascular and right ventricular remodeling. The beneficial effects may be related to the up-regulation of p21. Thus, inhibition of miR-17 may represent a novel therapeutic concept to ameliorate disease state in PH.
T-Cell and NK-Cell Infiltration into Solid Tumors: A Key Limiting Factor for Efficacious Cancer Immunotherapy
Authors: Ignacio Melero, Ana Rouzaut, Greg T. Motz, George Coukos
Journal: Cancer Discovery (2014)

Abstract Summary: Cancer immunotherapy has great promise, but is limited by diverse mechanisms used by tumors to prevent sustained antitumor immune responses. Tumors disrupt antigen presentation, T/NK–cell activation, and T/NK–cell homing through soluble and cell-surface mediators, the vasculature, and immunosuppressive cells such as myeloid-derived suppressor cells and regulatory T cells. However, many molecular mechanisms preventing the efficacy of antitumor immunity have been identified and can be disrupted by combination immunotherapy. Here, we examine immunosuppressive mechanisms exploited by tumors and provide insights into the therapies under development to overcome them, focusing on lymphocyte traffic. Cancer Discov; 4(5); 522–6. ©2014 AACR.
Phase II study of sunitinib as first-line treatment of urothelial cancer patients ineligible to receive cisplatin-based chemotherapy: baseline interleukin-8 and tumor contrast enhancement as potential predictive factors of activity
Authors: J. Bellmunt, J.L. González-Larriba, C. Prior, P. Maroto, J. Carles, D. Castellano, B. Mellado, E. Gallardo, J.L. Perez-Gracia, G. Aguilar, X. Villanueva, J. Albanell, A. Calvo
Journal: Annals of Oncology (2011)
Anti-CD20 Chimeric Monoclonal Antibody Treatment of Refractory Immune-Mediated Thrombocytopenia in a Patient with Chronic Graft-versus-Host Disease
Authors: Voravit Ratanatharathorn
Journal: Annals of Internal Medicine (2000)

Background: Autoimmune thrombocytopenia in chronic graft-versus-host disease may represent an instance of B-cell dysregulation leading to clinical disease. Objective: To attempt to treat refractory immune-mediated thrombocytopenia in a patient with chronic graft-versus-host disease by using anti-CD20 chimeric monoclonal antibody. Design: Case report. Setting: Academic medical center. Patient: A patient with chronic graft-versus-host disease after allogeneic peripheral blood stem-cell transplantation who had severe refractory immune-mediated thrombocytopenia. Intervention: Weekly infusion of rituximab, 375 mg/m2, for 4 weeks. Measurements: Platelet count, CD3+ cell count, and CD19+ cell count. Results: Rituximab therapy resulted in marked depletion of B cells in the peripheral blood and decreased levels of platelet-associated antibody. The increase in platelet count persisted despite tapering and discontinuation of immunosuppressive therapy for chronic graft-versus-host disease. Conclusion: The efficacy of rituximab for the treatment of immune-mediated thrombocytopenia suggests that this drug may have activity in other autoimmune diseases or chronic graft-versus-host disease.
Relationship of SV40 T‐antigen expression in vitro to disorders of bone marrow function
Authors: A. S. Lubiniecki, W. A. Blattner, H. Dosik, S. McIntosh, W. Wertelecki
Journal: American Journal of Hematology (1980)

Abstract Skin fibroblasts from patients with a variety of hematologic disorders were infected with SV40 virus in vitro in attempts to discover the reason for increased susceptibility of Fanconi anemia cells to this transforming virus. The proportion of skin fibroblasts expressing SV40 T‐antigen by immunofluorescent methods was elevated in 12 patients with Fanconi anemia and in seven of nine obligate heterozygous relatives. Elevated expression was also observed in three patients with other hematological disorders at high risk of acute nonlymphocytic leukemia, but was not apparent in seven sporadic aplastic anemia patients or four of their relatives. T‐antigen expression was elevated in about one‐half of patients with thrombocytopenia‐absent radius syndrome and related conditions, with familial aplastic anemia, and in their normal relatives. In the conditions under study, elevated T‐antigen expression seemed clearly correlated with predisposition to leukemia, which may be genetically determined, but it was not associated with cytogenetic or anemic manifestations.
Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response
Authors: Béatrice Jacquelin, Véronique Mayau, Brice Targat, Anne-Sophie Liovat, Désirée Kunkel, Gaël Petitjean, Marie-Agnès Dillies, Pierre Roques, Cécile Butor, Guido Silvestri, Luis D. Giavedoni, Pierre Lebon, Françoise Barré-Sinoussi, Arndt Benecke, Michaela C. Müller-Trutwin
Journal: Journal of Clinical Investigation (2009)

African green monkeys (AGMs) infected with the AGM type of SIV (SIVagm) do not develop chronic immune activation and AIDS, despite viral loads similar to those detected in humans infected with HIV-1 and rhesus macaques (RMs) infected with the RM type of SIV (SIVmac). Because chronic immune activation drives progressive CD4+ T cell depletion and immune cell dysfunctions, factors that characterize disease progression, we sought to understand the molecular basis of this AGM phenotype. To this end, we longitudinally assessed the gene expression profiles of blood- and lymph node-derived CD4+ cells from AGMs and RMs in response to SIVagm and SIVmac infection, respectively, using a genomic microarray platform. The molecular signature of acute infection was characterized, in both species, by strong upregulation of type I IFN-stimulated genes (ISGs). ISG expression returned to basal levels after postinfection day 28 in AGMs but was sustained in RMs, especially in the lymph node-derived cells. We also found that SIVagm induced IFN-alpha production by AGM cells in vitro and that low IFN-alpha levels were sufficient to induce strong ISG responses. In conclusion, SIV infection triggered a rapid and strong IFN-alpha response in vivo in both AGMs and RMs, with this response being efficiently controlled only in AGMs, possibly as a result of active regulatory mechanisms.
Accumulation of Cytosolic Calcium Induces Necroptotic Cell Death in Human Neuroblastoma
Authors: Motonari Nomura, Ayumi Ueno, Kotaro Saga, Masahiro Fukuzawa, Yasufumi Kaneda
Journal: Cancer Research (2013)

Necrosis has been studied extensively since the early days of medicine, with some patterns of necrosis found to be programmed like apoptotic cell death. However, mechanisms of programmed necrosis (necroptosis) are yet to be fully elucidated. In this study, we investigated how the hemagglutinating virus of Japan-envelope (HVJ-E) induces necrosis in mouse xenografts of human neuroblastoma cells. HVJ-E-induced necrosis in this system was found to depend on phosphorylation of the death receptor kinase receptor interacting protein kinase 1 (RIP1) and on the production of reactive oxygen species. This process was interpreted as necroptosis, based on its suppression by the small molecule necrostatin-1, and it did not involve the TNF-α receptor pathway. We also demonstrated that increased concentrations of cytoplasmic calcium triggered necroptosis by activating calcium-calmodulin kinase (CaMK) II. Finally, we determined that RIP1 phosphorylation was mediated by CaMK II activation. Together, our results define an upstream pathway for the activation of necroptosis in neuroblastoma cells, with potential therapeutic implications.
International Union of Pharmacology. XLIX. Nomenclature and Structure-Function Relationships of Transient Receptor Potential Channels
Authors: David E. Clapham, David Julius, Craig Montell, Günter Schultz
Journal: Pharmacological Reviews (2005)

The transient receptor potential (TRP[1][1]) ion channels are named after the role of the channels in Drosophila phototransduction. The mammalian genes are encoded by at least 28 channel subunit genes ([Fig. 1][2]) ([Clapham, 2003][3]; [Moran et al., 2004][4]). Six protein families comprise the
Ductus arteriosus. Advanced differentiation of smooth muscle cells demonstrated by myosin heavy chain isoform expression in rabbits.
Authors: H S Kim, M Aikawa, K Kimura, M Kuro-o, K Nakahara, T Suzuki, H Katoh, E Okamoto, Y Yazaki, R Nagai
Journal: Circulation (1993)

BACKGROUND The closure of the ductus arteriosus (DA) is one of the most striking cardiovascular events that occur at birth. It has been attributed to oxygenation and intrinsic prostaglandins. However, selective constriction of DA suggests the presence of highly specialized contractile mechanisms in DA. We previously reported that smooth muscle myosin heavy chain isoforms, SM1 and SM2, are molecular markers for smooth muscle differentiation because of their unique expression pattern during vascular development. SM1 and SM2 are generated from a single gene through developmentally regulated alternative RNA splicing; SM1 is expressed in almost all stages of differentiation of the vascular smooth muscles, but SM2 is found only after birth. METHODS AND RESULTS Immunohistochemistry was performed to study the expression of the different types of myosin heavy chain isoforms in DA of fetal and neonatal rabbits. Electron microscopic examinations were also carried out to demonstrate ultrastructural characteristics of ductus muscles. We found that SM2 is expressed before birth in the medial layer of DA, indicating advanced differentiation of smooth muscle cells in DA. The exact location of immunoreactivity for SM2 was in the smooth muscle cell of the medial layer of DA. Immunoreactivity for SM1, however, was not different for DA and adjacent great arteries. Transmission electron microscopy demonstrated greater amounts of myofilaments in medial smooth muscles of DA than those of aorta. CONCLUSIONS These results indicate that smooth muscles in DA are more differentiated than those in other arteries, which may be one of the cellular mechanisms responsible for the unique closure of DA at birth.