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orphan diseases

Min Chen, Bo Liao, Zejun Li
microRNAs (miRNAs) mutation and maladjustment are related to the occurrence and development of human diseases. Studies on disease-associated miRNA have contributed to disease diagnosis and treatment. To address the problems, such as low prediction accuracy and failure to predict the relationship between new miRNAs and diseases and so on, we design a Laplacian score of graphs to calculate the global similarity of networks and propose a Global Similarity method based on a Two-tier Random Walk for the prediction of miRNA-disease association (GSTRW) to reveal the correlation between miRNAs and diseases...
April 24, 2018: Scientific Reports
F Haubner, T Kühnel
Osler's disease is an autosomal dominant hereditary syndrome which belongs to the group of orphan diseases. Affected patients suffer primarily from severe epistaxis. Diagnosis is based on the Curaçao criteria and molecular genetic tests. Organ manifestations can be found in the form of arteriovenous shunts in the lung, liver, and gastrointestinal tract; more rarely also in the central nervous system (CNS) and other parts of the body. Many patients with gastrointestinal and other organ manifestations are frequently clinically asymptomatic; therefore, organ screening is essential to avoid later complications and should be performed in centers with particular expertise...
April 23, 2018: HNO
Keiji Kuba, Teruki Sato, Yumiko Imai, Tomokazu Yamaguchi
Apelin is an endogenous peptide ligand for the G protein-coupled receptor APJ/AGTRL1/APLNR and is widely expressed throughout human body. In adult hearts Apelin-APJ/Apelin receptor axis is potently inotropic, vasodilatory, and pro-angiogenic and thereby contributes to maintaining homeostasis in normal and pathological hearts. Apelin-APJ/Apelin receptor is also involved in heart development including endoderm differentiation, heart morphogenesis, and coronary vascular formation. APJ/Apelin receptor had been originally identified as an orphan receptor for its sequence similarity to Angiotensin II type 1 receptor, and it was later deorphanized by identification of Apelin in 1998...
April 20, 2018: Peptides
Torsten Schöneberg, Jaroslawna Meister, Alexander Bernd Knierim, Angela Schulz
Research on GPR34, which was discovered in 1999 as an orphan G protein-coupled receptor of the rhodopsin-like class, disclosed its physiologic relevance only piece by piece. Being present in all recent vertebrate genomes analyzed so far it seems to improve the fitness of species although it is not essential for life and reproduction as GPR34-deficient mice demonstrate. However, closer inspection of macrophages and microglia, where it is mainly expressed, revealed its relevance in immune cell function. Recent data clearly demonstrate that GPR34 function is required to arrest microglia in the M0 homeostatic non-phagocytic phenotype...
April 20, 2018: Pharmacology & Therapeutics
Md Kamrul Hasan, Jian Yu, George F Widhopf, Laura Z Rassenti, Liguang Chen, Zhouxin Shen, Steven P Briggs, Donna S Neuberg, Thomas J Kipps
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic protein expressed on chronic lymphocytic leukemia (CLL) that can serve as a receptor for Wnt5a, which can promote leukemia-cell migration, proliferation, and survival. We found Wnt5a could induce ROR1 to complex with DOCK2 and induce activation of Rac1/2; these effects could be blocked by cirmtuzumab, a humanized anti-ROR1 mAb. We find that silencing DOCK2 specifically impaired the capacity of Wnt5a to induce activation of Rac1/2 or enhance CLL-cell proliferation...
April 20, 2018: Blood
Mar Siles-Lucas, Adriano Casulli, Roberto Cirilli, David Carmena
Human cystic and alveolar echinococcosis are helmintic zoonotic diseases caused by infections with the larval stages of the cestode parasites Echinococcus granulosus and E. multilocularis, respectively. Both diseases are progressive and chronic, and often fatal if left unattended for E. multilocularis. As a treatment approach, chemotherapy against these orphan and neglected diseases has been available for more than 40 years. However, drug options were limited to the benzimidazoles albendazole and mebendazole, the only chemical compounds currently licensed for treatment in humans...
April 20, 2018: PLoS Neglected Tropical Diseases
F Amat, A Soria, P Tallon, M Bourgoin-Heck, N Lambert, A Deschildre, J Just
Atopic dermatitis (AD) is a complex disease with multiple causes and complex mechanistic pathways according to age of onset, severity of the illness, ethnic modifiers, response to therapy, and triggers. A group of difficult-to-manage patients characterized by early-onset AD and severe lifelong disease associated with allergic asthma and/or food allergy, has been identified. In this paper, we focus on these severe phenotypes, analyzing their links with other atopic comorbidities, and taking into account the results from recent cohort studies and meta-analyses...
April 20, 2018: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
Tali Czarnowicki, Helen He, Alexandra Leonard, Kunal Malik, Shai Magidi, Stephanie Rangel, Krishna Patel, Kara Ramsey, Morgan Murphrey, Teresa Song, Yeriel Estrada, Hue-Chi Wen, James G Krueger, Emma Guttman-Yassky, Amy S Paller
The ichthyoses are rare skin disorders with immune and barrier aberrations. Identifying blood phenotypes may advance targeted-therapeutics.We aimed to compare frequencies of skin homing/CLA+ vs. systemic/CLA- "polar" CD4+ /CD8+ and activated T-cell subsets in ichthyosis vs. atopic dermatitis/AD, psoriasis and control blood, with appropriate clinical correlations. Flow cytometry was used to measure IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4+ /CD8+ T-cells, with ICOS and HLA-DR defining mid- and long-term T-cell activation, respectively...
April 13, 2018: Journal of Investigative Dermatology
Yanina Hiriart, Romina Pardo, Lucas Bukata, Constanza Lauché, Luciana Muñoz, Mariana Colonna, Fernando Goldbaum, Santiago Sanguineti, Vanesa Zylberman
The typical hemolytic uremic syndrome (HUS) is an orphan disease caused by Shiga toxin(Stx) producing Escherichia coli strains and characterized by acute kidney damage, microangiopathic hemolytic anemia and low platelet count. It is endemic in Argentina, the country with the highest incidence of HUS in the world. Stx is essential for its development and therefore, HUS is considered a toxemic non-bacteremic disorder, which could be treated with antibodies. Herein we describe the development of a new treatment capable of neutralizing the toxic effect of Stx and its variants...
2018: Medicina
Petros Christopoulos, Marc A Schneider, Farastuk Bozorgmehr, Jonas Kuon, Walburga Engel-Riedel, Jens Kollmeier, Volker Baum, Thomas Muley, Philipp A Schnabel, Helge Bischoff, Christian Grohé, Monika Serke, Michael Thomas, Paul Fisch, Michael Meister
OBJECTIVES: This study was performed to evaluate for a potentially important role of T cells in the pathophysiology and treatment sensitivity of large cell neuroendocrine lung carcinoma (LCNEC), an orphan disease with poor prognosis and scarce data to guide novel therapeutic strategies. MATERIALS AND METHODS: We performed T-cell receptor (TCR) β-chain spectratyping on blood samples of patients treated within the CRAD001KDE37 trial (n = 35) using age-matched current or former (n = 11) and never smokers (n = 10) as controls...
May 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Proteesh Rana, Shalini Chawla
Research in rare diseases has contributed substantially toward the current understanding in the pathophysiology of the common diseases. However, medical needs of patients with rare diseases have always been neglected by the society and pharmaceutical industries based on their small numbers and unprofitability. The Orphan Drug Act (1983) was the first serious attempt to address the unmet medical needs for patients with rare diseases and to provide impetus for the pharmaceutical industry to promote orphan drug development...
April 12, 2018: Journal of Basic and Clinical Physiology and Pharmacology
Sean L Hammond, Katriana A Popichak, Xi Li, Lindsay G Hunt, Evan H Richman, Pranav Damale, Edwin Chong, Donald S Backos, Stephen Safe, Ronald B Tjalkens
The orphan nuclear receptor, Nurr1 (NR4A2), regulates inflammatory gene expression in glial cells, as well as genes associated with homeostatic and trophic function in dopaminergic neurons. Despite these known functions of Nurr1, an endogenous ligand has not been discovered. We postulated that activation of Nurr1 would suppress activation of glia and thereby protect against loss of dopamine (DA) neurons following subacute lesioning with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our previous studies have shown that a synthetic Nurr1 ligand, 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12), suppresses inflammatory gene expression in primary astrocytes and induces a dopaminergic phenotype in neurons...
April 6, 2018: Journal of Pharmacology and Experimental Therapeutics
James L J Coleman, Margaret A Mouat, Jianxin Wu, Nikola Jancovski, Jaspreet K Bassi, Andrea Y Chan, David T Humphreys, Nadine Mrad, Ze-Yan Yu, Tony Ngo, Siiri Iismaa, Cristobal G Dos Remedios, Michael P Feneley, Andrew M Allen, Robert M Graham, Nicola J Smith
BACKGROUND: Over 100 mammalian G protein-coupled receptors are yet to be matched with endogenous ligands; these so-called orphans are prospective drug targets for the treatment of disease. GPR37L1 is one such orphan, abundant in the brain and detectable as mRNA in the heart and kidney. GPR37L1 ablation was reported to cause hypertension and left ventricular hypertrophy, and thus, we sought to further define the role of GPR37L1 in blood pressure homeostasis. METHODS: We investigated the cardiovascular effects of GPR37L1 using wild-type (GPR37L1wt/wt ) and null (GPR37L1KO/KO ) mice established on a C57BL/6J background, both under baseline conditions and during AngII infusion...
April 6, 2018: Biology of Sex Differences
Heide Stirnadel-Farrant, Mahesh Kudari, Nadia Garman, Jessica Imrie, Bikramjit Chopra, Stefania Giannelli, Michela Gabaldo, Ambra Corti, Stefano Zancan, Alessandro Aiuti, Maria Pia Cicalese, Rohit Batta, Jonathan Appleby, Mario Davinelli, Pauline Ng
BACKGROUND: Strimvelis (autologous CD34+ cells transduced to express adenosine deaminase [ADA]) is the first ex vivo stem cell gene therapy approved by the European Medicines Agency (EMA), indicated as a single treatment for patients with ADA-severe combined immunodeficiency (ADA-SCID) who lack a suitable matched related bone marrow donor. Existing primary immunodeficiency registries are tailored to transplantation outcomes and do not capture the breadth of safety and efficacy endpoints required by the EMA for the long-term monitoring of gene therapies...
April 6, 2018: Orphanet Journal of Rare Diseases
Andrea Young, Devidas Menon, Jackie Street, Walla Al-Hertani, Tania Stafinski
INTRODUCTION: Reimbursement decisions on orphan drugs carry significant uncertainty, and as the amount increases, so does the risk of making a wrong decision, where harms outweigh benefits. Consequently, patients often face limited access to orphan drugs. Managed access programmes (MAPs) are a mechanism for managing risk while enabling access to potentially beneficial drugs. Patients and their caregivers have expressed support for these programmes and see patient input as critical to successful implementation...
April 6, 2018: Health Expectations: An International Journal of Public Participation in Health Care and Health Policy
Natsuko Saito-Sasaki, Yu Sawada, Emi Mashima, Takashi Yamaguchi, Shun Ohmori, Haruna Yoshioka, Sanehito Haruyama, Etsuko Okada, Motonobu Nakamura
The anti-inflammatory effect of omega 3 polyunsaturated fatty acids has been confirmed in various inflammatory disease models. Maresin-1 (MaR1) is a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid (DHA) that has displayed strong anti-inflammatory effects in various inflammatory disease models. However, the effect of topical MaR1 on cutaneous inflammation remains unclear. Therefore, we initially examined the anti-inflammatory effects of topical Maresin-1 using an imiquimod (IMQ)-induced psoriasis-like mouse model of inflammation...
April 3, 2018: Scientific Reports
Zhou Zhou, Zhiqiang Tian, Mengjie Zhang, Yuxun Zhang, Bing Ni, Fei Hao
Systemic lupus erythematosus (SLE) is a typical autoimmune disease. Genome-wide analyses have revealed that interleukin-1 receptor-associated kinase 1 (IRAK1) is associated with susceptibility to SLE. Our previous study investigated the role of IRAK1 in nuclear factor-κB (NF-κB)-related pathways in a mouse model of lupus. In this study, we aimed to further explore the etiological role of IRAK1. The gene expression and phosphorylation of IRAK1 in CD4+ T cells from lupus patients and healthy controls were examined by quantitative reverse transcription-polymerase chain reaction and western blotting, respectively...
April 3, 2018: Immunological Investigations
Haikun Song, Hexuan Li, Shimeng Guo, Yuyin Pan, Yuhua Fu, Zijian Zhou, Zhaoyang Li, Xue Wen, Xiaoli Sun, Bingqing He, Haifeng Gu, Quan Zhao, Cen Wang, Ping An, Shouqing Luo, Youhong Hu, Xin Xie, Boxun Lu
Lowering the levels of disease-causing proteins is an attractive treatment strategy for neurodegenerative disorders, among which Huntington's disease is an appealing disease for testing this strategy because of its monogenetic nature. Huntington's disease is mainly caused by cytotoxicity of the mutant HTT protein with an expanded polyglutamine repeat tract. Lowering the soluble mutant HTT may reduce its downstream toxicity and provide potential treatment for Huntington's disease. This is hard to achieve by small-molecule compound drugs because of a lack of effective targets...
March 28, 2018: Brain: a Journal of Neurology
Qingwen Cheng, Jean Danao, Santosh Talreja, Paul Wen, Jun Yin, Ning Sun, Chi-Ming Li, Danny Chui, David Tran, Samir Koirala, Hang Chen, Ian N Foltz, Songli Wang, Shilpa Sambashivan
Triggering receptor expressed on myeloid cells 2 (TREM2) is an orphan immune receptor expressed on cells of myeloid lineage such as macrophages and microglia. The rare-variant R47H TREM2 is associated with an increased risk for Alzheimer's disease (AD), supporting the hypothesis that TREM2 loss of function may exacerbate disease progression. However, a complete knockout of the TREM2 gene in different genetic models of neurodegenerative diseases has been reported to result in both protective and deleterious effects on disease-related endpoints and myeloid cell function...
March 29, 2018: Journal of Biological Chemistry
Kenta Kawasaki, Masayuki Fujii, Toshiro Sato
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) refer to a group of heterogeneous cancers of neuroendocrine cell phenotype that mainly fall into one of two subtypes: gastroenteropancreatic neuroendocrine tumors (GEP-NETs; well differentiated) or gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs; poorly differentiated). Although originally defined as orphan cancers, their steadily increasing incidence highlights the need to better understand their etiology. Accumulating epidemiological and clinical data have shed light on the pathological characteristics of these diseases...
February 26, 2018: Disease Models & Mechanisms
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