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https://www.readbyqxmd.com/read/28808239/compound-a-influences-gene-regulation-of-the-dexamethasone-activated-glucocorticoid-receptor-by-alternative-cofactor-recruitment
#1
S J Desmet, N Bougarne, L Van Moortel, L De Cauwer, J Thommis, M Vuylsteke, D Ratman, R Houtman, J Tavernier, K De Bosscher
The glucocorticoid receptor (GR) is a transcription factor of which the underlying gene regulatory mechanisms are complex and incompletely understood. The non-steroidal anti-inflammatory Compound A (CpdA), a selective GR modulating compound in various cell models, has been shown to favour GR-mediated gene repression but not GR-mediated gene activation. Shifting balances towards only a particular subset of GR gene regulatory events may be of benefit in the treatment of inflammatory diseases. We present evidence to support that the combination of CpdA with Dexamethasone (DEX), a classic steroidal GR ligand, can shape GR function towards a unique gene regulatory profile in a cell type-dependent manner...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28801400/protein-misfolding-amyotrophic-lateral-sclerosis-and-guanabenz-protocol-for-a-phase-ii-rct-with-futility-design-promise-trial
#2
Eleonora Dalla Bella, Irene Tramacere, Giovanni Antonini, Giuseppe Borghero, Margherita Capasso, Claudia Caponnetto, Adriano Chiò, Massimo Corbo, Roberto Eleopra, Massimiliano Filosto, Fabio Giannini, Enrico Granieri, Vincenzo La Bella, Christian Lunetta, Jessica Mandrioli, Letizia Mazzini, Sonia Messina, Maria Rosaria Monsurrò, Gabriele Mora, Nilo Riva, Romana Rizzi, Gabriele Siciliano, Vincenzo Silani, Isabella Simone, Gianni Sorarù, Paolo Volanti, Giuseppe Lauria
INTRODUCTION: Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug...
August 11, 2017: BMJ Open
https://www.readbyqxmd.com/read/28799485/monoclonal-antibodies-a-review
#3
Surjit Singh, Nitish Kumar, Pradeep Dwiwedi, Jaykaran Charan, Rimplejeet Kaur, Preeti Sidhu, Vinay Kumar Chugh
Over the last three decades, monoclonal antibodies (MAbs) have made a striking transformation from scientific tools to powerful human therapeutics. Muromonab CD3 a murine MAb, was first FDA approved therapeutic MAb for prevention of kidney transplant rejection. Since its approval in 1986, there has been decline in the further application and approvals until the late 1990s when the first chimeric Mab, Rituximab was approved for the treatment of low grade B cell lymphoma in 1997. With the approval by licensing authorities of chimeric, followed by humanized and then fully human monoclonal antibodies, rate of approval and monoclonal antibodies available in the market for the treatment of various diseases has increased dramatically...
August 9, 2017: Current Clinical Pharmacology
https://www.readbyqxmd.com/read/28783681/the-orphan-nuclear-receptor-ror%C3%AE-and-group-3-innate-lymphoid-cells-drive-fibrosis-in-a-mouse-model-of-crohn-s-disease
#4
Bernard C Lo, Matthew J Gold, Michael R Hughes, Frann Antignano, Yanet Valdez, Colby Zaph, Kenneth W Harder, Kelly M McNagny
Fibrosis is the result of dysregulated tissue regeneration and is characterized by excessive accumulation of matrix proteins that become detrimental to tissue function. In Crohn's disease, this manifests itself as recurrent gastrointestinal strictures for which there is no effective therapy beyond surgical intervention. Using a model of infection-induced chronic gut inflammation, we show that Rora-deficient mice are protected from fibrosis; infected intestinal tissues display diminished pathology, attenuated collagen deposition, and reduced fibroblast accumulation...
September 2, 2016: Science Immunology
https://www.readbyqxmd.com/read/28780080/-how-i-treat-autoimmune-diseases-state-of-the-art-on-the-management-of-rare-rheumatic-diseases-and-anca-associated-systemic-idiopathic-vasculitis
#5
EDITORIAL
Dario Roccatello
This Special Issue of Autoimmunity Reviews constitutes summaries of presentations at the 20th International Meeting on Immune Pathology and Orphan Diseases, held in Torino, Italy, 25-28th January 2017. As such, these presentations represent the state of the art on the pathophysiology of autoimmune diseases as well as the most recent insights into the management of these pathologic conditions. The latter includes both the optimal use of established drugs and approaches as well as novel knowledge on the means and consequences of targeted blocking of molecules or cellular mechanisms...
August 2, 2017: Autoimmunity Reviews
https://www.readbyqxmd.com/read/28774591/topical-ror-inverse-agonists-suppress-inflammation-in-mouse-models-of-atopic-dermatitis-and-acute-irritant-dermatitis
#6
Jun Dai, Min-Kyung Choo, Jin Mo Park, David E Fisher
The retinoic acid receptor-related orphan receptors RORα and RORγ are critical for the functions of specific subsets of T cells and innate lymphoid cells, which are key drivers of inflammatory disease in barrier tissues. Here, we investigate the anti-inflammatory potential of SR1001, a synthetic RORα/γ inverse agonist, in mouse models of atopic dermatitis and acute irritant dermatitis. Topical treatment with SR1001 reduces epidermal and dermal features of MC903-induced atopic dermatitis-like disease, and suppresses the production of type 2 cytokines and other inflammatory mediators in lesional skin...
July 31, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28763457/ror%C3%AE-t-and-ror%C3%AE-signature-genes-in-human-th17-cells
#7
Glenda Castro, Xuejun Liu, Karen Ngo, Aimee De Leon-Tabaldo, Shanrong Zhao, Rosa Luna-Roman, Jingxue Yu, Tinghua Cao, Robert Kuhn, Patrick Wilkinson, Krystal Herman, Marina I Nelen, Jonathan Blevitt, Xiaohua Xue, Anne Fourie, Wai-Ping Fung-Leung
RORγt and RORα are transcription factors of the RAR-related orphan nuclear receptor (ROR) family. They are expressed in Th17 cells and have been suggested to play a role in Th17 differentiation. Although RORγt signature genes have been characterized in mouse Th17 cells, detailed information on its transcriptional control in human Th17 cells is limited and even less is known about RORα signature genes which have not been reported in either human or mouse T cells. In this study, global gene expression of human CD4 T cells activated under Th17 skewing conditions was profiled by RNA sequencing...
2017: PloS One
https://www.readbyqxmd.com/read/28761880/therapeutic-effects-of-methanol-extract-from-euphorbia-kansui-radix-on-imiquimod-induced-psoriasis
#8
Soo Jeong Kim, Ye Won Jang, Kyung Eun Hyung, Da Kyoung Lee, Kee Hyeob Hyun, So-Young Park, Eon-Sub Park, Kwang Woo Hwang
The roots of Euphorbia kansui, which belong to the family Euphorbiaceae, have been used as a traditional medicine for the treatment of various diseases such as diabetes, ascites, and leukemia. Recently, it was reported that the methylene chloride fraction of E. kansui radix (EKC) regulated the differentiation of Th17 cells and alleviated the symptoms of Th17-related inflammatory bowel disease. Imiquimod (IMQ), a TLR7/8 agonist, has been used to induce psoriasis in a mouse model. In this study, we evaluated the effect of EKC in an IMQ-induced psoriasis model...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28755896/clinical-genomics-in-inflammatory-bowel-disease
#9
REVIEW
Holm H Uhlig, Aleixo M Muise
Genomic technologies inform the complex genetic basis of polygenic inflammatory bowel disease (IBD) as well as Mendelian disease-associated IBD. Aiming to diagnose patients that present with extreme phenotypes due to monogenic forms of IBD, genomics has progressed from 'orphan disease' research towards an integrated standard of clinical care. Advances in diagnostic clinical genomics are increasingly complemented by pathway-specific therapies that aim to correct the consequences of genetic defects. This highlights the exceptional potential for personalized precision medicine...
July 26, 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/28754721/activity-of-pazopanib-and-trabectedin-in-advanced-alveolar-soft-part-sarcoma
#10
Silvia Stacchiotti, Olivier Mir, Axel Le Cesne, Bruno Vincenzi, Alexander Fedenko, Robert G Maki, Neeta Somaiah, Shreyaskumar Patel, Mehedi Brahmi, Jean Y Blay, Kjetil Boye, Kirsten Sundby Hall, Hans Gelderblom, Nadia Hindi, Javier Martin-Broto, Hanna Kosela, Piotr Rutkowski, Antoine Italiano, Florence Duffaud, Eisuke Kobayashi, Paolo G Casali, Salvatore Provenzano, Akira Kawai
BACKGROUND: Alveolar soft part sarcoma (ASPS) is an exceedingly rare and orphan disease, without active drugs approved in the front line. Pazopanib and trabectedin are licensed for sarcoma treatment from second-line, but very little and contradictory data are available on their activity in ASPS. Lacking ongoing and/or planned clinical trials, we conducted a multi-institutional study involving the reference sites for sarcoma in Europe, U.S., and Japan, within the World Sarcoma Network, to investigate the efficacy of pazopanib and trabectedin...
July 28, 2017: Oncologist
https://www.readbyqxmd.com/read/28752290/factors-contributing-to-the-efficacy-effectiveness-gap-in-the-case-of-orphan-drugs-for-metabolic-diseases
#11
Y Schuller, C E M Hollak, C C Gispen-de Wied, V Stoyanova-Beninska, M Biegstraaten
INTRODUCTION: Authorization of orphan medicinal products (OMPs) is often based on studies with several methodological shortcomings. Hence, data are difficult to interpret and efficacy does not always correspond to real-world effectiveness. We investigated to what extent an efficacy-effectiveness gap exists for OMPs for metabolic diseases and set out to explore which factors contribute to it. METHODS: We included all OMPs for rare metabolic diseases authorized in the EU up to 1 January 2016...
July 27, 2017: Drugs
https://www.readbyqxmd.com/read/28750813/methods-for-the-development-of-in-silico-gpcr-models
#12
Paula Morales, Dow P Hurst, Patricia H Reggio
The Reggio group has constructed computer models of the inactive and G-protein-activated states of the cannabinoid CB1 and CB2 receptors, as well as, several orphan receptors that recognize a subset of cannabinoid compounds, including GPR55 and GPR18. These models have been used to design ligands, mutations, and covalent labeling studies. The resultant second-generation models have been used to design ligands with improved affinity, efficacy, and subtype selectivity. Herein, we provide a guide for the development of GPCR models using the most recent orphan receptor studied in our lab, GPR3...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28743204/the-use-of-clinical-databases-in-disease-outcomes-research-is-the-ethics-of-irb-review-keeping-up
#13
Eugene Bereza
There is a perceived tension in research ethics between protecting the interests of participants and promoting good research as a societal good. The challenge of balancing the potential benefits of large clinical databases for disease outcomes research while protecting patients' privacy and confidentiality is an example of this dynamic. What is new about this tension in the context of "data warehousing" is the conflation of many differing interpretations of relevant ethics terminology, the proliferation of different kinds of databases, as well as the growth of research on a global level without the requisite harmonization of regulatory frameworks...
July 1, 2017: Multiple Sclerosis: Clinical and Laboratory Research
https://www.readbyqxmd.com/read/28735214/indazole-based-ligands-for-estrogen-related-receptor-%C3%AE-as-potential-anti-diabetic-agents
#14
Raymond J Patch, Hui Huang, Sharmila Patel, Wing Cheung, Guozhang Xu, Bao-Ping Zhao, Derek A Beauchamp, Dionisios Rentzeperis, John G Geisler, Hossein B Askari, Jianying Liu, Jyotsna Kasturi, Meghan Towers, Micheal D Gaul, Mark R Player
Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkylthiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (IC50s < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre-diabetic rat model when administered orally (10 mg/kg)...
July 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28733840/identification-of-a%C3%A2-rare-coch-mutation-by-whole-exome-sequencing-implications-for-personalized-therapeutic-rehabilitation-in-an-austrian-family-with-non-syndromic-autosomal-dominant-late-onset-hearing-loss
#15
Thomas Parzefall, Alexandra Frohne, Martin Koenighofer, Andreas Kirchnawy, Berthold Streubel, Christian Schoefer, Wolfgang Gstoettner, Klemens Frei, Trevor Lucas
BACKGROUND: Non-syndromic autosomal dominant hearing impairment is characteristically postlingual in onset. Genetic diagnostics are essential for genetic counselling, disease prognosis and understanding of the molecular mechanisms of disease. To date, 36 causative genes have been identified, many in only individual families. Gene selection for genetic screening by traditional methods and genetic diagnosis in autosomal dominant patients has therefore been fraught with difficulty. Whole-exome sequencing provides a powerful tool to analyze all protein-coding genomic regions in parallel, thus allowing the comprehensive screening of all known genes and associated alterations...
July 21, 2017: Wiener Klinische Wochenschrift
https://www.readbyqxmd.com/read/28731526/drug-discovery-and-development-for-rare-genetic-disorders
#16
REVIEW
Wei Sun, Wei Zheng, Anton Simeonov
Approximately 7,000 rare diseases affect millions of individuals in the United States. Although rare diseases taken together have an enormous impact, there is a significant gap between basic research and clinical interventions. Opportunities now exist to accelerate drug development for the treatment of rare diseases. Disease foundations and research centers worldwide focus on better understanding rare disorders. Here, the state-of-the-art drug discovery strategies for small molecules and biological approaches for orphan diseases are reviewed...
July 21, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28730644/fungiscope-%C3%A2-global-emerging-fungal-infection-registry
#17
Danila Seidel, Luisa A Durán Graeff, Maria J G T Vehreschild, Hilmar Wisplinghoff, Maren Ziegler, J Janne Vehreschild, Blasius Liss, Axel Hamprecht, Philipp Köhler, Zdenek Racil, Nikolay Klimko, Donald C Sheppard, Raoul Herbrecht, Anuradha Chowdhary, Oliver A Cornely, FungiScope Group
Rare invasive fungal diseases (IFD) are challenging for the treating physicians because of their unspecific clinical presentation, as well as the lack of standardised diagnostic and effective treatment strategies. Late onset of treatment and inappropriate medication is associated with high mortality, thus, urging the need for a better understanding of these diseases. The purpose of FungiScope(™) is to continuously collect clinical information and specimens to improve the knowledge on epidemiology and eventually improve patient management of these orphan diseases...
August 2017: Mycoses
https://www.readbyqxmd.com/read/28728843/expression-and-prognostic-role-of-orphan-receptor-gpr110-in-glioma
#18
Haiping Shi, Shiyuan Zhang
Glioma is the most common type of malignancy in the central nervous system, which has a poor prognosis due to its rapid progression and diffuse invasion. Identification of novel biomarkers for glioma would be invaluable for studying disease mechanism and improving prognosis. Orphan G protein-coupled receptor 110 (GPR110) belongs to the subfamily VI of adhesion GPCR. The knowledge of the ligand, signaling pathway or physiology function of GPR110 is poorly elucidated. The potential role of GPR110 as an oncogene in mouse has been recently reported by mutagenesis screen...
July 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28720054/impact-of-novel-agents-on-patient-relevant-outcomes-in-patients-with-previously-untreated-cll-who-are-not-eligible-for-fludarabine-based-therapy
#19
Moushmi Singh, Stuart Mealing, Simona Baculea, Sarah Cote, Jo Whelan
BACKGROUND: Chronic lymphocytic leukemia (CLL) is an orphan disease that primarily affects the elderly. The majority of symptomatic patients eligible for frontline treatment are unfit for fludarabine based chemoimmunotherapy. Historical treatment includes chlorambucil (Chl), bendamustine/rituximab (BR), and chlorambucil/rituximab/ChlR combination. Clinical guidelines now recommend the use of novel agents, such as ibrutinib (Ibr), in both frontline and relapse settings and other novel agents, such as idelalisib (with rituximab), in relapse settings...
July 19, 2017: Journal of Medical Economics
https://www.readbyqxmd.com/read/28719647/morbidity-outcomes-and-cost-benefit-analysis-of-wildlife-rehabilitation-in-catalonia-spain
#20
Rafael Angel Molina-López, Santi Mañosa, Alex Torres-Riera, Manel Pomarol, Laila Darwich
BACKGROUND: There are few studies of careful examination of wildlife casualties in Wildlife Rehabilitation Centers. These studies are essential for detecting menaces to wild species and providing objective criteria about cost-benefit of treatments in those centers. The release rate is considered the main outcome indicator, but other parameters such as length of stay at the center and a cost-benefit index expressed as number of released animals per euro and day, could be used as reliable estimators of the rehabilitation costs...
2017: PloS One
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