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orphan diseases

Jacklyn M Nemunaitis, Ursa Brown-Glabeman, Heloisa Soares, Jessica Belmonte, Ben Liem, Itzhak Nir, Victor Phuoc, Rama R Gullapalli
Gallbladder cancer is a rare malignancy of the biliary tract with a poor prognosis, frequently presenting at an advanced stage. While rare in the United States overall, gallbladder cancer has an elevated incidence in geographically distinct locations of the globe including Chile, North India, Korea, Japan and the state of New Mexico in the United States. People with Native American ancestry have a much elevated incidence of gallbladder cancer compared to Hispanic and non-Hispanic white populations of New Mexico...
June 18, 2018: BMC Cancer
Vera Buchele, Benjamin Abendroth, Maike Büttner-Herold, Tina Vogler, Johanna Rothamer, Sakhila Ghimire, Evelyn Ullrich, Ernst Holler, Markus F Neurath, Kai Hildner
Intestinal graft-versus-host disease (GvHD) is a life-threatening, inflammatory donor T cell-mediated complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the light of the reported efficacy of interleukin-23 (IL-23)-blockade to mitigate syngeneic intestinal inflammation in inflammatory bowel disease patients, targeting IL-23 and thereby interleukin-17a (IL-17a) producing T helper (Th17) cells as the T cell subset assumed to be mostly regulated by IL-23, has emerged as a putatively general concept to harness immune-mediated mucosal inflammation irrespective of the underlying trigger...
2018: Frontiers in Immunology
Ann Christin Reiersølmoen, Jin Han, Eirik Sundby, Bård Helge Hoff
Inhibiting the interleukin 17 pathway is of interest in a number of autoimmune diseases. Herein, 42 fused pyrimidines have been evaluated as interleukin 17 secretion inhibitors using a phenotypic assay with peripheral blood mononuclear cells. 7H-Pyrrolo [2,3-d]pyrimidin-4-amines having aryl groups at C-5 or C-6 were found more active than the corresponding thieno- and furopyrimidines. Low cytotoxicity was seen for the most active inhibitors. However, the pyrrolopyrimidines also inhibit interleukin 5 secretion, suggesting that selective interleukin 17 inhibitors should rather be based on furopyrimidines...
June 14, 2018: European Journal of Medicinal Chemistry
Jinshuo Fan, Zhilei Lv, Guanghai Yang, Ting Ting Liao, Juanjuan Xu, Feng Wu, Qi Huang, Mengfei Guo, Guorong Hu, Mei Zhou, Limin Duan, Shuqing Liu, Yang Jin
Retinoic acid receptor-related orphan receptors (RORs) include RORα (NR1F1), RORβ (NR1F2), and RORγ (NR1F3). These receptors are reported to activate transcription through ligand-dependent interactions with co-regulators and are involved in the development of secondary lymphoid tissues, autoimmune diseases, inflammatory diseases, the circadian rhythm, and metabolism homeostasis. Researches on RORs contributing to cancer-related processes have been growing, and they provide evidence that RORs are likely to be considered as potential therapeutic targets in many cancers...
2018: Frontiers in Immunology
Clara T Schoeder, Maria Kaleta, Andhika B Mahardhika, Agnieszka Olejarz-Maciej, Dorota Łażewska, Katarzyna Kieć-Kononowicz, Christa E Müller
GPR18 is a cannabinoid-activated orphan G protein-coupled receptor (GPCR) that is selectively expressed on immune cells. Despite its significant potential as a drug target for inflammatory diseases and cancer immunotherapy, only very few GPR18 ligands have been described to date. In the present study we investigated the structure-activity relationships (SARs) of (Z)-2-(3-(4-chlorobenzyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB5, 5), the most potent GPR18 antagonist described to date...
June 1, 2018: European Journal of Medicinal Chemistry
Lipeng Tang, Xiaozhi Yang, Yongxin Liang, Hesong Xie, Zhenhua Dai, Guangjuan Zheng
Psoriasis, which is a common chronic inflammatory skin disease, endangers human health and brings about a major economic burden worldwide. To date, treatments for psoriasis remain unsatisfied because of their clinical limitations and various side effects. Thus, developing a safer and more effective therapy for psoriasis is compelling. Previous studies have explicitly shown that psoriasis is an autoimmune disease that is predominantly mediated by T helper 17 (Th17) cells, which express high levels of interleukin-17 (IL-17) in response to interleukin-23 (IL-23)...
2018: Frontiers in Immunology
Camilo Jimenez
Malignant pheochromocytomas and paragangliomas affect a very small percentage of the general population. A substantial number of these patients have a hereditary predisposition for the disease and consequently, bear the risk of developing these tumors throughout their entire lives. It is, however, unclear why some patients with no hereditary predisposition develop these tumors, which frequently share a similar molecular phenotype with their hereditary counterparts. Both hereditary and sporadic tumors usually appear at an early age, and affected people often die before reaching their expected lifespans...
2018: Frontiers in Endocrinology
Arezou Sayad, Tayyebali Salmani, Maryam Kazemzadeh Hemmesi, Maziar Ganji, Soudeh Ghafouri-Fard, Mahsa Hatami, Mohammad Soudyab, Mohammad Taheri
Multiple sclerosis (MS) is an autoimmune disease characterized by recurrent episodes of demyelination and loss of oligodendrocytes. The demyelination process is caused by various subsets of CD4+ T cells with a Th1 and Th17 phenotype. The retinoid acid-related orphan receptor A (RORA) is expressed in Th17 cells and promote Th17 differentiation. In this study, we compared the expression level of RORA gene in the blood of 50 relapsing-remitting MS (RRMS) patients who were treated with IFN-β and 50 healthy controls by TaqMan Quantitative Real-Time PCR...
May 25, 2018: Human Antibodies
Ricardo Villares, Gabriel Criado, Yasmina Juarranz, Mercedes Lopez-Santalla, Eva M García-Cuesta, José M Rodríguez-Frade, Javier Leceta, Pilar Lucas, José Luis Pablos, Carlos Martínez-A, Marina I Garin, Rosa P Gomariz, Mario Mellado
Evidence indicates an intimate connection between the neuroendocrine and the immune systems. A number of in vitro and in vivo studies have demonstrated growth hormone (GH) involvement in immune regulation. The GH receptor is expressed by several leukocyte subpopulations, and GH modulates immune cell proliferation and activity. Here, we found that sustained GH expression protected against collagen-induced arthritis (CIA); in GH-transgenic C57BL/6 (GHTg) mice, disease onset was delayed, and its overall severity was decreased...
2018: Frontiers in Immunology
Rong Ou, Yueming Shen, Ya Zeng, Lingzhi Zou, Na Jiang, Meihua Xu
To explore the role of Pim-1 in the pathology of inflammatory bowel disease and the potential effect of Pim-1 inhibitor on treating such disease.
 Methods: Forty-five BALB/c mice were randomly divided into 5 groups (n=9): A normal control group, a inflammatory bowel disease group, two different dose of Pim-1 inhibitor treatment groups, and steroidhormone treatment group. The model of inflammatory bowel disease was induced by intracolonic administration of 2, 4, 6-trinitrobenzenestdfonic acid (TNBS) and ethanol mixture...
May 28, 2018: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
Mariana Fuertes, Julieta Tkatch, Josefina Rosmino, Leandro Nieto, Mirtha Adriana Guitelman, Eduardo Arzt
Cushing's disease (CD) is an endocrine disorder originated by a corticotroph tumor. It is linked with high mortality and morbidity due to chronic hypercortisolism. Treatment goals are to control cortisol excess and achieve long-term remission, therefore, reducing both complications and patient's mortality. First-line of treatment for CD is pituitary's surgery. However, 30% of patients who undergo surgery experience recurrence in long-term follow-up. Persistent or recurrent CD demands second-line treatments, such as pituitary radiotherapy, adrenal surgery, and/or pharmacological therapy...
2018: Frontiers in Endocrinology
Mingsheng Qi, Wenguang Zheng, Xuefeng Zhao, Jessica D Hohenstein, Yuba Kandel, Seth O'Conner, Yifan Wang, Chuanlong Du, Dan Nettleton, Gustavo C MacIntosh, Gregory L Tylka, Eve Syrkin Wurtele, Steven A Whitham, Ling Li
Enhancing the nutritional quality and disease resistance of crops without sacrificing productivity is a key issue for developing varieties that are valuable to farmers and for simultaneously improving food security and sustainability. Expression of the Arabidopsis thaliana species-specific AtQQS (Qua-Quine Starch) orphan gene or its interactor, NF-YC4 (Nuclear Factor Y, subunit C4), has been shown to increase levels of leaf/seed protein without affecting the growth and yield of agronomic species. Here, we demonstrate that overexpression of AtQQS and NF-YC4 in Arabidopsis and soybean enhances resistance/reduces susceptibility to viruses, bacteria, fungi, aphids, and soybean cyst nematodes...
June 7, 2018: Plant Biotechnology Journal
Paola Monari, Ruggero Moro, Alberico Motolese, Cosimo Misciali, Carlotta Baraldi, Pier Alessandro Fanti, Stefano Caccavale, Mario Puviani, Daniela Olezzi, Pierfrancesco Zampieri, Giusto Trevisan, Katiuscia Nan, Chiara Fiorentini, Giovanni Pellacani, Giulio Gualdi
Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterised by painful, necrotic ulcerations. PG is described as a rare disease: the world-wide incidence is estimated to be around 3 to 10 cases per million population per year. These estimations are based mostly on case reports and retrospective case series; there are no prospective, multicentre studies on the matter. The apparent rarity of PG is in contrast with our clinical perception as dermatologists: in our opinion, PG is not so uncommon. Therefore, we decide to investigate the epidemiology of PG in the Italian population and confirm our clinical suspicions that it is not an orphan disease...
June 6, 2018: International Wound Journal
Matthias Zielonka, Sven F Garbade, Stefan Kölker, Georg F Hoffmann, Markus Ries
PURPOSE: Quantitative definition of the natural history of free sialic acid storage disease (SASD, OMIM 604369), an orphan disorder due to the deficiency of the proton-driven carrier SLC17A5. METHODS: Analysis of published cases with SASD (N = 116) respecting STROBE criteria. MAIN OUTCOME PARAMETERS: survival and diagnostic delay. Phenotype, phenotype-biomarker associations, and geographical patient distribution were explored. RESULTS: Median age at disease onset was 0...
June 6, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Iraj Daizadeh
BACKGROUND: FDA expedited program designations (EPDs) are intended to facilitate drug development for serious conditions with an unmet medical need. There are over 10 FDA-approved therapies for the rare disease pulmonary arterial hypertension (PAH). This work investigates the landscape of EPDs in the context of FDA-approved PAH therapies in order to inform on future drug development. METHODS: The publicly available FDA Action Package (AP) was manually culled for information related to EPDs for 10 FDA-approved treatments for PAH...
January 1, 2018: Therapeutic Innovation & Regulatory Science
Ryokichi Koyama, Yasunori Fukuda, Yusuke Kamada, Hideyuki Nakagawa, Darbi Witmer, Geza Ambrus-Aikelin, Bi-Ching Sang, Masaharu Nakayama, Hidehisa Iwata
The retinoic acid-related orphan receptor gamma T (RORγt) plays an important role in Th17 cell proliferation and functionality. Thus, RORγt inverse agonists are thought to be potent therapeutic agents for Th17-mediated autoimmune diseases, such as rheumatoid arthritis, asthma, inflammatory bowel disease, and psoriasis. Although RORγt has constitutive activity, it is recognized that the receptor is physiologically regulated by various cholesterol derivatives. In this study, we sought to identify RORγt inverse agonists through a high-throughput screening campaign...
June 6, 2018: Assay and Drug Development Technologies
Maryam F Afzali, Katriana A Popichak, Lindsey H Burton, Anna L Klochak, William J Wilson, Stephen Safe, Ronald B Tjalkens, Marie E Legare
The progression of rheumatoid arthritis involves the thickening of the synovial lining due to the proliferation of fibroblast-like synoviocytes (FLS) and infiltration by inflammatory cells. Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine involved in progression of the disease. Under rheumatoid conditions, FLS express the tumor necrosis factor (TNF)-recognition complex (TNFR1, TNFR2, VCAM-1 and ICAM-1), which induces local macrophage activation and leads to downstream nuclear factor κB (NF-κB) signaling...
June 2, 2018: Molecular Immunology
Irene Reyes-Resina, Gemma Navarro, David Aguinaga, Enric I Canela, Clara T Schoeder, Michal Zaluski, Katarzyna Kiec-Kononowicz, Carlos A Saura, Christa E Müller, Rafael Franco
GPR18, still considered an orphan receptor, may respond to endocannabinoids, whose canonical receptors are CB1 and CB2 . GPR18 and CB2 receptors share a role in peripheral immune response regulation and are co-expressed in microglia, which are immunocompetent cells in the central nervous system (CNS). We aimed at identifying heteroreceptor complexes formed by GPR18 and CB1 R or CB2 R in resting and activated microglia. Receptor-receptor interaction was assessed using energy-transfer approaches, and receptor function by determining cAMP levels and ERK1/2 phosphorylation in heterologous cells and primary cultures of microglia...
June 2, 2018: Biochemical Pharmacology
Nieves Álvarez, Amelia González
No abstract text is available yet for this article.
July 2018: European Journal of Anaesthesiology
Concezione Tommasino, Maura Albicini
No abstract text is available yet for this article.
July 2018: European Journal of Anaesthesiology
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