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https://www.readbyqxmd.com/read/29345621/the-circulating-t-helper-subsets-and-regulatory-t-cells-in-patients-with-common-variable-immunodeficiency-with-no-known-monogenic-disease
#1
G Azizi, A Mirshafiey, H Abolhassani, R Yazdani, F J Ansariha, M Shaghaghi, S S Mortazavi-Jahromi, F Noorbakhsh, N Rezaei, A Aghamohammadi
BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency (PID), characterized by heterogeneous clinical manifestations and defects in B- and T- cells. In the present study, we investigated the T helper (Th) cell subsets and regulatory T (Treg) cells, and their related cytokines and transcription factors in the CVID patients with no definite genetic diagnosis. METHODS: The study population comprised 13 CVID patients and 13 healthy controls (HC)...
January 18, 2018: Journal of Investigational Allergology & Clinical Immunology
https://www.readbyqxmd.com/read/29342416/identification-of-novel-quinazolinedione-derivatives-as-ror%C3%AE-t-inverse-agonist
#2
Yoshiyuki Fukase, Ayumu Sato, Yoshihide Tomata, Atsuko Ochida, Mitsunori Kono, Kazuko Yonemori, Keiko Koga, Toshitake Okui, Masashi Yamasaki, Yasushi Fujitani, Hideyuki Nakagawa, Ryoukichi Koyama, Masaharu Nakayama, Robert Skene, Bi-Ching Sang, Isaac Hoffman, Junya Shirai, Satoshi Yamamoto
Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity...
December 28, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29327657/rare-disease-prevention-and-treatment-the-need-for-a-level-playing-field
#3
Dyfrig A Hughes, Catrin O Plumpton
Pharmacogenetic tests are being used increasingly to prevent rare and potentially life-threatening adverse drug reactions. For many tests, however, cost-effectiveness is hard to demonstrate, and with the exception of a few cases, widespread implementation remains a distant prospect. Many orphan drugs for rare diseases are also not cost effective but are nonetheless normally reimbursed. In this article, we argue that the health technology assessment of pharmacogenetic tests aimed to prevent rare but severe adverse drug reactions should be on a level playing field with orphan drugs...
January 12, 2018: Pharmacogenomics
https://www.readbyqxmd.com/read/29327456/discovery-and-characterization-of-cd12681-a-potent-ror%C3%AE-inverse-agonist-preclinical-candidate-for-the-topical-treatment-of-psoriasis
#4
Gilles Ouvry, Nicolas Atrux-Tallau, Franck Bihl, Aline Bondu, Claire Bouix-Peter, Isabelle Carlavan, Olivier Christin, Marie-Josée Cuadrado, Claire Defoin-Platel, Sophie Deret, Denis Duvert, Christophe Feret, Mathieu Forissier, Jean-François Fournier, David Froude, Fériel Hacini-Rachinel, Craig Steven Harris, Catherine Hervouet, Hélène Huguet, Guillaume Lafitte, Anne-Pascale Luzy, Branislav Musicki, Danielle Orfila, Benjamin Ozello, Coralie Pascau, Jonathan Pascau, Véronique Parnet, Guillaume Peluchon, Romain Pierre, David Piwnica, Catherine Raffin, Patricia Rossio, Delphine Spiesse, Nathalie Taquet, Etienne Thoreau, Rodolphe Vatinel, Emmanuel Vial, Laurent François Hennequin
With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a very sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated with the discovery of CD12681 (compound 14; N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide), a potent inverse agonist with in vivo activity in an IL-23 induced skin inflammation model in mouse...
January 12, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29315288/the-promise-of-immunotherapy-in-anal-squamous-cell-carcinoma-a-novel-approach-for-an-orphan-disease
#5
Benny Johnson, Cathy Eng
An estimated 8200 men and women in the United States will receive a diagnosis of squamous cell carcinoma of the anal canal (SCCA) in 2017. Although SCCA is rare, accounting for 2.6% of gastrointestinal cancers, its incidence rate has been steadily increasing over the last few decades in the United States and around the world. More than 90% of cases of SCCA occur in the context of prior human papillomavirus (HPV) infection. To date, preventive vaccinations against HPV remain markedly underutilized. Most patients who have SCCA present with locoregional disease that is cured with chemoradiation...
December 2017: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/29310675/failure-to-shorten-the-diagnostic-delay-in-two-ultra-orphan-diseases-mucopolysaccharidosis-types-i-and-iii-potential-causes-and-implications
#6
Gé-Ann Kuiper, Olga L M Meijer, Eveline J Langereis, Frits A Wijburg
BACKGROUND: Rare diseases are often un- or misdiagnosed for extended periods, resulting in a long diagnostic delay that may significantly add to the burden of the disease. An early diagnosis is particularly essential if a disease-modifying treatment is available. The purpose of this study was to assess the extent of the diagnostic delay in the two ultra-rare diseases, i.e., mucopolysaccharidosis I (MPS I) and III (MPS III), both of which are lysosomal storage disorders with different phenotypic severities (MPS 1 is characterized by the severe Hurler and the more attenuated non-Hurler phenotypes, MPS III is characterized by the severe rapidly progressing (RP) phenotype and more attenuated slowly progressing (SP) phenotype)...
January 8, 2018: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/29301098/an-antimicrobial-peptide-and-its-neuronal-receptor-regulate-dendrite-degeneration-in-aging-and-infection
#7
Lezi E, Ting Zhou, Sehwon Koh, Marian Chuang, Ruchira Sharma, Nathalie Pujol, Andrew D Chisholm, Cagla Eroglu, Hiroaki Matsunami, Dong Yan
Infections have been identified as possible risk factors for aging-related neurodegenerative diseases, but it remains unclear whether infection-related immune molecules have a causative role in neurodegeneration during aging. Here, we reveal an unexpected role of an epidermally expressed antimicrobial peptide, NLP-29 (neuropeptide-like protein 29), in triggering aging-associated dendrite degeneration in C. elegans. The age-dependent increase of nlp-29 expression is regulated by the epidermal tir-1/SARM-pmk-1/p38 MAPK innate immunity pathway...
January 3, 2018: Neuron
https://www.readbyqxmd.com/read/29299833/engagement-of-canadian-patients-with-rare-diseases-and-their-families-in-the-lifecycle-of-therapy-a-qualitative-study
#8
Andrea Young, Devidas Menon, Jackie Street, Walla Al-Hertani, Tania Stafinski
INTRODUCTION: Patient involvement is increasingly recognized as critical to the development, introduction and use (i.e. the lifecycle) of new and effective therapies, particularly those for rare diseases, where natural histories and the impact on patients and families are less well-understood than for common diseases. However, little is known about how patients and families would like to be involved during the lifecycle. OBJECTIVE: The aim of this study was to explore ways in which Canadian patients with rare diseases and their families would like to be involved in the lifecycle of therapies and identify their priorities for involvement...
January 3, 2018: Patient
https://www.readbyqxmd.com/read/29298833/production-of-il-17-by-mait-cells-is-increased-in-multiple-sclerosis-and-is-associated-with-il-7-receptor-expression
#9
Anne Willing, Jan Jäger, Stefanie Reinhardt, Nina Kursawe, Manuel A Friese
Multiple sclerosis (MS) is a T cell-driven inflammatory disease of the CNS. Research on T cell subsets involved in MS pathogenesis has mainly focused on classical CD4+ T cells, especially Th17 cells, as they produce the proinflammatory, MS-associated cytokine IL-17. However, the abundant unconventional mucosal-associated invariant T (MAIT) cells are also able to produce IL-17. MAIT cells are characterized by high CD161 expression and a semi-invariant Vα7.2 TCR, with which they recognize bacterial and yeast Ags derived from the riboflavin (vitamin B2) metabolism...
January 3, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29295821/anaplastic-thyroid-carcinoma-review-of-treatment-protocols
#10
Vera Tiedje, Martin Stuschke, Frank Weber, Henning Dralle, Laura Moss, Dagmar Führer
Anaplastic thyroid carcinoma (ATC) is an orphan disease and in most patients fatal. So far no established treatment is available that prolongs survival. Several large retrospective studies have identified negative prognostic markers, analyzed efficacy of multimodal approaches such as radiotherapy with and without concurrent chemotherapy and chemotherapy protocols. Recently, single case reports have suggested some effectiveness of newer therapies targeting single somatic alterations in ATC. All in all, the conclusions that can be drawn from published retrospective studies and the scarce prospective approaches is that new treatment protocols should be developed including surgery, radiotherapy, chemotherapy and targeted therapy approaches and combinational therapy with immunotherapies...
January 2, 2018: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29285097/mir-34a-and-mir-125b-are-upregulated-in-peripheral-blood-mononuclear-cells-from-patients-with-type-2-diabetes-mellitus
#11
Yanxin Shen, Huiling Xu, Xiaoyuan Pan, Weijiang Wu, Hui Wang, Linlin Yan, Miaomiao Zhang, Xia Liu, Sheng Xia, Qixiang Shao
Type 2 diabetes mellitus (T2DM) is a leading cause of blindness, non-traumatic amputation and end-stage renal disease, as well as a major cardiovascular risk factor. To determine whether miR-125b and miR-34a serve an important role in the development of T2DM, the current study investigated the expression profile of two microRNAs (miR-34a and miR-125b) and their relative genes in peripheral blood mononuclear cells from 73 patients with T2DM and 52 healthy donors by reverse transcription-quantitative polymerase chain reaction In addition, the association between miR-34a, miR-125b and their relevant genes expression profile were analyzed with respect to the pathogenesis of T2DM...
December 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29284292/the-national-rare-diseases-registry-system-nrdrs-of-china-and-the-related-cohort-studies-vision-and-roadmap
#12
Shi Feng, Shuang Liu, Chong Zhu, Mengchun Gong, Yicheng Zhu, Shuyang Zhang
Rare diseases are major challenges in healthcare and medical research and have been involved in national development strategies in many countries. However, inadequate definition of rare diseases and lags in orphan drug development in China hinder rare diseases research. The first nationwide rare diseases registry system, National Rare Diseases Registry System of China (NRDRS) has been established and various cohort studies have been launched since 2016. More than 20 top academic institutions participate in this joint effort to carry out nationwide registration of rare diseases...
December 28, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/29284076/percutaneous-hepatic-perfusion-with-melphalan-in-uveal-melanoma-a-safe-and-effective-treatment-modality-in-an-orphan-disease
#13
Ioannis Karydis, Alexandra Gangi, Matthew J Wheater, Junsung Choi, Iain Wilson, Kerry Thomas, Neil Pearce, Arjun Takhar, Sanjay Gupta, Danielle Hardman, Sean Sileno, Brian Stedman, Jonathan S Zager, Christian Ottensmeier
BACKGROUND: Metastatic uveal melanoma (UM) carries a poor prognosis; liver is the most frequent and often solitary site of recurrence. Available systemic treatments have not improved outcomes. Melphalan percutaneous hepatic perfusion (M-PHP) allows selective intrahepatic delivery of high dose cytotoxic chemotherapy. METHODS: Retrospective analysis of outcomes data of UM patients receiving M-PHP at two institutions was performed. Tumor response and toxicity were evaluated using RECIST 1...
December 28, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/29282706/the-association-of-rar-related-orphan-receptor-a-rora-gene-polymorphisms-with-the-risk-of-asthma
#14
Xulong Cai, Mali Lin, Shan Cao, Yunguang Liu, Na Lin
Asthma is a common, heterogeneous chronic respiratory disease characterized by chronic inflammation of the airway, airway hyperreactivity, and airway remodeling. The RAR-related orphan receptor A (RORA) gene has been identified for the pathogenesis of asthma. The purpose of this research was to investigate the relationship between RORA gene polymorphisms and asthma susceptibility in the Chinese Zhuang population. This was a case-control study including 231 children with asthma and 343 healthy controls. The RORA gene polymorphisms were measured by the polymerase chain reaction-ligase detection reaction genotyping assays and confirmed by sequencing...
December 28, 2017: Annals of Human Genetics
https://www.readbyqxmd.com/read/29282318/src1-promotes-th17-differentiation-by-overriding-foxp3-suppression-to-stimulate-ror%C3%AE-t-activity-in-a-pkc-%C3%AE-dependent-manner
#15
Subha Sen, Fei Wang, Jing Zhang, Zhiheng He, Jian Ma, Yousang Gwack, Jianming Xu, Zuoming Sun
Th17 cells are major players in multiple autoimmune diseases and are developmentally contingent on reciprocal functionality between the transcription factor Retineic acid receptor-related orphan nuclear receptor gamma (RORγt) and Forkhead box protein P3 (Foxp3). Here we deciphered a previously unappreciated role of Steroid receptor coactivator 1 (SRC1) in defining the lineage decision for the development of Th17 versus induced T-regulatory (iTreg) cells. We demonstrate that SRC1 functions as a critical coactivator for RORγt in vivo to promote the functional dominance of RORγt over Foxp3 and thus establishing an unopposed Th17 differentiation program...
December 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29275836/a-cellular-and-molecular-view-of-t-helper-17%C3%A2-cell-plasticity-in-autoimmunity
#16
REVIEW
Ralph Stadhouders, Erik Lubberts, Rudi W Hendriks
Since the original identification of the T helper 17 (Th17) subset in 2005, it has become evident that these cells do not only contribute to host defence against pathogens, such as bacteria and fungi, but that they are also critically involved in the pathogenesis of many autoimmune diseases. In contrast to the classic Th1 and Th2 cells, which represent rather stably polarized subsets, Th17 cells display remarkable heterogeneity and plasticity. This has been attributed to the characteristics of the key transcription factor that guides Th17 differentiation, retinoic acid receptor-related orphan nuclear receptor gamma (RORγ)...
December 21, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/29274233/efficacy-of-anti-pd-1-on-skin-carcinomas-and-melanoma-metastases-in-an-xeroderma-pigmentosum-patient
#17
G Salomon, A Maza, S Boulinguez, C Paul, L Lamant, E Tournier, J Mazereeuw-Hautier, N Meyer
Xeroderma pigmentosum is an orphan disease of poor prognosis. We report one case of parallel efficacy with anti-PD-1 antibody on both melanoma and skin carcinoma in a xeroderma pigmentosum patient. A 17-year old patient presented with metastatic melanoma and multiple non melanoma skin cancers. He was treated with pembrolizumab, a monoclonal anti-PD-1 antibody, at the dose of 2mg/Kg 3 weeks apart. Parallel therapeutic efficacy of anti-PD1 was observed in metastatic melanoma and skin carcinomas, and maintained at week 24...
December 23, 2017: British Journal of Dermatology
https://www.readbyqxmd.com/read/29273068/exploring-patient-and-family-involvement-in-the-lifecycle-of-an-orphan-drug-a-scoping-review
#18
REVIEW
Andrea Young, Devidas Menon, Jackie Street, Walla Al-Hertani, Tania Stafinski
BACKGROUND: Patients and their families have become more active in healthcare systems and research. The value of patient involvement is particularly relevant in the area of rare diseases, where patients face delayed diagnoses and limited access to effective therapies due to the high level of uncertainty in market approval and reimbursement decisions. It has been suggested that patient involvement may help to reduce some of these uncertainties. This review explored existing and proposed roles for patients, families, and patient organizations at each stage of the lifecycle of therapies for rare diseases (i...
December 22, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/29258712/discovery-of-orally-efficacious-ror%C3%AE-t-inverse-agonists-part-2-design-synthesis-and-biological-evaluation-of-novel-tetrahydroisoquinoline-derivatives
#19
Mitsunori Kono, Tsuneo Oda, Michiko Tawada, Takashi Imada, Yoshihiro Banno, Naohiro Taya, Tetsuji Kawamoto, Hidekazu Tokuhara, Yoshihide Tomata, Naoki Ishii, Atsuko Ochida, Yoshiyuki Fukase, Tomoya Yukawa, Shoji Fukumoto, Hiroyuki Watanabe, Keiko Uga, Akira Shibata, Hideyuki Nakagawa, Mikio Shirasaki, Yasushi Fujitani, Masashi Yamasaki, Junya Shirai, Satoshi Yamamoto
A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile...
December 11, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29237557/erepo-orp-exploring-the-opportunity-space-to-combat-orphan-diseases-with-existing-drugs
#20
Michal Brylinski, Misagh Naderi, Rajiv Gandhi Govindaraj, Jeffrey Lemoine
About 7000 rare, or orphan, diseases affect more than 350 million people worldwide. Although these conditions collectively pose significant health care problems, drug companies seldom develop drugs for orphan diseases due to extremely limited individual markets. Consequently, developing new treatments for often life-threatening orphan diseases is primarily contingent on financial incentives from governments, special research grants, and private philanthropy. Computer-aided drug repositioning is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research...
December 10, 2017: Journal of Molecular Biology
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