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https://www.readbyqxmd.com/read/27919403/trace-amine-associated-receptor-1-agonists-as-narcolepsy-therapeutics
#1
Sarah W Black, Michael D Schwartz, Tsui-Ming Chen, Marius C Hoener, Thomas S Kilduff
BACKGROUND: Narcolepsy, a disorder of rapid eye movement (REM) sleep, is characterized by excessive daytime sleepiness and cataplexy, a loss of muscle tone triggered by emotional stimulation. Current narcolepsy pharmacotherapeutics include controlled substances with abuse potential or drugs with undesirable side effects. As partial agonists at trace amine-associated receptor 1 (TAAR1) promote wakefulness in mice and rats, we evaluated whether TAAR1 agonism had beneficial effects in two mouse models of narcolepsy...
October 18, 2016: Biological Psychiatry
https://www.readbyqxmd.com/read/27917083/practical-concerns-and-controversies-in-the-management-of-alcoholic-hepatitis
#2
Gene Y Im, Michael R Lucey
Recent advances in the treatment of alcoholic hepatitis (AH) have reinforced the utility of glucocorticoids, a treatment that has been in use for nearly 4 decades, to enhance short-term survival. As multi-institutional consortia research new therapeutic advances, this orphan disease, which afflicts younger patients and has poor outcomes, continues to be difficult to manage. AH has a protean clinical presentation and course, with various prediction models and treatment approaches that can challenge even experienced providers...
August 2016: Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/27914633/what-can-big-data-offer-the-pharmacovigilance-of-orphan-drugs
#3
John Price
The pharmacovigilance of drugs for orphan diseases presents problems related to the small patient population. Obtaining high-quality information on individual reports of suspected adverse reactions is of particular importance for the pharmacovigilance of orphan drugs. The possibility of mining "big data" to detect suspected adverse reactions is being explored in pharmacovigilance generally but may have limited application to orphan drugs. Sources of big data such as social media may be infrequently used as communication channels by patients with rare disease or their caregivers or by health care providers; any adverse reactions identified are likely to reflect what is already known about the safety of the drug from the network of support that grows up around these patients...
November 30, 2016: Clinical Therapeutics
https://www.readbyqxmd.com/read/27913459/children-with-rare-diseases-of-neutrophil-granulocytes-from-therapeutic-orphans-to-pioneers-of-individualized-medicine
#4
Christoph Klein
Neutrophil granulocytes are the most abundant immune cells in the blood yet the pathways orchestrating their differentiation and biological function remain incompletely understood. Studying (ultra-) rare patients with monogenetic defects of neutrophil granulocytes may open new horizons to understand basic principles of hematopoiesis and innate immunity. Here, recent insights into genetic factors controlling myelopoiesis and their more general role in biology will be presented in a clinical perspective. Advances in supportive care, first and foremost the use of recombinant human granulocyte-colony stimulating factor, has made a substantial difference for the quality of life and life expectancy of patients with congenital neutropenia (CN)...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27910955/pgc-1%C3%AE-dictates-endothelial-function-through-regulation-of-enos-expression
#5
Siobhan M Craige, Swenja Kröller-Schön, Chunying Li, Shashi Kant, Shenghe Cai, Kai Chen, Mayur M Contractor, Yongmei Pei, Eberhard Schulz, John F Keaney
Endothelial dysfunction is a characteristic of many vascular related diseases such as hypertension. Peroxisome proliferator activated receptor gamma, coactivator 1α (PGC-1α) is a unique stress sensor that largely acts to promote adaptive responses. Therefore, we sought to define the role of endothelial PGC-1α in vascular function using mice with endothelial specific loss of function (PGC-1α EC KO) and endothelial specific gain of function (PGC-1α EC TG). Here we report that endothelial PGC-1α is suppressed in angiotensin-II (ATII)-induced hypertension...
December 2, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27905482/pharmacologic-modulation-of-ror%C3%AE-t-translates-to-efficacy-in-preclinical-and-translational-models-of-psoriasis-and-inflammatory-arthritis
#6
Xiaohua Xue, Pejman Soroosh, Aimee De Leon-Tabaldo, Rosa Luna-Roman, Marciano Sablad, Natasha Rozenkrants, Jingxue Yu, Glenda Castro, Homayon Banie, Wai-Ping Fung-Leung, Luis Santamaria-Babi, Thomas Schlueter, Michael Albers, Kristi Leonard, Alison L Budelsky, Anne M Fourie
The IL-23/IL-17 pathway is implicated in autoimmune diseases, particularly psoriasis, where biologics targeting IL-23 and IL-17 have shown significant clinical efficacy. Retinoid-related orphan nuclear receptor gamma t (RORγt) is required for Th17 differentiation and IL-17 production in adaptive and innate immune cells. We identified JNJ-54271074, a potent and highly-selective RORγt inverse agonist, which dose-dependently inhibited RORγt-driven transcription, decreased co-activator binding and promoted interaction with co-repressor protein...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27904831/orphan-drug-development-in-china-turning-challenges-into-opportunities
#7
Xiaowei Jin, Li Chen
Of over 7,000 known rare diseases, only 5% currently have an available treatment option worldwide. Moreover, the vast majority of rare disease patients in China have no access to treatment due to limited availability and the lack of appropriate infrastructure in China's healthcare system. Despite increased interest in orphan drug development, drug companies in China with active programs on drugs to treat rare diseases are still limited. Hence, there is a huge unmet need in China, with over 10 million patients suffering from rare diseases...
November 2016: Intractable & Rare Diseases Research
https://www.readbyqxmd.com/read/27904685/phylogenetic-analysis-of-basic-helix-loop-helix-transcription-factors-in-the-genome-of-a-typical-human-disease-vector
#8
Meng-Yun Chen, Ying Dong, Rui-Xue Chang, Qian-Qian Ang, Ran Zhang, Yan-Yan Wu, Yi-Hui Xu, Wen-Sheng Lu, Xiao-Dong Zheng
Ixodes scapularis, the black-legged tick, is one of the most common human-disease vectors and transmits Borrelia species, such as B. burgdorferi, as well as Theileria microti, Anaplasma phagocytophilum, etc. As basic helix-loop-helix (bHLH) transcription factors have been recognized for many years as important regulators of various developmental processes, we performed phylogenetic analysis of the black-legged tick genome in order to identify the number and family of bHLH transcription factors. Because bHLH family members have been identified in many organisms, including silkworm and fruit fly, we were able to conduct this survey and identify 58 putative bHLH transcription factors...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27902884/synthesis-and-biological-evaluation-of-new-triazolo-and-imidazolopyridine-ror%C3%AE-t-inverse-agonists
#9
Samuel Hintermann, Christine Guntermann, Henri Mattes, David A Carcache, Juergen Wagner, Anna Vulpetti, Andreas Billich, Janet Dawson, Klemens Kaupmann, Joerg Kallen, Rowan Stringer, David Orain
Retinoic-acid-related orphan receptor γt (RORγt) is a key transcription factor implicated in the production of pro-inflammatory Th17 cytokines, which drive a number of autoimmune diseases. Despite diverse chemical series having been reported, combining high potency with a good physicochemical profile has been a very challenging task in the RORγt inhibitor field. Based on available chemical structures and incorporating in-house knowledge, a new series of triazolo- and imidazopyridine RORγt inverse agonists was designed...
November 30, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27889907/activation-of-nur77-in-microglia-attenuates-proinflammatory-mediators-production-and-protects-dopaminergic-neurons-from-inflammation-induced-cell-death
#10
Tian-Ya Liu, Xiao-Ying Yang, Long-Tai Zheng, Guang-Hui Wang, Xue-Chu Zhen
Microglia-mediated neuroinflammation plays a critical role in the pathological development of Parkinson's disease (PD). Orphan nuclear receptor Nur77 (Nur77) is abundant in neurons, while its role in microglia-mediated neuroinflammation remains unclear. The present data demonstrated that the expression of Nur77 in microglia was reduced accompanied with microglia activation in response to lipopolysaccharide (LPS) in vitro and in experimental MPTP-PD mouse model. Nur77 overexpression or application of Nur77 agonist CsnB suppressed the expression of proinflammatory genes, such as iNOS, COX-2, IL-1β, and TNF-α in the activated microglia, while silenced Nur77 exaggerated the inflammatory responses in microglia...
November 27, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27889032/metastatic-anal-cancer-and-novel-agents
#11
REVIEW
Van Morris, Cathy Eng
Squamous cell carcinoma of the anal canal (SCCA) represents an orphan disease. Although prior infection with human papilloma virus is associated with the development of SCCA, knowledge of this relationship has proven ineffective in identifying therapeutic agents that have activity in the management of metastatic SCCA. Combination chemotherapy with traditional cytotoxic agents has demonstrated efficacy in multiple small series. However, immune checkpoint blockade agents have demonstrated efficacy for patients with refractory metastatic SCCA; these agents hold promise in the horizon for patients with metastatic SCCA...
January 2017: Surgical Oncology Clinics of North America
https://www.readbyqxmd.com/read/27888388/cardiac-bin1-cbin1-is-a-regulator-of-cardiac-contractile-function-and-an-emerging-biomarker-of-heart-muscle-health
#12
REVIEW
Kang Zhou, Tingting Hong
In recent decades, a cardiomyocyte membrane scaffolding protein bridging integrator 1 (BIN1) has emerged as a critical multifunctional regulator of transverse-tubule (t-tubule) function and calcium signaling in cardiomyocytes. Encoded by a single gene with 20 exons that are alternatively spliced, more than ten BIN1 protein isoforms are expressed with tissue and disease specificity. The recently discovered cardiac alternatively spliced isoform BIN1 (cBIN1 or BIN1+13+17) plays a crucial role in organizing membrane microfolds within cardiac t-tubules...
November 23, 2016: Science China. Life Sciences
https://www.readbyqxmd.com/read/27879179/-two-sisters-with-lung-emphysema
#13
I Piscaer, F M E Franssen, N H T Ten Hacken, E F M Wouters, R Janssen
BACKGROUND: α1-antitrypsin is an antiprotease that is mainly produced in the liver; it plays a crucial role in the protection of lung parenchyma against the destructive effects of proteases. Mutations in the α1-antitrypsin gene can cause α1-antitrypsin deficiency. Individuals homozygous for the Z-genotype have drastically lowered serum α1-antitrypsine concentrations and often develop lung emphysema at an early age. CASE DESCRIPTION: A 38-year-old woman and her 43-year-old sister both developed lung emphysema at an early age; this could be attributed to severe α1-antitrypsin deficiency...
2016: Nederlands Tijdschrift Voor Geneeskunde
https://www.readbyqxmd.com/read/27879053/n-arylsulfonyl-indolines-as-retinoic-acid-receptor-related-orphan-receptor%C3%A2-%C3%AE-ror%C3%AE-agonists
#14
Christelle Doebelin, Rémi Patouret, Ruben D Garcia-Ordonez, Mi Ra Chang, Venkatasubramanian Dharmarajan, Dana S Kuruvilla, Scott J Novick, Li Lin, Michael D Cameron, Patrick R Griffin, Theodore M Kamenecka
The nuclear retinoic acid receptor-related orphan receptor γ (RORγ; NR1F3) is a key regulator of inflammatory gene programs involved in T helper 17 (TH 17) cell proliferation. As such, synthetic small-molecule repressors (inverse agonists) targeting RORγ have been extensively studied for their potential as therapeutic agents for various autoimmune diseases. Alternatively, enhancing TH 17 cell proliferation through activation (agonism) of RORγ may boost an immune response, thereby offering a potentially new approach in cancer immunotherapy...
December 6, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27871853/nur77-downregulation-triggers-pulmonary-artery-smooth-muscle-cell-proliferation-and-migration-in-mice-with-hypoxic-pulmonary-hypertension-via-the-axin2-%C3%AE-catenin-signaling-pathway
#15
Xiaowei Nie, Jianxin Tan, Youai Dai, Wenjun Mao, Yuan Chen, Guowei Qin, Guirong Li, Chenyou Shen, Jingjing Zhao, Jingyu Chen
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by remodeling of the pulmonary vasculature, including marked proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Members of the nuclear receptor 4A (NR4A) subfamily are involved in a variety of biological events, such as cell apoptosis, proliferation, inflammation, and metabolism. Activation of Nur77 (an orphan nuclear receptor that belongs to NR4A subfamily) has recently been reported to be as a beneficial agent in the treatment of cardiovascular and metabolic diseases...
November 15, 2016: Vascular Pharmacology
https://www.readbyqxmd.com/read/27857828/determining-the-value-of-medical-technologies-to-treat-ultra-rare-disorders-a-consensus-statement
#16
Michael Schlander, Silvio Garattini, Peter Kolominsky-Rabas, Erik Nord, Ulf Persson, Maarten Postma, Jeff Richardson, Steven Simoens, Oriol de Solà-Morales, Keith Tolley, Mondher Toumi
BACKGROUND: In most jurisdictions, policies have been adopted to encourage the development of treatments for rare or orphan diseases. While successful as assessed against their primary objective, these policies have prompted concerns among payers about the economic burden that might be caused by an annual cost per patient in some cases exceeding 100,000 Euro. At the same time, many drugs for rare disorders do not meet conventional standards for cost-effectiveness or 'value for money'...
2016: Journal of Market Access & Health Policy
https://www.readbyqxmd.com/read/27843450/elder-orphans-hiding-in-plain-sight-a-growing-vulnerable-population
#17
Maria T Carney, Janice Fujiwara, Brian E Emmert, Tara A Liberman, Barbara Paris
Adults are increasingly aging alone with multiple chronic diseases and are geographically distant from family or friends. It is challenging for clinicians to identify these individuals, often struggling with managing the growing difficulties and the complexities involved in delivering care to this population. Clinicians often may not recognize or know how to address the needs that these patients have in managing their own health. While many such patients function well at baseline, the slightest insult can initiate a cascade of avoidable negative events...
2016: Current Gerontology and Geriatrics Research
https://www.readbyqxmd.com/read/27830715/novel-agonist-bioisosteres-and-common-structure-activity-relationships-for-the-orphan-g-protein-coupled-receptor-gpr139
#18
Mohamed A Shehata, Anne C Nøhr, Delphine Lissa, Christoph Bisig, Vignir Isberg, Kirsten B Andersen, Kasper Harpsøe, Fredrik Björkling, Hans Bräuner-Osborne, David E Gloriam
GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression levels in the hypothalamus and striatum, regions regulating metabolism and locomotion, respectively, and has therefore been suggested as a potential target for obesity and Parkinson's disease. The two aromatic amino acids L-Trp and L-Phe have been proposed as putative endogenous agonists, and three structurally related benzohydrazide, glycine benzamide, and benzotriazine surrogate agonist series have been published...
November 10, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27825463/preclinical-models-of-waldenstr%C3%A3-m-s-macroglobulinemia-and-drug-resistance
#19
REVIEW
Sikander Ailawadhi, Aneel Paulus, Asher Chanan-Khan
Newer therapeutic strategies are emerging in Waldenström's Macroglobulinemia (WM), which has traditionally been an orphan disease diagnosis. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor was FDA-approved in 2015 as the first ever drug for the treatment of WM. This being a targeted therapy, has given rise to increased research into novel agents and pathways that can be exploited for clinical benefit in WM. In order to understand the underlying mechanisms of disease behavior as well as to test the benefit of various drugs, appropriate preclinical models are required...
June 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27816107/carbohydrate-processing-enzymes-of-the-lysosome-diseases-caused-by-misfolded-mutants-and-sugar-mimetics-as-correcting-pharmacological-chaperones
#20
Arnold E Stütz, Tanja M Wrodnigg
Lysosomal storage diseases are hereditary disorders caused by mutations on genes encoding for one of the more than fifty lysosomal enzymes involved in the highly ordered degradation cascades of glycans, glycoconjugates, and other complex biomolecules in the lysosome. Several of these metabolic disorders are associated with the absence or the lack of activity of carbohydrate-processing enzymes in this cell compartment. In a recently introduced therapy concept, for susceptible mutants, small substrate-related molecules (so-called pharmacological chaperones), such as reversible inhibitors of these enzymes, may serve as templates for the correct folding and transport of the respective protein mutant, thus improving its concentration and, consequently, its enzymatic activity in the lysosome...
2016: Advances in Carbohydrate Chemistry and Biochemistry
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