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https://www.readbyqxmd.com/read/28647377/establishing-rarity-in-the-context-of-orphan-medicinal-product-designation-in-the-european-union
#1
REVIEW
Stelios Tsigkos, Matthias Hoffer, Maria Sheean, Segundo Mariz, Kristina Larsson, Frauke Naumann-Winter, Laura Fregonese, Bruno Sepodes
In the European Union (EU) legislative framework for orphan medicinal product designation, establishing that a condition affects not more than five in 10 000 people is a prerequisite for applications based on rarity. Demonstrating this requirement to the Committee of Orphan Medicinal Products (COMP) can be a particularly challenging task for sponsors. Here, we identify and examine three common issues with the estimation of prevalence in orphan drug applications in the EU (the discernment between diagnosed and undiagnosed cases; the duration of the disease; and the need for an explicit contemporary conclusion) as critical factors for acceptable prevalence estimation...
June 21, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28646017/ror%C3%AE-modulates-semaphorin-3e-transcription-and-neurovascular-interaction-in-pathological-retinal-angiogenesis
#2
Ye Sun, Chi-Hsiu Liu, Zhongxiao Wang, Steven S Meng, Samuel B Burnim, John Paul SanGiovanni, Theodore M Kamenecka, Laura A Solt, Jing Chen
Pathological proliferation of retinal blood vessels commonly causes vision impairment in proliferative retinopathies, including retinopathy of prematurity. Dysregulated crosstalk between the vasculature and retinal neurons is increasingly recognized as a major factor contributing to the pathogenesis of vascular diseases. Class 3 semaphorins (SEMA3s), a group of neuron-secreted axonal and vascular guidance factors, suppress pathological vascular growth in retinopathy. However, the upstream transcriptional regulators that mediate the function of SEMA3s in vascular growth are poorly understood...
June 23, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28642167/mice-lacking-gpr37-exhibit-decreased-expression-of-the-myelin-associated-glycoprotein-mag-and-increased-susceptibility-to-demyelination
#3
Brilee M Smith, Michelle M Giddens, Jessica Neil, Sharon Owino, TrangKimberly T Nguyen, Duc Duong, Fengqiao Li, Randy A Hall
GPR37 is an orphan G protein-coupled receptor that is predominantly expressed in the brain and found at particularly high levels in oligodendrocytes. GPR37 has been shown to exert effects on oligodendrocyte differentiation and myelination during development, but the molecular basis of these actions is incompletely understood and moreover nothing is known about the potential role(s) of this receptor under demyelinating conditions. To shed light on the fundamental biology of GPR37, we performed proteomic studies comparing protein expression levels in the brains of mice lacking GPR37 and its close relative GPR37-like 1 (GPR37L1)...
June 19, 2017: Neuroscience
https://www.readbyqxmd.com/read/28639105/towards-efficiency-in-rare-disease-research-what-is-distinctive-and-important
#4
REVIEW
Jinmeng Jia, Tieliu Shi
Characterized by their low prevalence, rare diseases are often chronically debilitating or life threatening. Despite their low prevalence, the aggregate number of individuals suffering from a rare disease is estimated to be nearly 400 million worldwide. Over the past decades, efforts from researchers, clinicians, and pharmaceutical industries have been focused on both the diagnosis and therapy of rare diseases. However, because of the lack of data and medical records for individual rare diseases and the high cost of orphan drug development, only limited progress has been achieved...
June 16, 2017: Science China. Life Sciences
https://www.readbyqxmd.com/read/28638936/nuclear-receptors-in-neural-stem-progenitor-cell-homeostasis
#5
REVIEW
Dimitrios Gkikas, Matina Tsampoula, Panagiotis K Politis
In the central nervous system, embryonic and adult neural stem/progenitor cells (NSCs) generate the enormous variety and huge numbers of neuronal and glial cells that provide structural and functional support in the brain and spinal cord. Over the last decades, nuclear receptors and their natural ligands have emerged as critical regulators of NSC homeostasis during embryonic development and adult life. Furthermore, substantial progress has been achieved towards elucidating the molecular mechanisms of nuclear receptors action in proliferative and differentiation capacities of NSCs...
June 21, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28637666/nr4a-orphan-nuclear-receptor-family-members-nr4a2-and-nr4a3-regulate-neutrophil-number-and-survival
#6
Lynne R Prince, Svenja Dannewitz Prosseda, Kathryn Higgins, Jennifer Carlring, Elizabeth C Prestwich, Nikolay V Ogryzko, Atiqur Rahman, Alexander Basran, Francesco Falciani, Philip Taylor, Stephen A Renshaw, Moira K B Whyte, Ian Sabroe
Neutrophil lifespan is plastic and highly responsive to factors that regulate cellular survival. Defects in neutrophil number and survival are common to both hematologic disorders and chronic inflammatory diseases. At sites of inflammation, neutrophils respond to multiple signals that activate protein kinase A (PKA) signaling, which positively regulates neutrophil survival. The aim of this study was to define transcriptional responses to PKA activation and to delineate the roles of these factors in neutrophil function and survival...
June 21, 2017: Blood
https://www.readbyqxmd.com/read/28630384/modulation-of-cd4-t-cell-subsets-by-euphorbia-microciadia-and-euphorbia-osyridea-plant-extracts
#7
Haideh Namdari, Maryam Izad, Zahra Amirghofran
BACKGROUND: Euphorbia plants are traditionally used in folk medicine for infections, inflammation, and cancer. OBJECTIVES: To investigate the effects of the butanolic extracts of Euphorbia micorociadia and Euphorbia osyridea on specific transcription factors and cytokines expression of T cell subsets. METHODS: Activated mouse splenocytes were cultured in the presence of non-cytotoxic concentrations of the extracts. Cells were evaluated for the gene expressions of T cell transcription factors and cytokines of T helper (Th)1 [T-bet and interferon gamma (IFNγ)], Th17 [retinoic acid receptor related orphan receptor (RORγt) and interleukin (IL)-17], and T regulatory (Treg) cells [forkhead box P3(Foxp3), IL-10, and Transforming growth factor (TGF)-β] using real-time PCR...
June 2017: Iranian Journal of Immunology: IJI
https://www.readbyqxmd.com/read/28629392/do-investors-value-the-fda-orphan-drug-designation
#8
Kathleen L Miller
BACKGROUND: The Orphan Drug Act is an important piece of legislation that uses financial incentives to encourage the development of drugs that treat rare diseases. This analysis studies the effects of a portion of the Orphan Drug Act, the orphan drug designation. Specifically, it studies the value that investors place on the orphan drug designation, by investigating how investors react to companies' announcing that their product has received the designation. RESULTS: The results, on average, show that the stock price of a company increases by 3...
June 19, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28627642/effect-of-retinoid-x-receptor-%C3%AE-nuclear-export-inhibition-on-apoptosis-of-neurons-in%C3%A2-vivo-and-in%C3%A2-vitro
#9
Yingchun Liu, Jiangguo Tang, Xiaoxiao Gao, Min Wang, Jie Shen, Xiaoqing You
Alzheimer's disease (AD), which is characte-rized by excessive apoptosis of neurons, is considered to be a global public health crisis. Retinoid-induced apoptosis is dependent on the orphan nuclear receptor Nur77, a transcription factor that is expressed predominantly in brain tissues. Nur77 nuclear export requires retinoid X receptor‑α (RXRα) as a carrier. However, the involvement of Nur77 in mediating β‑amyloid (Aβ)‑induced neuronal apoptosis has not yet been elucidated. The primary aim of the present study was to investigate the potential of Nur77 in Aβ‑induced neuron apoptosis, and to evaluate the effect of RXRα nuclear export inhibition on neuronal apoptosis...
June 14, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28627588/il%C3%A2-22-expression-is-increased-variedly-in-the-initial-phase-onset-and-chronic-phase-of-a-pristane%C3%A2-induced-arthritis-rat-model
#10
Weikun Hou, Bo Wang, Yan Zhou, Ke Xu, Liesu Meng, Wenhua Zhu, Congshan Jiang, Peng Xu, Shemin Lu
The aim of the present study was to investigate the expression pattern of T helper (Th) 17 and Th22 cell-related factors in a pristane‑induced arthritis (PIA) rat model. PIA rats were divided into the initial phase group [day (D) 6 post‑pristane injection], the onset of clinical arthritis group (D12), the acute arthritis group (D26) and the chronic arthritis group (D70). Rats injected with saline alone were used as the control group. The mRNA expression levels of interleukin (IL)‑17A, IL‑17F, interferon (IFN)‑γ, IL‑22, IL‑22 receptor (R) 1, IL‑22 binding protein (BP) and RAR‑related orphan receptor α were examined in the spleen and/or synovium of the various phases of PIA rats by reverse transcription‑quantitative polymerase chain reaction analysis...
June 9, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28617945/microrna-cluster-106a-363-is-involved-in-t-helper-17-th17-cell-differentiation
#11
Marc Kaestle, Sabine Bartel, Kerstin Geillinger-Kästle, Martin Irmler, Johannes Beckers, Bernhard Ryffel, Oliver Eickelberg, Susanne Krauss-Etschmann
T-helper cell 17 (Th17) mediated inflammation is associated with various diseases including autoimmune encephalitis, inflammatory bowel disease and lung diseases such as chronic obstructive pulmonary disease and asthma. Differentiation into distinct Th subtypes needs to be tightly regulated to ensure an immunological balance. As microRNAs (miRNAs) are critical regulators of signaling pathways, we aimed to identify specific miRNAs implicated in controlling Th17 differentiation. We were able to create a regulatory network model of murine Th cell differentiation by combining Affymetrix mRNA and miRNA arrays and in-silico analysis...
June 15, 2017: Immunology
https://www.readbyqxmd.com/read/28607111/a-distinct-inhibitory-function-for-mir-18a-in-th17-cell-differentiation
#12
Misty M Montoya, Julia Maul, Priti B Singh, Heather H Pua, Frank Dahlström, Nanyan Wu, Xiaozhu Huang, K Mark Ansel, Dirk Baumjohann
Th17 cell responses orchestrate immunity against extracellular pathogens but also underlie autoimmune disease pathogenesis. In this study, we uncovered a distinct and critical role for miR-18a in limiting Th17 cell differentiation. miR-18a was the most dynamically upregulated microRNA of the miR-17-92 cluster in activated T cells. miR-18a deficiency enhanced CCR6(+) RAR-related orphan receptor (ROR)γt(+) Th17 cell differentiation in vitro and increased the number of tissue Th17 cells expressing CCR6, RORγt, and IL-17A in airway inflammation models in vivo...
June 12, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28606480/sphingosine-kinase-2-in-autoimmune-inflammatory-disease-and-the-development-of-sphingosine-kinase-2-inhibitors
#13
REVIEW
Nigel J Pyne, David R Adams, Susan Pyne
The purpose of this Opinion is to present a case for targeting sphingosine kinase 2 (SK2) in autoimmune/inflammatory disease. Data obtained using Sphk2(-/-) mice suggest that SK2 is an anti-inflammatory enzyme, although this might be misleading because of a compensatory increase in the expression of a second isoform, sphingosine kinase 1 (SK1), which functions as a proinflammatory enzyme. SK2 is involved in regulating interleukin (IL)-12/interferon gamma (IFN-γ) and histone deacetylase-1/2 (HDAC-1/2) signalling and, potentially, retinoid-related orphan receptor gamma t (ROR-γt) stability linked with T helper (Th) 17 cell polarisation...
June 9, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28604565/droxidopa-for-symptomatic-neurogenic-hypotension
#14
Nadia Ferguson-Myrthil
Droxidopa is a first-in-class, orally available, synthetic amino acid precursor of norepinephrine that received accelerated Food and Drug Administration approval in February 2014 after Orphan Drug status for a debilitating condition known as symptomatic neurogenic orthostatic hypotension. Neurogenic disorders often lead to postural hypotension as a result of poor norepinephrine release from its storage sites. Clinical data suggest increases in standing systolic blood pressure and improvements in many other markers for subjective relief in patients with symptomatic neurogenic hypotension who received droxidopa therapy over 1-2 weeks...
May 4, 2017: Cardiology in Review
https://www.readbyqxmd.com/read/28603679/galactosialidosis-historic-aspects-and-overview-of-investigated-and-emerging-treatment-options
#15
Ida Annunziata, Alessandra d'Azzo
INTRODUCTION: Galactosialidosis is a glycoprotein storage disease caused by mutations in the CTSA gene, encoding lysosomal protective protein/cathepsin A (PPCA). The enzyme's catalytic activity is distinct from its protective function towards β-galactosidase (β-GAL) and neuraminidase 1 (NEU1), with which PPCA forms a complex. In this configuration the two glycosidases acquire their full activity and stability in lysosomes. Deficiency of PPCA results in combined NEU1/β-GAL deficiency...
2017: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/28591094/non-clear-cell-renal-cell-carcinomas-biological-insights-and-therapeutic-challenges-and-opportunities
#16
Gabriel G Malouf, Richard W Joseph, Amishi Y Shah, Nizar M Tannir
The non-clear cell renal cell carcinomas (nccRCCs) are a diverse group of rare-variant renal carcinomas. Each subtype harbors a distinct cell of origin and exhibits a distinct clinical behavior and response to therapy. The advent of next-generation sequencing has drastically advanced our understanding of key genetic and epigenetic drivers in these tumors, although mechanistic studies are needed to elucidate pathogenesis. The only 2 randomized clinical trials in nccRCC included patients with diverse histologic subtypes...
May 2017: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/28579852/treatment-of-myelofibrosis-old-and-new-strategies
#17
REVIEW
Alessandra Iurlo, Daniele Cattaneo
Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm that is mainly characterised by reactive bone marrow fibrosis, extramedullary haematopoiesis, anaemia, hepatosplenomegaly, constitutional symptoms, leukaemic progression, and shortened survival. As such, this malignancy is still orphan of curative treatments; indeed, the only treatment that has a clearly demonstrated impact on disease progression is allogeneic haematopoietic stem cell transplantation, but only a minority of patients are eligible for such intensive therapy...
2017: Clinical Medicine Insights. Blood Disorders
https://www.readbyqxmd.com/read/28578255/development-and-validation-of-an-ultra-performance-liquid-chromatography-tandem-mass-spectrometry-method-for-quantification-of-sr1001-an-inverse-agonist-of-retinoid-related-orphan-receptors-and-its-application-to-pharmacokinetic-studies-in-streptozotocin-induced
#18
Cuipei Lin, Hanqing Wang, Hua Sun, Chengju Xiao, Yunxia Xue, Jun Liu, Ting Fu, Yifei Wang, Dong Dong, Zhijie Li
Retinoic acid receptor-related orphan receptors (RORs) play critical roles in the onset and progression of type I diabetes, an autoimmune disease characterized by the destruction of pancreatic β-cells. SR1001, an ROR inverse agonist, has been proven to be an effective diabetes treatment in the non-obese diabetic (NOD) mouse model. However, optimization of this treatment is challenging because knowledge of SR1001 pharmacokinetic (PK) behaviors in type I diabetic animals is limited. The aim of our study was to develop and validate a specific and sensitive ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to measure the concentrations of SR1001 in plasma and biological samples...
May 24, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28571738/gpr3-and-gpr6-novel-molecular-targets-for-cannabidiol
#19
Alyssa S Laun, Zhao-Hui Song
GPR3 and GPR6 are members of a family of constitutively active, Gs protein-coupled receptors. Previously, it has been reported that GPR3 is involved in Alzheimer's disease whereas GPR6 plays potential roles in Parkinson's disease. GPR3 and GPR6 are considered orphan receptors because there are no confirmed endogenous agonists for them. However, GPR3 and GPR6 are phylogenetically related to the cannabinoid receptors. In this study, the activities of endocannabinoids and phytocannabinoids were tested on GPR3 and GPR6 using a β-arrestin2 recruitment assay...
May 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28571491/insights-into-unbound-bound-states-of-gpr142-receptor-in-a-membrane-aqueous-system-using-molecular-dynamics-simulations
#20
Aman Chandra Kaushik, Shakti Sahi
G protein coupled receptors (GPCRs) are source machinery in signal transduction pathways and being one of the major therapeutic targets play a significant in drug discovery. GPR142, an orphan GPCR, has been implicated in the regulation of insulin, thereby having a crucial role in Type II diabetes management. Deciphering of the structures of orphan GPCRs (O-GPCRs) offer better prospects for advancements in research in ion translocation and transduction of extracellular signals. As the crystallographic structure of GPR142 is not available in PDB, therefore, threading and abinitio based approaches were used for 3D modeling of GPR142...
June 1, 2017: Journal of Biomolecular Structure & Dynamics
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