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https://www.readbyqxmd.com/read/29342921/rna-targeted-therapies-and-amyotrophic-lateral-sclerosis
#1
REVIEW
Stéphane Mathis, Gwendal Le Masson
Amyotrophic lateral sclerosis (ALS) is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS...
January 15, 2018: Biomedicines
https://www.readbyqxmd.com/read/29331501/incorporating-upper-motor-neuron-health-in-als-drug-discovery
#2
REVIEW
Ina Dervishi, P Hande Ozdinler
Amyotrophic lateral sclerosis (ALS) is a complex disease, affecting the motor neuron circuitry. After consecutive failures in clinical trials for the past 20 years, edaravone was recently approved as the second drug for ALS. This generated excitement in the field and revealed the need to improve preclinical assays for continued success. Here, we focus on the importance and relevance of upper motor neuron (UMN) pathology in ALS, and discuss how incorporation of UMN survival in preclinical assays will improve inclusion criteria for clinical trials and expedite the drug discovery effort in ALS and related motor neuron diseases...
January 10, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29331073/cerebrospinal-fluid-macrophage-biomarkers-in-amyotrophic-lateral-sclerosis
#3
A G Thompson, E Gray, M-L Thézénas, P D Charles, S Evetts, M T Hu, K Talbot, R Fischer, B M Kessler, M R Turner
Objective The neurodegenerative disease amyotrophic lateral sclerosis (ALS) is a heterogeneous clinical syndrome involving multiple molecular pathways. The development of biomarkers for use in therapeutic trials is a priority. We sought to use a high-throughput proteomic method to identify novel biomarkers in individual cerebrospinal fluid samples. Methods Liquid chromatography-tandem mass spectrometry with label-free quantification was used to identify cerebrospinal fluid proteins using samples from a well-characterised longitudinal cohort comprising patients with ALS (n=43), the upper motor neuron variant primary lateral sclerosis (PLS, n=6), cross-sectional healthy (n=20) and disease controls (Parkinsons's n=20, ALS mimic disorders n=12)...
January 13, 2018: Annals of Neurology
https://www.readbyqxmd.com/read/29315334/immune-related-genetic-enrichment-in-frontotemporal-dementia-an-analysis-of-genome-wide-association-studies
#4
Iris Broce, Celeste M Karch, Natalie Wen, Chun C Fan, Yunpeng Wang, Chin Hong Tan, Naomi Kouri, Owen A Ross, Günter U Höglinger, Ulrich Muller, John Hardy, Parastoo Momeni, Christopher P Hess, William P Dillon, Zachary A Miller, Luke W Bonham, Gil D Rabinovici, Howard J Rosen, Gerard D Schellenberg, Andre Franke, Tom H Karlsen, Jan H Veldink, Raffaele Ferrari, Jennifer S Yokoyama, Bruce L Miller, Ole A Andreassen, Anders M Dale, Rahul S Desikan, Leo P Sugrue
BACKGROUND: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. METHODS AND FINDINGS: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis...
January 2018: PLoS Medicine
https://www.readbyqxmd.com/read/29287521/could-conservative-iron-chelation-lead-to-neuroprotection-in-amyotrophic-lateral-sclerosis
#5
Caroline Moreau, Véronique Danel, Jean Christophe Devedjian, Guillaume Grolez, Kelly Timmerman, Charlotte Laloux, Maud Petrault, Flore Gouel, Aurélie Jonneaux, Mary Dutheil, Cedrick Lachaud, Renaud Lopes, Gregory Kuchinski, Florent Auger, Maeva Kyheng, Alain Duhamel, Thierry Perez, Pierre-Francois Pradat, Helene Blasco, Charlotte Veyrat-Durebex, Philippe Corcia, Patrick Oeckl, Markus Otto, Luc Dupuis, Guillaume Garçon, Luc Defebvre, Ioav Zvi Cabantchik, James Duce, Régis Bordet, David Devos
Iron accumulation has been observed in mouse models and both sporadic and familial forms of Amyotrophic lateral sclerosis. Iron chelation could reduce iron accumulation and the related excess of oxidative stress in the motor pathways. However, classical iron chelation would induce systemic iron depletion. We assess the safety and efficacy of conservative iron chelation (i.e. chelation with low risk of iron depletion) in a murine preclinical model and pilot clinical trial. In Sod1G86R mice, deferiprone increased the mean life span as compared with placebo...
December 29, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/29260911/a-retrospective-investigation-of-the-relationship-between-baseline-covariates-and-rate-of-alsfrs-r-decline-in-als-clinical-trials
#6
Iyas Daghlas, Teresa E Lever, Emily Leary
The revised ALS functional rating scale (ALSFRS-R) is a longitudinal measure of global function commonly used to assess progression of amyotrophic lateral sclerosis (ALS), and as an endpoint in ALS clinical trials. Understanding how baseline covariates affect the rate of functional decline in ALS offers valuable information to clinical trialists. We used a mixed modeling approach in a retrospective study of the pooled resource open-Access ALS clinical trials database to elucidate the associations between baseline covariates and the rate of ALSFRS-R decline over time...
December 20, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/29260584/longitudinal-modeling-to-predict-vital-capacity-in-amyotrophic-lateral-sclerosis
#7
Samad Jahandideh, Albert A Taylor, Danielle Beaulieu, Mike Keymer, Lisa Meng, Amy Bian, Nazem Atassi, Jinsy Andrews, David L Ennist
OBJECTIVES: Death in amyotrophic lateral sclerosis (ALS) patients is related to respiratory failure, which is assessed in clinical settings by measuring vital capacity. We developed ALS-VC, a modeling tool for longitudinal prediction of vital capacity in ALS patients. METHODS: A gradient boosting machine (GBM) model was trained using the PRO-ACT (Pooled Resource Open-access ALS Clinical Trials) database of over 10,000 ALS patient records. We hypothesized that a reliable vital capacity predictive model could be developed using PRO-ACT...
December 20, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/29249183/aav-gene-delivery-to-the-spinal-cord-serotypes-methods-candidate-diseases-and-clinical-trials
#8
Nathan Hardcastle, Nicholas M Boulis, Thais Federici
Adeno-associated viral (AAV) vector-mediated gene delivery to the spinal cord has finally entered the pathway towards regulatory approval. Phase 1 clinical trials using AAV gene therapy for pediatric disorders - spinal muscular atrophy (SMA) and giant axonal neuropathy (GAN) - are now underway. Areas covered: This review addresses the latest progress in the field of AAV gene delivery to the spinal cord, particularly focusing on the most prominent AAV serotypes and delivery methodologies to the spinal cord. Candidate diseases and scaling up experiments in large animals are also discussed...
December 18, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29244213/trajectories-of-impairment-in-als-insights-from-the-pro-act-cohort
#9
Nimish J Thakore, Brittany R Lapin, Erik P Pioro
INTRODUCTION: Rate of decline of the revised ALS functional rating scale (ALSFRS-R) is a common outcome measure and a powerful predictor of mortality in amyotrophic lateral sclerosis (ALS). METHODS: Observed rate of decline (post-slope) of ALSFRS-R, its linearity, and its relationship to decline at first visit (pre-slope) were examined in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) cohort using longitudinal mixed effects models. RESULTS: Mean ALSFRS-R post-slope in 3,367 patients was -0...
December 15, 2017: Muscle & Nerve
https://www.readbyqxmd.com/read/29235200/concise-review-the-cellular-conspiracy-of-als
#10
REVIEW
Andrea Serio, Rickie Patani
Amyotrophic lateral sclerosis (ALS) is incurable and devastating. A dearth of therapies has galvanized experimental focus onto the cellular and molecular mechanisms that both initiate and subsequently drive motor neuron (MN) degeneration. A traditional view of ALS pathogenesis posits that disease-specific injury to a subtype of neurons is mechanistically cell-autonomous. This "neuron-centric" view has biased past research efforts. However, a wealth of accumulating evidence now strongly implicates non-neuronal cells as being major determinants of ALS...
December 13, 2017: Stem Cells
https://www.readbyqxmd.com/read/29214883/longitudinal-structural-changes-in-als-a-three-time-point-imaging-study-of-white-and-gray-matter-degeneration
#11
Peter Bede, Orla Hardiman
BACKGROUND: Cross-sectional imaging studies offer valuable pathological insights into the neurodegenerative changes of amyotrophic lateral sclerosis. However, clinical trials urgently require sensitive monitoring markers that can detect subtle progressive changes over relatively short periods of time. We have conducted a three time-point longitudinal study to explore anatomical patterns of disease spread and to determine whether MRI metrics capture longitudinal changes over four and eight-month intervals...
December 7, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/29202456/neuroleptics-as-therapeutic-compounds-stabilizing-neuromuscular-transmission-in-amyotrophic-lateral-sclerosis
#12
Shunmoogum A Patten, Dina Aggad, Jose Martinez, Elsa Tremblay, Janet Petrillo, Gary Ab Armstrong, Alexandre La Fontaine, Claudia Maios, Meijiang Liao, Sorana Ciura, Xiao-Yan Wen, Victor Rafuse, Justin Ichida, Lorne Zinman, Jean-Pierre Julien, Edor Kabashi, Richard Robitaille, Lawrence Korngut, J Alexander Parker, Pierre Drapeau
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice...
November 16, 2017: JCI Insight
https://www.readbyqxmd.com/read/29181534/association-between-decline-in-slow-vital-capacity-and-respiratory-insufficiency-use-of-assisted-ventilation-tracheostomy-or-death-in-patients-with-amyotrophic-lateral-sclerosis
#13
Jinsy A Andrews, Lisa Meng, Sarah F Kulke, Stacy A Rudnicki, Andrew A Wolff, Michael E Bozik, Fady I Malik, Jeremy M Shefner
Importance: The prognostic value of slow vital capacity (SVC) in relation to respiratory function decline and disease progression in patients with amyotrophic lateral sclerosis (ALS) is not well understood. Objective: To investigate the rate of decline in percentage predicted SVC and its association with respiratory-related clinical events and mortality in patients with ALS. Design, Setting, and Participants: This retrospective study included 893 placebo-treated patients from 2 large clinical trials (EMPOWER and BENEFIT-ALS, conducted from March 28, 2011, to November 1, 2012, and from October 23, 2012, to March 21, 2014, respectively) and an ALS trial database (PRO-ACT, containing studies completed between 1990 and 2010) to investigate the rate of decline in SVC...
November 27, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/29162476/prevention-and-treatment-of-respiratory-viral-infections-presentations-on-antivirals-traditional-therapies-and-host-directed-interventions-at-the-5th-isirv-antiviral-group-conference
#14
Jennifer L McKimm-Breschkin, Shibo Jiang, David S Hui, John H Beigel, Elena A Govorkova, Nelson Lee
The International Society for Influenza and other Respiratory Virus Diseases held its 5th Antiviral Group (isirv-AVG) Conference in Shanghai, China, in conjunction with the Shanghai Public Health Center and Fudan University from 14-16 June, 2017. The three-day programme encompassed presentations on some of the clinical features, management, immune responses and virology of respiratory infections, including influenza A(H1N1)pdm09 and A(H7N9) viruses, MERS-CoV, SARS-CoV, adenovirus Type 80, enterovirus D68, metapneumovirus and respiratory syncytial virus (RSV)...
November 18, 2017: Antiviral Research
https://www.readbyqxmd.com/read/29149058/neurotrophic-and-neuroregenerative-effects-of-gh-igf1
#15
Vittorio Emanuele Bianchi, Vittorio Locatelli, Laura Rizzi
INTRODUCTION: Human neurodegenerative diseases increase progressively with age and present a high social and economic burden. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are both growth factors exerting trophic effects on neuronal regeneration in the central nervous system (CNS) and peripheral nervous system (PNS). GH and IGF-1 stimulate protein synthesis in neurons, glia, oligodendrocytes, and Schwann cells, and favor neuronal survival, inhibiting apoptosis. This study aims to evaluate the effect of GH and IGF-1 on neurons, and their possible therapeutic clinical applications on neuron regeneration in human subjects...
November 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29121998/circulating-brain-enriched-micrornas-as-novel-biomarkers-for-detection-and-differentiation-of-neurodegenerative-diseases
#16
Kira S Sheinerman, Jon B Toledo, Vladimir G Tsivinsky, David Irwin, Murray Grossman, Daniel Weintraub, Howard I Hurtig, Alice Chen-Plotkin, David A Wolk, Leo F McCluskey, Lauren B Elman, John Q Trojanowski, Samuil R Umansky
BACKGROUND: Minimally invasive specific biomarkers of neurodegenerative diseases (NDs) would facilitate patient selection and disease progression monitoring. We describe the assessment of circulating brain-enriched microRNAs as potential biomarkers for Alzheimer's disease (AD), frontotemporal dementia (FTD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). METHODS: In this case-control study, the plasma samples were collected from 250 research participants with a clinical diagnosis of AD, FTD, PD, and ALS, as well as from age- and sex-matched control subjects (n = 50 for each group), recruited from 2003 to 2015 at the University of Pennsylvania Health System, including the Alzheimer's Disease Center, the Parkinson's Disease and Movement Disorders Center, the Frontotemporal Degeneration Center, and the Amyotrophic Lateral Sclerosis Clinic...
November 9, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/29116031/mirna-profiling-of-nurown%C3%A2-mesenchymal-stem-cells-secreting-neurotrophic-factors
#17
Yael Gothelf, Haggai Kaspi, Natalie Abramov, Revital Aricha
BACKGROUND: MSC-NTF cells are Mesenchymal Stromal Cells (MSC) induced to express high levels of neurotrophic factors (NTFs) using a culture-medium based approach. MSC-NTF cells have been successfully studied in clinical trials for Amyotrophic Lateral Sclerosis (ALS) patients. MicroRNAs (miRNA) are short non-coding RNA molecules that coordinate post-transcriptional regulation of multiple gene targets. The purpose of this study was to determine whether the miRNA profile could provide a tool for MSC-NTF cell characterization and to distinguish them from the matched MSC from which they are derived...
November 7, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/29100791/monitoring-progression-of-amyotrophic-lateral-sclerosis-using-ultrasound-morpho-textural-muscle-biomarkers-a-pilot-study
#18
Jacinto J Martínez-Payá, José Ríos-Díaz, Francesc Medina-Mirapeix, Juan F Vázquez-Costa, María Elena Del Baño-Aledo
The need is increasing for progression biomarkers that allow the loss of motor neurons in amyotrophic lateral sclerosis (ALS) to be monitored in clinical trials. In this prospective longitudinal study, muscle thickness, echointensity, echovariation and gray level co-occurrence matrix textural features are examined as possible progression ultrasound biomarkers in ALS patients during a 5-mo follow-up period. We subjected 13 patients to 3 measurements for 20 wk. They showed a significant loss of muscle, an evident tendency to loss of thickness and increased echointensity and echovariation...
October 31, 2017: Ultrasound in Medicine & Biology
https://www.readbyqxmd.com/read/29095723/antiviral-treatment-of-severe-non-influenza-respiratory-virus-infection
#19
Nathan J Brendish, Tristan W Clark
PURPOSE OF REVIEW: Non-influenza respiratory virus infections are a frequent cause of severe acute respiratory infections, especially in infants, the elderly, and the immunocompromised. We review here the current treatment options for non-influenza respiratory viruses and promising candidate antiviral agents currently in development. RECENT FINDINGS: Small molecule antiviral agents active against respiratory syncytial virus (RSV), such as ALS-8176 and GS-5806, show considerable promise in challenge studies and are undergoing late-phase clinical trials in hospitalised adults and children...
December 2017: Current Opinion in Infectious Diseases
https://www.readbyqxmd.com/read/29061611/effects-of-advanced-life-support-versus-basic-life-support-on-the-mortality-rates-of-patients-with-trauma-in-prehospital-settings-a-study-protocol-for-a-systematic-review-and-meta-analysis
#20
Yutaka Kondo, Tatsuma Fukuda, Ryo Uchimido, Toru Hifumi, Kei Hayashida
INTRODUCTION: Advanced life support (ALS) is thought to be associated with improved survival in prehospital trauma care when compared with basic life support (BLS). However, evidence on the benefits of prehospital ALS for patients with trauma is controversial. Therefore, we aim to clarify if ALS improves mortality in patients with trauma when compared with BLS by conducting a systematic review and meta-analysis of the recent literature. METHODS AND ANALYSIS: We will perform searches in PubMed, Embase and the Cochrane Central Register of Controlled Trials for published observational studies, controlled before-and-after studies, randomised controlled trials and other controlled trials conducted in humans and published until March 2017...
October 22, 2017: BMJ Open
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