-
Nature Medicine Apr 2024Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, is being investigated as a potential disease-modifying therapy in early-stage Parkinson's...
Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, is being investigated as a potential disease-modifying therapy in early-stage Parkinson's disease. Although in the PASADENA phase 2 study, the primary endpoint (Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) sum of Parts I + II + III) was not met, prasinezumab-treated individuals exhibited slower progression of motor signs than placebo-treated participants (MDS-UPDRS Part III). We report here an exploratory analysis assessing whether prasinezumab showed greater benefits on motor signs progression in prespecified subgroups with faster motor progression. Prasinezumab's potential effects on disease progression were assessed in four prespecified and six exploratory subpopulations of PASADENA: use of monoamine oxidase B inhibitors at baseline (yes versus no); Hoehn and Yahr stage (2 versus 1); rapid eye movement sleep behavior disorder (yes versus no); data-driven subphenotypes (diffuse malignant versus nondiffuse malignant); age at baseline (≥60 years versus <60 years); sex (male versus female); disease duration (>12 months versus <12 months); age at diagnosis (≥60 years versus <60 years); motor subphenotypes (akinetic-rigid versus tremor-dominant); and motor subphenotypes (postural instability gait dysfunction versus tremor-dominant). In these subpopulations, the effect of prasinezumab on slowing motor signs progression (MDS-UPDRS Part III) was greater in the rapidly progressing subpopulations (for example, participants who were diffuse malignant or taking monoamine oxidase B inhibitors at baseline). This exploratory analysis suggests that, in a trial of 1-year duration, prasinezumab might reduce motor progression to a greater extent in individuals with more rapidly progressing Parkinson's disease. However, because this was a post hoc analysis, additional randomized clinical trials are needed to validate these findings.
Topics: Humans; Male; Female; Middle Aged; Parkinson Disease; Tremor; Antiparkinson Agents; Monoamine Oxidase; Disease Progression
PubMed: 38622249
DOI: 10.1038/s41591-024-02886-y -
The Lancet. Neurology Nov 2023
Topics: Humans; alpha-Synuclein; Parkinson Disease
PubMed: 37863605
DOI: 10.1016/S1474-4422(23)00371-X -
Immune escape of avian oncogenic Marek's disease herpesvirus and antagonistic host immune responses.NPJ Vaccines Jun 2024Marek's disease virus (MDV) is a highly pathogenic and oncogenic alpha herpesvirus that causes Marek's disease (MD), which is one of the most important immunosuppressive... (Review)
Review
Marek's disease virus (MDV) is a highly pathogenic and oncogenic alpha herpesvirus that causes Marek's disease (MD), which is one of the most important immunosuppressive and rapid-onset neoplastic diseases in poultry. The onset of MD lymphomas and other clinical diseases can be efficiently prevented by vaccination; these vaccines are heralded as the first demonstration of a successful vaccination strategy against a cancer. However, the persistent evolution of epidemic MDV strains towards greater virulence has recently resulted in frequent outbreaks of MD in vaccinated chicken flocks worldwide. Herein, we provide an overall review focusing on the discovery and identification of the strategies by which MDV evades host immunity and attacks the immune system. We have also highlighted the decrease in the immune efficacy of current MD vaccines. The prospects, strategies and new techniques for the development of efficient MD vaccines, together with the possibilities of antiviral therapy in MD, are also discussed.
PubMed: 38879650
DOI: 10.1038/s41541-024-00905-0 -
International Journal of Molecular... Sep 2023Pseudorabies virus (PRV), an alpha herpesvirus, induces significant economic losses to the swine industry and infects multiple kinds of animals. Therefore, it is of...
Pseudorabies virus (PRV), an alpha herpesvirus, induces significant economic losses to the swine industry and infects multiple kinds of animals. Therefore, it is of great importance to explore anti-PRV compounds. In this study, to explore the anti-PRV compounds, a library of natural compounds was screened through a cell-based ELISA assay, and it was discovered that bufalin, a Na/K-ATPase inhibitor, had a robust inhibitory effect on PRV replication. A time-of-addition experiment and temperature-shift assay showed that bufalin significantly inhibited the entry stage of PRV. NaCl- or KCl-treatment showed that NaCl could enhance the inhibitory effect of bufalin on PRV replication, whereas there was no significant effect under the treatment of KCl. Meanwhile, it was also found that bufalin possessed antiviral activity against other alpha herpesviruses, including human herpes simplex virus type 1 (HSV-1) and chicken Marek's disease virus (MDV). Finally, it was found that bufalin could decrease the viral load in multiple tissues, and reduce the morbidity and mortality in PRV-challenged BALB/c mice. Overall, our findings demonstrated that bufalin has the potential to be developed as an anti-PRV compound.
Topics: Mice; Animals; Swine; Humans; Herpesvirus 1, Suid; Sodium Chloride; Adenosine Triphosphatases; Herpesviridae
PubMed: 37833925
DOI: 10.3390/ijms241914479 -
Hepatology (Baltimore, Md.) May 2024New guidelines for the definitions of steatotic liver disease have named the entity of MetALD as an overlap condition of metabolic-dysfunction associated steatotic liver...
New guidelines for the definitions of steatotic liver disease have named the entity of MetALD as an overlap condition of metabolic-dysfunction associated steatotic liver disease (MASLD) and alcohol-related liver disease. There is a broad range of therapeutics in all stages of development for MASLD but these therapeutics in general have not been studied in patients with significant ongoing alcohol use. In this review we discuss the current understanding of the endogenous and exogenous risks for MASLD and MetALD. Rational strategies for therapeutic intervention in MetALD include biopsychosocial interventions, alcohol use cessation strategies including the use of medications for alcohol use disorder and judicious use of therapeutics for steatotic liver disease. Therapeutics with promise for MetALD include incretin-based therapies, fibroblast growth factor 21 (FGF21) agonists, thyroid hormone receptor beta (THR- β) agonists, sodium-glucose co-transporter 2 (SGLT2) inhibitors and agents to modify de-novo lipogenesis (DNL). Currently glucagon like peptide 1 receptor agonists (GLP-1ra) and peroxisome proliferator-activated receptor (PPAR) γ agonists have the largest body of literature supporting their use in MASLD and there is a paucity of agents in trials for alcohol-related liver disease. From existing studies, it is not clear if unique therapeutics or a combinatorial approach are needed for MetALD. Further elucidation of the safety and benefits of MASLD-related therapies are of paramount importance for advancing therapeutics for MetALD in carefully designed inclusive clinical trials.
PubMed: 38820071
DOI: 10.1097/HEP.0000000000000935 -
Avian Pathology : Journal of the W.V.P.A Dec 2023Marek's disease (MD) is caused by oncogenic MD virus serotype 1 (MDV1) and is characterized by lymphoproliferative lesions resulting in high morbidity and mortality in...
Marek's disease (MD) is caused by oncogenic MD virus serotype 1 (MDV1) and is characterized by lymphoproliferative lesions resulting in high morbidity and mortality in chickens. Despite being ubiquitous on poultry farms, there is a dearth of information on its molecular characteristics in Nigeria. This study aimed at characterizing three virulence genes ( and ) of MDV1 from chickens in Ogun state, Nigeria. Blood, feather quill, and tumour samples of chickens from different commercial poultry farms in Ogun State were pooled, spotted on 107 FTA cards, and screened for MDV1 by polymerase chain reaction (PCR). Phylogenetic analysis was carried out to compare Nigerian MDV1 , and genes sequences with the published references. Thirteen samples were MDV1-positive and the , as well as and genes from the different samples were 100% identical. The genes contained 339 amino acids (aa) with three PPPP motifs in the transactivation domain and two interruptions of the PPPP motifs due to proline-to-arginine substitutions at positions 176 and 217 resulting in a 20.88% proline composition. Phylogenetic analysis revealed that the gene clustered with strains from Egypt and very virulent ATE2539 strain from Hungary. Mutations were observed in the pp38 protein (at positions 107 and 109) and protein (at positions 4 and 31). Based on the molecular analysis of the three genes, the results indicate the presence of MDV1 with virulence signatures; therefore, further studies on pathotyping of Nigerian MDV1 from all states should be performed. genes were 100% identical between Nigerian MDV strains.Proline content in Nigerian gene was 20.88% with two PPPP motifs interruptions. genes of Nigerian MDV were similar to Egyptian and Indian strains.
Topics: Animals; Chickens; Phylogeny; Oncogene Proteins, Viral; Marek Disease; Nigeria; Herpesvirus 2, Gallid; Poultry; Proline; Poultry Diseases
PubMed: 37605844
DOI: 10.1080/03079457.2023.2243838 -
Lancet (London, England) Jun 2024Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.
BACKGROUND
Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain.
METHODS
RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.
FINDINGS
Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths.
INTERPRETATION
Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy.
FUNDING
Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.
Topics: Humans; Male; Prostatic Neoplasms; Androgen Antagonists; Prostatectomy; Aged; Tosyl Compounds; Middle Aged; Anilides; Nitriles; Oligopeptides; Gonadotropin-Releasing Hormone; Prostate-Specific Antigen; Combined Modality Therapy; Drug Administration Schedule
PubMed: 38763153
DOI: 10.1016/S0140-6736(24)00549-X -
Neurology Feb 2024In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-β-amyloid...
BACKGROUND AND OBJECTIVES
In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-β-amyloid 1-42 (Aβ), phosphorylated tau 181 (p-tau), and total tau (t-tau)-in PD is poorly understood and may be distinct from clinical AD. Moreover, it is unclear whether CSF p-tau and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aβ. First, we describe longitudinal trajectories of biofluid markers in PD. Second, we modified the AD β-amyloid/tau/neurodegeneration (ATN) framework for application in PD (ATN) using CSF Aβ (A), p-tau (T), and serum NfL (N) and tested ATN prediction of longitudinal cognitive decline in PD.
METHODS
Participants were selected from the Parkinson's Progression Markers Initiative cohort, clinically diagnosed with sporadic PD or as controls, and followed up annually for 5 years. Linear mixed-effects models (LMEMs) tested the interaction of diagnosis with longitudinal trajectories of analytes (log transformed, false discovery rate [FDR] corrected). In patients with PD, LMEMs tested how baseline ATN status (AD [A+T+N±] vs not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank transformed, FDR corrected).
RESULTS
Participants were 364 patients with PD and 168 controls, with comparable baseline mean (±SD) age (patients with PD = 62 ± 10 years; controls = 61 ± 11 years]; Mann-Whitney Wilcoxon: = 0.4) and sex distribution (patients with PD = 231 male individuals [63%]; controls = 107 male individuals [64%]; χ: = 1). Patients with PD had overall lower CSF p-tau (β = -0.16, 95% CI -0.23 to -0.092, = 2.2e-05) and t-tau than controls (β = -0.13, 95% CI -0.19 to -0.065, = 4e-04), but not Aβ ( = 0.061) or NfL ( = 0.32). Over time, patients with PD had greater increases in serum NfL than controls (β = 0.035, 95% CI 0.022 to 0.048, = 9.8e-07); slopes of patients with PD did not differ from those of controls for CSF Aβ ( = 0.18), p-tau ( = 1), or t-tau ( = 0.96). Using ATN, PD classified as A+T+N± (n = 32; 9%) had worse cognitive decline on global MoCA (β = -73, 95% CI -110 to -37, = 0.00077) than all other ATN statuses including A+ alone (A+T-N-; n = 75; 21%).
DISCUSSION
In patients with early PD, CSF p-tau and t-tau were low compared with those in controls and did not increase over 5 years of follow-up. Our study shows that classification using modified ATN (incorporating CSF Aβ, CSF p-tau, and serum NfL) can identify biologically relevant subgroups of PD to improve prediction of cognitive decline in early PD.
Topics: Humans; Male; Middle Aged; Aged; Parkinson Disease; tau Proteins; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Prognosis; Biomarkers
PubMed: 38306599
DOI: 10.1212/WNL.0000000000208033 -
Computers in Biology and Medicine Feb 2024This article presents an overview of existing approaches to perform vectorcardiographic (VCG) diagnostics of ischemic heart disease (IHD). Individual methodologies are... (Review)
Review
This article presents an overview of existing approaches to perform vectorcardiographic (VCG) diagnostics of ischemic heart disease (IHD). Individual methodologies are divided into categories to create a comprehensive and clear overview of electrical cardiac activity measurement, signal pre-processing, features extraction and classification procedures. An emphasis is placed on methods describing the electrical heart space (EHS) by several features extraction techniques based on spatiotemporal characteristics or signal modelling and signal transformations. Performance of individual methodologies are compared depending on classification of extent of ischemia, acute forms - myocardial infarction (MI) and myocardial scars localization. Based on a comparison of imaging methods, the advantages of VCG over the standard 12-leads ECG such as providing a 3D orthogonal leads imaging, better performance, and appropriate computer processing are highlighted. The issues of electrical cardiac activity measurements on body surface, the lack of VKG databases supported by a more accurate imaging method, possibility of comparison with the physiology of individual cases are outlined as potential reserves for future research.
Topics: Humans; Vectorcardiography; Heart; Myocardial Infarction; Myocardium; Signal Processing, Computer-Assisted; Electrocardiography
PubMed: 38103481
DOI: 10.1016/j.compbiomed.2023.107781 -
Poultry Science Dec 2023Marek's disease virus (MDV), a naturally oncogenic, highly contagious alpha herpesvirus, induces a T cell lymphoma in chickens that causes severe economic loss. Marek's...
Marek's disease virus (MDV), a naturally oncogenic, highly contagious alpha herpesvirus, induces a T cell lymphoma in chickens that causes severe economic loss. Marek's disease (MD) outcome in an individual is attributed to genetic and environmental factors. Further investigation of the host-virus interaction mechanisms that impact MD resistance is needed to achieve greater MD control. This study analyzed genome-wide DNA methylation patterns in 2 highly inbred parental lines 6 and 7 and 5 recombinant congenic strains (RCS) C, L, M, N, and X strains from those parents. Lines 6 and 7, are MD resistant and susceptible, respectively, whereas the RCS have different combinations of 87.5% Line 6 and 12.5% Line 7. Our DNA methylation cluster showed a strong association with MD incidence. Differentially methylated regions (DMRs) between the parental lines and the 5 RCS were captured. MD-resistant and MD-susceptible markers of DNA methylation were identified as transgenerational epigenetic inheritable. In addition, the growth of v-src DNA tumors and antibody response against sheep red blood cells differed among the 2 parental lines and the RCS. Overall, our results provide very solid evidence that DNA methylation patterns are transgenerational epigenetic inheritance (TEI) in chickens and also play a vital role in MD tumorigenesis and other immune responses; the specific methylated regions may be important modulators of general immunity.
Topics: Animals; Sheep; Chickens; Disease Resistance; Marek Disease; Herpesvirus 2, Gallid; Disease Susceptibility; Epigenesis, Genetic; Sheep Diseases
PubMed: 37832188
DOI: 10.1016/j.psj.2023.103036