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Vaccines Jul 2021Vaccination as an important tool in the fight against infections has been suggested as a possible trigger of autoimmunity over the last decades. To confirm or refute... (Review)
Review
Vaccination as an important tool in the fight against infections has been suggested as a possible trigger of autoimmunity over the last decades. To confirm or refute this assumption, a Meta-analysis of Autoimmune Disorders Association With Immunization (MADAWI) was conducted. Included in the meta-analysis were a total of 144 studies published in 1968-2019 that were available in six databases and identified by an extensive literature search conducted on 30 November 2019. The risk of bias classification of the studies was performed using the Newcastle-Ottawa Quality Assessment Scale. The strength of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation. While our primary analysis was conducted in terms of measures of association employed in studies with a low risk of bias, the robustness of the MADAWI outcome was tested using measures independent of each study risk of bias. Additionally, subgroup analyses were performed to determine the stability of the outcome. The pooled association of 0.99 (95% confidence interval, 0.97-1.02), based on a total of 364 published estimates, confirmed an equivalent occurrence of autoimmune disorders in vaccinated and unvaccinated persons. The same level of association reported by studies independently of the risk of bias was supported by a sufficient number of studies, and no serious limitation, inconsistency, indirectness, imprecision, and publication bias. A sensitivity analysis did not reveal any discrepancy in the primary result. Current common vaccination is not the cause of any of the examined autoimmune disorders in the medium and long terms.
PubMed: 34451946
DOI: 10.3390/vaccines9080821 -
PLoS Pathogens Jun 2023Efficient transmission of herpesviruses is essential for dissemination in host populations; however, little is known about the viral genes that mediate transmission,...
Efficient transmission of herpesviruses is essential for dissemination in host populations; however, little is known about the viral genes that mediate transmission, mostly due to a lack of natural virus-host model systems. Marek's disease is a devastating herpesviral disease of chickens caused by Marek's disease virus (MDV) and an excellent natural model to study skin-tropic herpesviruses and transmission. Like varicella zoster virus that causes chicken pox in humans, the only site where infectious cell-free MD virions are efficiently produced is in epithelial skin cells, a requirement for host-to-host transmission. Here, we enriched for heavily infected feather follicle epithelial skin cells of live chickens to measure both viral transcription and protein expression using combined short- and long-read RNA sequencing and LC/MS-MS bottom-up proteomics. Enrichment produced a previously unseen breadth and depth of viral peptide sequencing. We confirmed protein translation for 84 viral genes at high confidence (1% FDR) and correlated relative protein abundance with RNA expression levels. Using a proteogenomic approach, we confirmed translation of most well-characterized spliced viral transcripts and identified a novel, abundant isoform of the 14 kDa transcript family via IsoSeq transcripts, short-read intron-spanning sequencing reads, and a high-quality junction-spanning peptide identification. We identified peptides representing alternative start codon usage in several genes and putative novel microORFs at the 5' ends of two core herpesviral genes, pUL47 and ICP4, along with strong evidence of independent transcription and translation of the capsid scaffold protein pUL26.5. Using a natural animal host model system to examine viral gene expression provides a robust, efficient, and meaningful way of validating results gathered from cell culture systems.
Topics: Humans; Animals; Marek Disease; Chickens; Proteogenomics; Herpesviridae; Herpesvirus 2, Gallid
PubMed: 37289833
DOI: 10.1371/journal.ppat.1011204 -
Molecular Neurodegeneration Jun 2023Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer's Disease (AD). Although ApoE4 differs from its non-pathological ApoE3...
BACKGROUND
Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer's Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown.
METHODS
Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray crystallography, site-directed mutagenesis, hydrogen-deuterium mass spectrometry (HDX-MS), static light scattering and molecular dynamics simulations. Treatment of ApoE ε3/ε3 and ε4/ε4 cerebral organoids with tramiprosate was used to compare the effect of tramiprosate on ApoE4 aggregation at the cellular level.
RESULTS
We found that C112R substitution in ApoE4 induces long-distance (> 15 Å) conformational changes leading to the formation of a V-shaped dimeric unit that is geometrically different and more aggregation-prone than the ApoE3 structure. AD drug candidate tramiprosate and its metabolite 3-sulfopropanoic acid induce ApoE3-like conformational behavior in ApoE4 and reduce its aggregation propensity. Analysis of ApoE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage products of excess cholesterol.
CONCLUSIONS
Our results connect the ApoE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing.
Topics: Humans; Apolipoprotein E4; Alzheimer Disease; Apolipoprotein E3; Mutation; Apolipoproteins E
PubMed: 37280636
DOI: 10.1186/s13024-023-00620-9 -
Biological Trace Element Research Sep 2022Several studies have indicated that selenium deficiency may be detrimental in the context of various viral disorders, and in the case of COVID-19, several studies have...
Several studies have indicated that selenium deficiency may be detrimental in the context of various viral disorders, and in the case of COVID-19, several studies have reported heterogeneous results concerning the association of selenium deficiency with the severity of disease. To summarize the available data surrounding the association of body selenium levels with the outcomes of COVID-19, a systematic search was performed in the Medline database (PubMed), Scopus, Cochrane Library, Embase, and Web of Science using keywords including "SARS-CoV-2," "COVID-19," and "selenium," Studies evaluating the association of COVID-19 with body selenium levels were included. Among 1,862 articles viewed in the database search, 10 articles were included after title, abstract, and full-text review. One study was further included after searching the literature again for any newly published articles. Out of 11 included studies, 10 studies measured serum selenium level, and one study investigated urinary selenium level. Three of 10 studies measured serum SELENOP level as well as selenium level. Glutathione peroxidase-3 level in serum was also assessed in one study. The reported outcomes were severity, mortality, and risk of COVID-19. Nine studies indicated that a lower serum selenium level is associated with worse outcomes. Two studies reported no significant association between serum selenium level and COVID-19. In one study, urinary selenium level was reported to be higher in severe and fatal cases compared to non-severe and recovered patients, respectively. In most cases, selenium deficiency was associated with worse outcomes, and selenium levels in COVID-19 patients were lower than in healthy individuals. Thus, it could be concluded that cautious selenium supplementation in COVID-19 patients may be helpful to prevent disease progression. However, randomized clinical trials are needed to confirm this.
Topics: COVID-19; Humans; Malnutrition; SARS-CoV-2; Selenium; Selenoprotein P
PubMed: 34739678
DOI: 10.1007/s12011-021-02997-4 -
Journal of Clinical Oncology : Official... Dec 2023There is a significant unmet need for new and efficacious therapies in urothelial cancer (UC). To provide recommendations on appropriate clinical trial designs across...
Definitions, End Points, and Clinical Trial Designs for Bladder Cancer: Recommendations From the Society for Immunotherapy of Cancer and the International Bladder Cancer Group.
PURPOSE
There is a significant unmet need for new and efficacious therapies in urothelial cancer (UC). To provide recommendations on appropriate clinical trial designs across disease settings in UC, the Society for Immunotherapy of Cancer (SITC) and the International Bladder Cancer Group (IBCG) convened a multidisciplinary, international consensus panel.
METHODS
Through open communication and scientific debate in small- and whole-group settings, surveying, and responses to clinical questionnaires, the consensus panel developed recommendations on optimal definitions of the disease state, end points, trial design, evaluations, sample size calculations, and pathology considerations for definitive studies in low- and intermediate-risk nonmuscle-invasive bladder cancer (NMIBC), high-risk NMIBC, muscle-invasive bladder cancer in the neoadjuvant and adjuvant settings, and metastatic UC. The expert panel also solicited input on the recommendations through presentations and public discussion during an open session at the 2021 Bladder Cancer Advocacy Network (BCAN) Think Tank (held virtually).
RESULTS
The consensus panel developed a set of stage-specific bladder cancer clinical trial design recommendations, which are summarized in the table that accompanies this text.
CONCLUSION
These recommendations developed by the SITC-IBCG Bladder Cancer Clinical Trial Design consensus panel will encourage uniformity among studies and facilitate drug development in this disease.
Topics: Humans; Clinical Trials as Topic; Urinary Bladder Neoplasms; Adjuvants, Immunologic; Carcinoma, Transitional Cell; Immunotherapy
PubMed: 37793077
DOI: 10.1200/JCO.23.00307 -
Journal of Parkinson's Disease 2022Glucocerebrosidase gene (GBA) mutations influence risk and prognosis of Parkinson's disease (PD), possibly through accumulation of glycosphingolipids, including... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients with Parkinson's Disease and a GBA Mutation: Results from Part 1 of the Randomized, Double-Blinded, Placebo-Controlled MOVES-PD Trial.
BACKGROUND
Glucocerebrosidase gene (GBA) mutations influence risk and prognosis of Parkinson's disease (PD), possibly through accumulation of glycosphingolipids, including glucosylceramide (GL-1). Venglustat is a novel, brain penetrant glucosylceramide synthase inhibitor.
OBJECTIVE
Evaluate venglustat pharmacology, safety, and tolerability in patients with PD and GBA mutations (GBA-PD).
METHODS
Part 1 of the phase 2 MOVES-PD trial (NCT02906020) was a randomized, double-blinded, placebo-controlled, dose-escalation study performed in six countries. Eligible participants included Japanese and non-Japanese patients aged 18-80 years with PD diagnosis and heterozygous GBA mutation. Participants were randomized to three doses of once-daily oral venglustat or placebo and were followed up to 36 weeks (Japanese participants: 52 weeks). Primary endpoint was venglustat safety and tolerability versus placebo. Secondary and exploratory endpoints included venglustat pharmacokinetics and pharmacodynamics.
RESULTS
Participants (N = 29) received venglustat (Japanese, n = 9; non-Japanese, n = 13) or placebo (n = 3; n = 4). Eight (89%) Japanese and 12 (92%) non-Japanese venglustat-treated participants experienced at least one adverse event (AE) versus two (67%) and four (100%) participants from the respective placebo groups. Most AEs were mild or moderate; no serious AEs or deaths occurred. Two venglustat-treated non-Japanese participants discontinued due to AEs (confusional state and panic attack). Over 4 weeks, venglustat exposure in plasma and cerebrospinal fluid (CSF) increased, and GL-1 levels in plasma and CSF decreased, both in a dose-dependent manner. At the highest dose, CSF GL-1 decreased by 72.0% in Japanese and 74.3% in non-Japanese participants.
CONCLUSION
Venglustat showed favorable safety and tolerability in MOVES-PD Part 1 and target engagement was achieved in CSF.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Enzyme Inhibitors; Glucosylceramidase; Glucosylceramides; Humans; Middle Aged; Mutation; Parkinson Disease; Young Adult
PubMed: 34897099
DOI: 10.3233/JPD-212714 -
Cancers Mar 2020Marek's disease virus (MDV) infects chickens and causes one of the most frequent cancers in animals. Over 100 years of research on this oncogenic alphaherpesvirus has... (Review)
Review
Marek's disease virus (MDV) infects chickens and causes one of the most frequent cancers in animals. Over 100 years of research on this oncogenic alphaherpesvirus has led to a profound understanding of virus-induced tumor development. Live-attenuated vaccines against MDV were the first that prevented cancer and minimized the losses in the poultry industry. Even though the current gold standard vaccine efficiently protects against clinical disease, the virus continuously evolves towards higher virulence. Emerging field strains were able to overcome the protection provided by the previous two vaccine generations. Research over the last few years revealed important insights into the virus life cycle, cellular tropism, and tumor development that are summarized in this review. In addition, we discuss recent data on the MDV transcriptome, the constant evolution of this highly oncogenic virus towards higher virulence, and future perspectives in MDV research.
PubMed: 32164311
DOI: 10.3390/cancers12030647 -
Animals : An Open Access Journal From... Feb 2022Marek's disease is an infectious disease in poultry that usually appears in neural and visceral tumors. This disease is caused by infection in lymphocytes, and its meq... (Review)
Review
Marek's disease is an infectious disease in poultry that usually appears in neural and visceral tumors. This disease is caused by infection in lymphocytes, and its meq gene is commonly used in virulent studies for coding the key protein functional in oncogenic transformation of the lymphocytes. Although vaccines have been introduced in many countries to control its spread and are proven to be efficient, recent records show a decline of such efficiency due to viral evolution. In this study, we reviewed the outbreak of Marek's disease in Asia for the last 10 years, together with associated sequences, finding a total of 36 studies recording outbreaks with 132 viral strains in 12 countries. The visceral type is the most common (13 in 16 studies) form of Marek's disease, but additional unobserved neural changes may exist. MD induces liver lymphoma most frequently (11 in 14 studies), and tumors were also found in spleen, kidney, heart, gizzard, skin, intestine, lung, and sciatic nerve. Twelve viral strains distributed in China have been reported to escape the CVI988 vaccine, reaching a mortality rate of more than 30%. Phylogenetic analyses show the internal connection between the Middle East (Turkey, Iraq, Iran, Saudi Arabia), South Asia (India, Indonesia), and East Asia (China and Japan), while external viral communications might occasionally occur. In 18 strains with both sequential and mortality data, amino acid alignment showed several point substitutions that may be related to its virulence. We suggest more behavioral monitoring in Marek's disease-endemic regions and further studies on strain virulence, together with its Meq protein structural changes.
PubMed: 35268107
DOI: 10.3390/ani12050540 -
Annals of Agricultural and... Sep 2023Intensive poultry farming is usually associated with massive exposure to organic dust, which is largely composed of microbiological origin particulates. The aim of the...
INTRODUCTION AND OBJECTIVE
Intensive poultry farming is usually associated with massive exposure to organic dust, which is largely composed of microbiological origin particulates. The aim of the study is to assess occupational and environmental exposures to airborne bacteria, fungi, and Marek's disease virus emitted by a poultry house.
MATERIAL AND METHODS
The concentrations of airborne microorganisms in a poultry house and its vicinity (250-500 m) at 3 different stages of the production cycle (i.e. empty poultry house, with 7-day-old and 42-day-old chickens) were stationary measured using Andersen and MAS impactors, as well as Coriolis and BioSampler impingers. The collected microbiota was taxonomically identified using molecular and biochemical techniques to characterize occupational exposure and its spatial dissemination.
RESULTS
Although Marek's disease virus was not present in the tested air samples, the appearance of reared chickens in the poultry house resulted in an increase in airborne bacterial and fungal concentrations up to levels of 1.26 × 10 CFU/m and 3.77 × 10 CFU/m, respectively. These pollutants spread around through the ventilation system, but their concentrations significantly decreased at a distance of 500 m from the chicken coop. A part of the identified microbiota was pathogens that were successfully isolated from the air by all 4 tested samplers.
CONCLUSIONS
The poultry house employees were exposed to high concentrations of airborne microorganisms, including pathogens that may lead to adverse health outcomes. To protect them, highly efficient hygienic and technical measures regarding the poultry house interior and its ventilation, respectively, should be introduced to prevent both unwanted pollution and subsequent emission of microbial contaminants during intensive chicken breeding.
PubMed: 37772519
DOI: 10.26444/aaem/172770 -
Frontiers in Neurology 2021Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease. The...
Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease. The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD. The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40-80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations. Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve). The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD. NCT03100149.
PubMed: 34659081
DOI: 10.3389/fneur.2021.705407