Application of Precision Medicine in Neurodegenerative Diseases

One of the main challenges for healthcare systems is the increasing prevalence of neurodegenerative pathologies together with the rapidly aging populations. The enormous progresses made in the field of biomedical research and informatics have been crucial for improving the knowledge of how genes, epigenetic modifications, aging, nutrition, drugs and microbiome impact health and disease. In fact, the availability of high technology and computational facilities for large-scale analysis enabled a deeper investigation of neurodegenerative disorders, providing a more comprehensive overview of disease and encouraging the development of a precision medicine approach for these pathologies. On this subject, the creation of collaborative networks among medical centers, research institutes and highly qualified specialists can be decisive for moving the precision medicine from the bench to the bedside. To this purpose, the present review has been thought to discuss the main components which may be part of precise and personalized treatment programs applied to neurodegenerative disorders. Parkinson Disease will be taken as an example to understand how precision medicine approach can be clinically useful and provide substantial benefit to patients. In this perspective, the realization of web-based networks can be decisive for the implementation of precision medicine strategies across different specialized centers as well as for supporting clinical/therapeutical decisions and promoting a more preventive and participative medicine for neurodegenerative disorders. These collaborative networks are essentially addressed to find innovative, sustainable and effective strategies able to provide optimal and safer therapies, discriminate at risk individuals, identify patients at preclinical or early stage of disease, set-up individualized and preventative strategies for improving prognosis and patient's quality of life

Whole exome sequencing highlights rare variants in CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1 as associated with FSHD

Introduction: Despite the progress made in the study of Facioscapulohumeral Dystrophy (FSHD), the wide heterogeneity of disease complicates its diagnosis and the genotype-phenotype correlation among patients and within families. In this context, the present work employed Whole Exome Sequencing (WES) to investigate known and unknown genetic contributors that may be involved in FSHD and may represent potential disease modifiers, even in presence of a D4Z4 Reduced Allele (DRA).Methods: A cohort of 126 patients with clinical signs of FSHD were included in the study, which were characterized by D4Z4 sizing, methylation analysis and WES. Specific protocols were employed for D4Z4 sizing and methylation analysis, whereas the Illumina® Next-Seq 550 system was utilized for WES. The study included both patients with a DRA compatible with FSHD diagnosis and patients with longer D4Z4 alleles. In case of patients harboring relevant variants from WES, the molecular analysis was extended to the family members.Results: The WES data analysis highlighted 20 relevant variants, among which 14 were located in known genetic modifiers (SMCHD1, DNMT3B and LRIF1) and 6 in candidate genes (CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1). Most of them were found together with a permissive short (4–7 RU) or borderline/long DRA (8–20 RU), supporting the possibility that different genes can contribute to disease heterogeneity in presence of a FSHD permissive background. The segregation and methylation analysis among family members, together with clinical findings, provided a more comprehensive picture of patients.Discussion: Our results support FSHD pathomechanism being complex with a multigenic contribution by several known (SMCHD1, DNMT3B, LRIF1) and possibly other candidate genes (CTCF, DNMT1, DNMT3A, EZH2, SUV39H1) to disease penetrance and expressivity. Our results further emphasize the importance of extending the analysis of molecular findings within the proband’s family, with the purpose of providing a broader framework for understanding single cases and allowing finer genotype-phenotype correlations in FSHD-affected families

Case Report: Sars-CoV-2 Infection in a Vaccinated Individual: Evaluation of the Immunological Profile and Virus Transmission Risk

During the COVID19 pandemic, a range of vaccines displayed high efficacy in preventing disease, severe outcomes of infection, and mortality. However, the immunological correlates of protection, the duration of immune response, the transmission risk over time from vaccinated individuals are currently under active investigation. In this brief report, we describe the case of a vaccinated Healthcare Professional infected with a variant of Sars-CoV-2, who has been extensively investigated in order to draw a complete trajectory of infection. The patient has been monitored for the whole length of infection, assessing the temporal viral load decay, the quantification of viral RNA and subgenomic mRNA, antibodies (anti Sars-CoV-2, IgA, IgG, IgM) and cell-mediated (cytokine, B- and T-cell profiles) responses. Overall, this brief report highlights the efficacy of vaccine in preventing COVID19 disease, accelerating the recovery from infection, reducing the transmission risk, although the use of precautionary measures against Sars-CoV-2 spreading still remain critical

Comparative analysis between saliva and buccal swabs as source of DNA: lesson from HLA-B*57:01 testing

Aim: Our work aimed to designate the optimal DNA source for pharmacogenetic assays, such as the screening for HLA-B*57:01 allele. Materials & methods: A saliva and four buccal swab samples were taken from 104 patients. All the samples were stored at different time and temperature conditions and then genotyped for the HLA-B*57:01 allele by SSP-PCR and classical/capillary electrophoresis. Results: The genotyping analysis reported different performance rates depending on the storage conditions of the samples. Given our results, the buccal swab demonstrated to be more resistant and stable in time with respect to the saliva. Conclusion: Our investigation designates the buccal swab as the optimal DNA source for pharmacogenetic assays in terms of resistance, low infectivity, low-invasiveness and easy sampling, and safe transport in centralized medical centers providing specialized pharmacogenetic tests

Long-Term Structural and Functional Assessment of Doyne Honeycomb Retinal Dystrophy following Nanosecond 2RT Laser Treatment: A Case Series

Introduction: Doyne honeycomb retinal dystrophy (DHRD), or autosomal dominant radial drusen, is a genetic disease caused by pathogenic variants of the epidermal growth factor (EGF)-containing fibulin-like extracellular matrix protein 1 EFEMP1 gene and is characterized by the formation of subretinal drusenoid deposits. In a previous study, we reported the short-term beneficial effects of nanosecond laser treatment (2RT) on retinal function in DHRD. The aim of the present report was to describe the findings of a long-term follow-up of retinal structure/function in a small case series of patients with DHRD who underwent 2RT treatment. Case Presentation: Three DHRD patients (case 1, male and cases 2 and 3, two sister females, age range 41–46) with EFEMP1 pathogenic variant (c.1033C>T; p.R345W) and drusenoid deposits at the posterior pole were examined at baseline and after 2RT treatment, at regular intervals (every 2–4 months) up to 30 months. All 3 patients underwent one or two treatment sessions in one or both eyes during the follow-up period. Case 3 was treated with only the left eye (LE). Each patient underwent a full ophthalmologic examination, spectral domain optical coherence tomography (OCT), central perimetry with frequency doubling technology, and mesopic and photopic Ganzfeld electroretinograms. Compared to baseline findings, during follow-up, visual acuity improved in both eyes in case 1 and LE in case 2, while it decreased in the right eye in case 2 and LE in case 3; perimetric sensitivity was stable in case 1 and improved in both eyes in cases 2 and 3; and electroretinogram amplitude improved in cases 1 and 2 and was stable in case 3 (both eyes). OCT central macular thickness and retinal structure were stable in all cases. None of the patients had treatment-related side effects. Conclusion: This is the first report showing that in a long-term follow-up, 2RT treatment in DHRD may improve or stabilize some retinal function parameters without significant structural changes

Laryngopharyngeal reflux diagnosis in obstructive sleep apnea patients using the pepsin salivary test

Background: To investigate the presence of laryngopharyngeal reflux in patients with obstructive sleep apnea (OSA) employing the salivary pepsin concentration method. To compare the results of pepsin concentration with the severity of the pathology. Methods: Seventy-five OSA patients (44 males, 31 females) were enrolled in the study. For each patient, the AHI (apnea–hypopnea index) and the BMI (body mass index) were initially evaluated. All the patients enrolled were assessed using the reflux symptom index (RSI) and the reflux finding score (RFS) in order to perform a clinical diagnosis of laryngopharyngeal reflux. In all patients a salivary sample was taken to estimate the presence of pepsin and its concentration. Results: The incidence of LPR (laryngopharyngeal reflux) in OSA patients, evaluated using the salivary pepsin concentration test (PEP-test), was found to be 32% of cases. Linear regression testing did not show any correlation between AHI and pepsin concentration in salivary samples (p = 0.1). Conclusion: A high number of patients with OSA seem to show positivity for salivary pepsin, correlated to an LPR. There does not appear to be a correlation between the severity of apnea and the grade of salivary pepsin reflux. On the other hand, direct correlation between BMI and the value of pepsin in salivary specimens was observed

Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with {MeCP}2 non-sense mutations

Rett Syndrome (RTT) is a rare X-linked neurodevelopmental disorder which affects about 1: 10000 live births. In >95% of subjects RTT is caused by a mutation in Methyl-CpG binding protein-2 (MECP2) gene, which encodes for a transcription regulator with pleiotropic genetic/epigenetic activities. The molecular mechanisms underscoring the phenotypic alteration of RTT are largely unknown and this has impaired the development of therapeutic approaches to alleviate signs and symptoms during disease progression. A defective proteasome biogenesis into two skin primary fibroblasts isolated from RTT subjects harbouring non-sense (early-truncating) MeCP2 mutations (i.e., R190fs and R255X) is herewith reported. Proteasome is the proteolytic machinery of Ubiquitin Proteasome System (UPS), a pathway of overwhelming relevance for post-mitotic cells metabolism. Molecular, transcription and proteomic analyses indicate that MeCP2 mutations down-regulate the expression of one proteasome subunit, α7, and of two chaperones, PAC1 and PAC2, which bind each other in the earliest step of proteasome biogenesis. Furthermore, this molecular alteration recapitulates in neuron-like SH-SY5Y cells upon silencing of MeCP2 expression, envisaging a general significance of this transcription regulator in proteasome biogenesis

A Novel Smad7 Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn's Disease

Down-regulation of Smad7 with a specific Smad7 antisense (AS) oligonucleotide-containing oral drug (Mongersen) was effective in pre-clinical studies and initial clinical trials in Crohn's disease (CD) patients. A recent phase 3 trial was discontinued due to an apparent inefficacy of the drug, but factors contributing to the failure of this study remain unknown. Here, we analysed the frequency in CD of rs144204026 C/T single nucleotide polymorphism (SNP), which maps on the corresponding region targeted by the Smad7 AS contained in the Mongersen formulation and examined whether such a variant allele affects the ability of Smad7 AS to knockdown Smad7

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Doyne honeycomb retinal dystrophy – functional improvement following subthreshold nanopulse laser treatment: a case report

Abstract Background Based on phenotypic similarities between age-related macular degeneration and the autosomal disorder Doyne honeycomb retinal dystrophy, we report on a single nanolaser treatment of a patient with genotype Doyne honeycomb retinal dystrophy confirmation and evidence of disease progression over 12 months. The case study is the first report of short-term results of subthreshold nanolaser treatment in a patient with Doyne honeycomb retinal dystrophy. Case presentation A 43-year-old Caucasian man with moderate loss of visual acuity in his left eye (20/40) and normal visual acuity in his right eye (20/20), with clinical Doyne honeycomb retinal dystrophy diagnosis and genetic confirmation of the common heterozygous mutation (EFEMP1) by genetic testing, underwent nanopulse subthreshold laser treatment in his left eye. A safety examination, carried out 7 days after treatment, and clinical follow-up, conducted 60 days following laser treatment, showed improvement of visual acuity from baseline by two letters and a subjective improvement of blurring. While no apparent morphological changes were found on fundoscopy, increased autofluorescence in the treated eye was observed on imaging. In addition, 2 months after nanopulse subthreshold laser treatment, rod-mediated and cone-mediated full-field electroretinography b-wave amplitudes showed an increase from baseline in both the treated eye (300%) and untreated eye (50%). At 2 months after nanopulse subthreshold laser treatment, multifocal electroretinograms showed improvement. Acuity and full-field electroretinography improvement persisted at 6-month follow-up. Conclusions Sustained improvements in retinal function on electroretinography persisted in both eyes 6 months after treatment, suggesting an enhancement of phototransduction and retinoid recycling induced by nanopulse subthreshold laser treatment. The functional improvement observed in the untreated eye is hypothesized to arise from an increased expression and release of metalloproteinases that circulate systemically