Molecular Taxonomy: Use of Transcriptional Profiles to Identify Different ALS Subtypes

Advances in diagnostic techniques and high-throughput biotechnologies provide a compelling opportunity to improve the diagnosis and treatment of diseases by developing a “New Taxonomy” that defines diseases on the basis of their underlying molecular and environmental factors rather than on traditional physical signs and symptoms. Oncology represents the first interesting example of how genomic medicine has changed the understanding of diseases and their therapy. However, much work remains to be completed on the molecular characterization and classification of complex and multifactorial diseases, including neurodegenerative disorders. Our research group has recently shown the genomic heterogeneity of sporadic amyotrophic lateral sclerosis (SALS), identifying two divergent subtypes associated with differentially expressed genes and pathways and providing several potential biomarkers and therapeutic targets. This chapter reviews the results emerged from our work, highlighting how molecular characterization of SALS patients may provide a framework for developing a more precise and accurate classification of diseases that could revolutionize the diagnosis, therapy, and clinical decisions of diseases, leading to more individualized treatments and improved outcomes for patients

Taxonomy Meets Neurology, the Case of Amyotrophic Lateral Sclerosis

Recent landmark publications from our research group outline a transformative approach to defining, studying and treating amyotrophic lateral sclerosis (ALS). Rather than approaching ALS as a single entity, we advocate targeting therapies to distinct “clusters” of patients based on their specific genomic and molecular features. Our findings point to the existence of a molecular taxonomy for ALS, bringing us a step closer to the establishment of a precision medicine approach in neurology practice

Tidal notches in Mediterranean Sea: a comprehensive analysis

Recent works (Evelpidou et al., 2012) suggest that the modern tidal notch is disappearing worldwide due sea level rise over the last century. In order to assess this hypothesis, we measured modern tidal notches in several of sites along the Mediterranean coasts. We report observations on tidal notches cut along carbonate coasts from 73 sites from Italy, France, Croatia, Montenegro, Greece, Malta and Spain, plus additional observations carried outside the Mediterranean. At each site, we measured notch width and depth, and we described the characteristics of the biological rim at the base of the notch. We correlated these parameters with wave energy, tide gauge datasets and rock lithology. Our results suggest that, considering \u2018the development of tidal notches the consequence of midlittoral bioerosion\u2019 (as done in Evelpidou et al., 2012) is a simplification that can lead to misleading results, such as stating that notches are disappearing. Important roles in notch formation can be also played by wave action, rate of karst dissolution, salt weathering and wetting and drying cycles. Of course notch formation can be augmented and favoured also by bioerosion which can, in particular cases, be the main process of notch formation and development. Our dataset shows that notches are carved by an ensemble rather than by a single process, both today and in the past, and that it is difficult, if not impossible, to disentangle them and establish which one is prevailing. We therefore show that tidal notches are still forming, challenging the hypothesis that sea level rise has drowned them

New national and regional Annex I Habitat records: from #45 to #59

New Italian data on the distribution of Annex I Habitats are reported in this contribution. Specifically, 8 new occurrences in Natura 2000 sites are presented and 27 new cells are added in the EEA 10 km × 10 km reference grid. The new data refer to the Italian administrative regions of Apulia, Campania, Calabria, Lazio, Tuscany, Umbria, Sardinia, and Sicily

Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway

Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2+/- mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2+/- mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2+/- mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4\u202f 7 10-2) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis

Evolving trends in the management of acute appendicitis during COVID-19 waves. The ACIE appy II study

Background: In 2020, ACIE Appy study showed that COVID-19 pandemic heavily affected the management of patients with acute appendicitis (AA) worldwide, with an increased rate of non-operative management (NOM) strategies and a trend toward open surgery due to concern of virus transmission by laparoscopy and controversial recommendations on this issue. The aim of this study was to survey again the same group of surgeons to assess if any difference in management attitudes of AA had occurred in the later stages of the outbreak. Methods: From August 15 to September 30, 2021, an online questionnaire was sent to all 709 participants of the ACIE Appy study. The questionnaire included questions on personal protective equipment (PPE), local policies and screening for SARS-CoV-2 infection, NOM, surgical approach and disease presentations in 2021. The results were compared with the results from the previous study. Results: A total of 476 answers were collected (response rate 67.1%). Screening policies were significatively improved with most patients screened regardless of symptoms (89.5% vs. 37.4%) with PCR and antigenic test as the preferred test (74.1% vs. 26.3%). More patients tested positive before surgery and commercial systems were the preferred ones to filter smoke plumes during laparoscopy. Laparoscopic appendicectomy was the first option in the treatment of AA, with a declined use of NOM. Conclusion: Management of AA has improved in the last waves of pandemic. Increased evidence regarding SARS-COV-2 infection along with a timely healthcare systems response has been translated into tailored attitudes and a better care for patients with AA worldwide

Molecular Taxonomy of Sporadic Amyotrophic Lateral Sclerosis Using Disease-Associated Genes

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of upper and lower motor neurons. Despite intensive research, the origin and progression of ALS remain largely unknown, suggesting that the traditional clinical diagnosis and treatment strategies might not be adequate to completely capture the molecular complexity underlying the disease. In our previous work, comprehensive genomic profiling of 41 motor cortex samples enabled to discriminate control from sporadic ALS patients and segregated these latter into two distinct subgroups, each associated with different deregulated genes and pathways. Interestingly, some deregulated genes in sporadic ALS were previously associated with familiar ALS, indicating shared pathogenic mechanisms between the two forms of disease. In this, we performed cluster analysis on the same whole-genome expression profiles using a restricted (203) subset of genes extensively implicated in monogenic forms of ALS. Surprisingly, this short and unbiased gene list was sufficiently representative to allow the accurate separation of SALS patients from controls and the stratification of SALS patients into two molecularly distinct subgroups. Overall, our findings support the existence of a molecular taxonomy for ALS and represent a further step toward the establishment of a molecular-based diagnosis and patient-tailored therapies

Integrative multi-omic analysis identifies new drivers and pathways in molecularly distinct subtypes of ALS

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease. Increasing the chances of success for future clinical strategies requires more in-depth knowledge of the molecular basis underlying disease heterogeneity. We recently laid the foundation for a molecular taxonomy of ALS by whole-genome expression profiling of motor cortex from sporadic ALS (SALS) patients. Here, we analyzed copy number variants (CNVs) occurring in the same patients, by using a customized exon-centered comparative genomic hybridization array (aCGH) covering a large panel of ALS-related genes. A large number of novel and known disease-associated CNVs were detected in SALS samples, including several subgroup-specific loci, suggestive of a great divergence of two subgroups at the molecular level. Integrative analysis of copy number profiles with their associated transcriptomic data revealed subtype-specific genomic perturbations and candidate driver genes positively correlated with transcriptional signatures, suggesting a strong interaction between genomic and transcriptomic events in ALS pathogenesis. The functional analysis confirmed our previous pathway-based characterization of SALS subtypes and identified 24 potential candidates for genomic-based patient stratification. To our knowledge, this is the first comprehensive “omics” analysis of molecular events characterizing SALS pathology, providing a road map to facilitate genome-guided personalized diagnosis and treatments for this devastating disease