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N 6 -Methyladenosine (m 6 A) is the most abundant internal modification in mRNAs. Despite accumulating evidence for the profound impact of m 6 A on cancer biology, there are conflicting reports that alterations in genes encoding the m 6 A machinery proteins can either promote or suppress cancer, even in the same tumor type. Using data from The Cancer Genome Atlas, we performed a pan-cancer investigation of 15 m 6 A core factors in nearly 10000 samples from 31 tumor types to reveal underlying cross-tumor patterns. Altered expression, largely driven by copy number variations at the chromosome arm level, results in the most common mode of dysregulation of these factors. YTHDF1, YTHDF2, YTHDF3 and VIRMA are the most frequently altered factors and the only ones to be uniquely altered when tumors are grouped according to the expression pattern of the m 6 A factors. These genes are also the only ones with coherent, pan-cancer predictive power for progression-free survival. On the contrary, METTL3, the most intensively studied m 6 A factor as a cancer target, shows much lower levels of alteration and no predictive power for patient survival. Therefore, we propose the non-enzymatic YTHDF and VIRMA genes as preferred subjects to dissect the role of m 6 A in cancer and as priority cancer targets., (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Cancer.)

Altered RNA modification patterns and dysregulated expression of epitranscriptomic machinery proteins (EMPs) have been causatively correlated with several diseases. Modulation of EMP gene expression has shown promise in reversing disease-associated phenotypes, making EMPs attractive therapeutic targets. Various therapeutic strategies, including small-molecule modulators, proteolysis-targeting chimeras, and molecular tools for site-specific engineering of RNA modifications, have been introduced to modulate EMPs and RNA modifications themselves and are currently being investigated to enrich the physician's armamentarium. At the forefront of research are small-molecule inhibitors of the key players involved in the N 6 -methyladenosine RNA modification, with an inhibitor of methyltransferase 3 in clinical trials. Preclinical studies have also demonstrated proof-of-concept for the other approaches, raising expectations for this exciting new frontier of therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We discuss the coexistence of a postmortem cut and a pathological alteration, recorded on a skeleton belonging to an adult man that was discovered during the archaeological investigations of the cemetery of the Church of Santa Maria Maggiore in Vercelli (northern Italy, 18 th -19 th century). The skull presents an oblique cleft, which from the top of the frontal bone bends towards the occipital, and the left styloid process is elongated compared to normal values (48 mm). The elongated styloid process is due to the ossification of the styloid ligament which has several possible causes. To increase the knowledge about this pathological condition in the past, it was necessary to compare all the data present in the literature today and consider the few cases published in the paleopathological field. In this paper, our main goals are: i) to investigate the reasons for which the craniotomy was performed; ii) to examine the possible cause of the ossification of the styloid process, described as Eagle's syndrome; iii) to enrich the archaeological literature of elongated styloid process cases and iv) to investigate the presence of a hypothetical relationship between the autopsy cut and the diagnosed Eagle's syndrome on this skull.

Neuroblastoma (NB) is an aggressive childhood tumor, with high-risk cases having a 5-year overall survival probability of approximately 50%. The multimodal therapeutic approach for NB includes treatment with the retinoid isotretinoin (13-cis retinoic acid; 13cRA), which is used in the post-consolidation phase as an antiproliferation and prodifferentiation agent to minimize residual disease and prevent relapse. Through small-molecule screening, we identified isorhamnetin (ISR) as a synergistic compound with 13cRA in inhibiting up to 80% of NB cell viability. The synergistic effect was accompanied by a marked increase in the expression of the adrenergic receptor α1B (ADRA1B) gene. Genetic knockout of ADRA1B or its specific blockade using α1/α1B adrenergic antagonists led to selective sensitization of MYCN-amplified NB cells to cell viability reduction and neural differentiation induced by 13cRA, thus mimicking ISR activity. Administration of doxazosin, a safe α1-antagonist used in pediatric patients, in combination with 13cRA in NB xenografted mice exerted marked control of tumor growth, whereas each drug alone was ineffective. Overall, this study identified the α1B adrenergic receptor as a pharmacologic target in NB, supporting the evaluation of adding α1-antagonists to the post-consolidation therapy of NB to more efficiently control residual disease., Significance: Targeting α-adrenergic receptors synergizes with isotretinoin to suppress growth and to promote differentiation of neuroblastoma, revealing a combinatorial approach for more effective management of the disease and prevention of relapse., (©2023 American Association for Cancer Research.)

RNA G-quadruplexes (RG4s) are non-canonical, disease-associated post-transcriptional regulators of gene expression whose functions are driven by RNA-binding proteins (RBPs). Being able to explore transcriptome-wide RG4 formation and interaction with RBPs is thus paramount to understanding how they are regulated and exploiting them as potential therapeutic targets. Towards this goal, we present QUADRatlas (https://rg4db.cibio.unitn.it), a database of experimentally-derived and computationally predicted RG4s in the human transcriptome, enriched with biological function and disease associations. As RBPs are key to their function, we mined known interactions of RG4s with such proteins, complemented with an extensive RBP binding sites dataset. Users can thus intersect RG4s with their potential regulators and effectors, enabling the formulation of novel hypotheses on RG4 regulation, function and pathogenicity. To support this capability, we provide analysis tools for predicting whether an RBP can bind RG4s, RG4 enrichment in a gene set, and de novo RG4 prediction. Genome-browser and table views allow exploring, filtering, and downloading the data quickly for individual genes and in batch. QUADRatlas is a significant step forward in our ability to understand the biology of RG4s, offering unmatched data content and enabling the integrated analysis of RG4s and their interactions with RBPs., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

A variety of single-gene human diseases are caused by haploinsufficiency, a genetic condition by which mutational inactivation of one allele leads to reduced protein levels and functional impairment. Translational enhancement of the spare allele could exert a therapeutic effect. Here we developed BOOST, a novel gene-editing approach to rescue haploinsufficiency loci by the change of specific single nucleotides in the Kozak sequence, which controls translation by regulating start codon recognition. We evaluated for translational strength 230 Kozak sequences of annotated human haploinsufficient genes and 4621 derived variants, which can be installed by base editing, by a high-throughput reporter assay. Of these variants, 149 increased the translation of 47 Kozak sequences, demonstrating that a substantial proportion of haploinsufficient genes are controlled by suboptimal Kozak sequences. Validation of 18 variants for 8 genes produced an average enhancement in an expression window compatible with the rescue of the genetic imbalance. Base editing of the NCF1 gene, whose monoallelic loss causes chronic granulomatous disease, resulted in the desired increase of NCF1 (p47phox) protein levels in a relevant cell model. We propose BOOST as a fine-tuned approach to modulate translation, applicable to the correction of dozens of haploinsufficient monogenic disorders independently of the causing mutation., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Fly ash from municipal solid waste incineration (MSWI-FA) contains leachable heavy metals. In the present study the correlations between heavy metal content, particle size, speciation distribution with respect to water leaching are investigated, using a combination of solid-state bulk analytical techniques, leaching treatments, sequential extractions and thermodynamic geochemical modelling. Among the analyzed heavy metals, Zn and Pb are the most abundant in any grain size class, followed by Cu, Cr, Cd and Ni, with concentration that tends to increase with a decrease of the grain size. The phase composition is constituted of salt (halite, sylvite, anhydrite and syngenite), which provide the main minerals regardless of the particle size class; calcite, quartz and gehlenite occur in comparatively lower amounts, while 50% wt is composed of amorphous fraction. Heavy metal leaching is strongly correlated to speciation distribution, and in particular to the fraction (F1) associated with salt, carbonate and weak surface sorption. Leaching from speciation due to surface complexation on Al/Fe (hydr)oxide becomes relevant at acidic regime. Particle size and heavy metal content, in turn, moderately correlate with leaching. The F1-speciation as a function of particle size does not exhibit a definite trend shared by all heavy metals under investigation. This suggests that i) differences in speciation distribution, rather than bare heavy metal content or particle size, govern leaching from MSWI-FA; ii) F1 can be regarded as a marker of the potential heavy metal leaching; iii) a comparatively modest efficiency in managing MSWI-FA is expected from grain size separation strategies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The MODOMICS database has been, since 2006, a manually curated and centralized resource, storing and distributing comprehensive information about modified ribonucleosides. Originally, it only contained data on the chemical structures of modified ribonucleosides, their biosynthetic pathways, the location of modified residues in RNA sequences, and RNA-modifying enzymes. Over the years, prompted by the accumulation of new knowledge and new types of data, it has been updated with new information and functionalities. In this new release, we have created a catalog of RNA modifications linked to human diseases, e.g., due to mutations in genes encoding modification enzymes. MODOMICS has been linked extensively to RCSB Protein Data Bank, and sequences of experimentally determined RNA structures with modified residues have been added. This expansion was accompanied by including nucleotide 5'-monophosphate residues. We redesigned the web interface and upgraded the database backend. In addition, a search engine for chemically similar modified residues has been included that can be queried by SMILES codes or by drawing chemical molecules. Finally, previously available datasets of modified residues, biosynthetic pathways, and RNA-modifying enzymes have been updated. Overall, we provide users with a new, enhanced, and restyled tool for research on RNA modification. MODOMICS is available at https://iimcb.genesilico.pl/modomics/., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Untranslated regions of mRNA (UTRs) are involved in defining the fate of the transcript through processes such as mRNA localization, degradation, translation initiation regulation, and several others: the action of trans-factors such as RNA-binding proteins and non-coding RNAs, combined with the presence of defined sequence and structural cis-elements, ultimately determines protein synthesis levels. Identifying functional regions in UTRs and uncovering post-transcriptional regulators acting upon these is thus of paramount importance to understand this regulatory layer: these tasks can now be approached computationally to reduce the testable hypothesis space and drive the experimental validation in a more effective way.This chapter will focus on presenting databases and tools allowing to study the various aspects of post-transcriptional regulation, including the profiling of actively translated mRNAs, regulatory network analysis (e.g., RBP and ncRNA binding sites), trans-factor binding sites prediction, motif search (sequence and secondary structure), and other aspects of this regulatory layer: two potential analysis pipelines are also presented as practical examples of how these tools could be integrated and effectively employed., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

RNA modifications have recently emerged as a widespread and complex facet of gene expression regulation. Counting more than 170 distinct chemical modifications with far-reaching implications for RNA fate, they are collectively referred to as the epitranscriptome. These modifications can occur in all RNA species, including messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). In mRNAs the deposition, removal, and recognition of chemical marks by writers, erasers and readers influence their structure, localization, stability, and translation. In turn, this modulates key molecular and cellular processes such as RNA metabolism, cell cycle, apoptosis, and others. Unsurprisingly, given their relevance for cellular and organismal functions, alterations of epitranscriptomic marks have been observed in a broad range of human diseases, including cancer, neurological and metabolic disorders. Here, we will review the major types of mRNA modifications and editing processes in conjunction with the enzymes involved in their metabolism and describe their impact on human diseases. We present the current knowledge in an updated catalog. We will also discuss the emerging evidence on the crosstalk of epitranscriptomic marks and what this interplay could imply for the dynamics of mRNA modifications. Understanding how this complex regulatory layer can affect the course of human pathologies will ultimately lead to its exploitation toward novel epitranscriptomic therapeutic strategies., (© 2021 Destefanis et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

The increase in the amount of carbon dioxide (CO 2 ) emissions related to many anthropic activities is a persistent and growing problem. During the last years, many solutions have been set out, none of them being the ultimate one. Investigators agree on the need of a synergic approach to the problem, in terms of many complementary methods of sequestration that, combined with the reduction of production, will be able to decrease the concentration of the CO 2 in the atmosphere. In this work, we explore the use of a green reaction to trap the CO 2 into a stable crystalline phase (weddellite) resorting to a multidisciplinary approach. CO 2 is reduced and precipitated as calcium oxalate through vitamin C as a sacrificial reductant. Calcium oxalate crystals obtained show a startling good quality that increases their already great stability over a wide chemical and physical conditions' range., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The aim of this study is twofold: (i) characterization of the bottom ashes from the Incinerator plant of the city of Turin (northern Italy), in terms of their chemical/phase compositions and capacity to release heavy metals in leachates, as a function of particle size; (ii) investigation of thermal treatments' efficacy to promote inertization of the same bottom ashes, exploring time-temperature ranges with t ≤ 6 h and T ≤ 1000 °C. Special attention is paid to macro-sampling techniques in order to have samples that are representative of the average bottom ashes production. Micro-XRF, ICP-OES, SEM-EDS, Ion Chromatography and X-ray powder diffraction were used to investigate bottom ashes and leachates. Bottom ashes are mainly constituted by an amorphous phase, ∼66-97 wt%, regardless of particle size; the remaining phases are quartz, calcite, Fe-oxides, melilite and other minor crystalline materials. The amorphous phase exhibits a relevant dependence on particle size, and undergoes dissolution in water up to 20 wt%, thus being the most important component in affecting chemical species release. The smaller the bottom ashes' particle size, the more the heavy metals (major species: Zn, Cu, Ti, Pb) and calcium contents increase, whereas silicon's decreases. Electrolytic current observations in combination with phase/chemical composition and metals release as a function of particle size, suggest that bottom ashes partition into two classes, i.e. ≥1 and <1 mm, for inertization purposes. Thermal treatments exhibit partial efficacy to curb heavy metals mobility: whilst they reduce Cu release, they lead to a inverse effect in the case of Cr., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Neuroblastoma (NB), the most common and deadly extracranial solid tumour of childhood, represents a challenging in paediatric oncology. Soluble tumour necrosis factor (TNF)-related apoptosis-inducing ligand (sTRAIL) is a cancer cell-specific molecule exerting remarkable anti-tumour activities against paediatric malignancies both in vitro and in preclinical settings. However, due to its too fast elimination and to the undesired related side effects, the improvement of sTRAIL in vivo bioavailability and the specific delivery to the tumour is mandatory for increasing its therapeutic efficacy. In this manuscript, we developed an innovative pegylated liposomal formulation carrying the sTRAIL at the outer surface (sTRAIL-SL) with the intent to improve its serum half-life and increase its efficacy in vivo, while reducing side effects. Furthermore, the possibility to combine sTRAIL-SL with the proteasome inhibitor Bortezomib (BTZ) was investigated, being BTZ able to sensitize tumour cells toward TRAIL-induced apoptosis. We demonstrated that sTRAIL preserved and improved its anti-tumour activity when coupled to nanocarriers. Moreover, sTRAIL-SL ameliorated its PK profile in blood allowing sTRAIL to exert a more potent anti-tumour activity, which led, upon BTZ priming, to a statistically significant enhanced life spans in two models of sTRAIL-resistant NB-bearing mice. Finally, mechanistic studies indicated that the combination of sTRAIL with BTZ sensitized sTRAIL-resistant NB tumour cells to sTRAIL-induced cell death, both in vitro and in vivo, through the Akt/GSK3/β-catenin axis-dependent mechanism. In conclusion, our results suggest that sTRAIL-SL might be an efficient vehicle for sTRAIL delivery and that its use in clinic, in combination with BTZ, might represent an adjuvant strategy for the treatment of stage IV, sTRAIL-resistant, NB patients., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Cervical artery dissection is an important cause of stroke in young patients and accounts of 10%-20% of stroke or TIA in patients aged less than 50 years. Basilar artery occlusion (BAO) is an infrequent cause of acute stroke, which invariably leads to death or long-term disability if not recanalized. We describe three patients with BAO caused by vertebral dissection, successfully treated with intra-arterial thrombolysis. The lysis of the occluding embolus was obtained by injection of the thrombolytic drug directly or near the thrombus without haemorrhagic complications. Our cases confirm the safety and efficacy of intra-arterial thrombolysis in patients with BAO due to a vertebral artery dissection.

Moya-Moya is a rare cerebrovascular occlusive disease characterized by bilateral stenosis or occlusion at the terminal portion of the internal carotid artery and abnormal vascular network at the base of the brain, named "moya-moya". In children, Moya-Moya disease usually presents with ischemic cerebrovascular events, mainly TIA or lacunar stroke, leading to mental deterioration. In adults, especially in females, it presents with intracranial haemorrhages. We describe the case of an adult patient with an atherosclerotic Moya-Moya disease which presented with a cerebral borderzone infarction.

Lipoprotein(a) [Lp(a)] is a plasma lipoprotein that consists of a low-density lipoprotein (LDL)-like particle containing APO B-100 and apolipoprotein(a), linked by a disulphide bridge. There is evidence that higher serum level of Lp(a) is a predictor of various vascular diseases, such as myocardial infarction, coronary stenosis, re-occlusion of aortocoronary bypass vein grafts, peripheral atherosclerosis and cerebral infarction [1-4]. We describe a young man with a cryptogenic stroke with very high serum level of Lp(a) as the only vascular risk factor.

The aim of this study was to evaluate the risk of recurrent ischaemic cerebrovascular events (stroke or transient ischaemic attack (TIA)) in patients with patent foramen ovale (PFO) or atrial septal aneurysm (ASA) treated with different therapeutic regimens. We enrolled 86 patients aged 18-60 years with an unexplained ischaemic stroke or TIA referred to our inpatient department in the period May 1994-December 1999. Follow-up lasted until April 2003. Patients were excluded if the stroke or TIA was related to large-artery atherosclerosis, small artery occlusion, major cardiac sources of embolism or other uncommon causes. During a follow-up (mean+/-SD) of 64.1+/-28.8 months (range 8.1-105.6) a recurrent ischaemic cerebrovascular event occurred in 11/86 patients (12.8%) (5 TIA and 6 strokes). Eight events (4 TIA, 4 strokes) occurred in the 59 patients with PFO alone, three (1 TIA, 2 strokes) in the 21 with PFO plus ASA and none in the 6 patients with ASA alone. In the overall population the cumulative risk of recurrent stroke/TIA was 1.2% at 2 years, 5.5% at 4 years, 7.6% at 6 years and 23.6% at 8 years, and was similar in patients with PFO alone vs. patients with PFO plus ASA (9.0% vs. 6.1% at 6 years, 26.0% vs. 23.1% at 8 years; p>0.05). Nine cerebral ischaemic events (4 TIA, 5 strokes) occurred in the 48 patients treated with antiplatelet drugs (7 in patients with PFO, 2 in patients with PFO plus ASA), and two (1 TIA, 1 stroke) in the 17 patients treated with oral anticoagulants (1 with PFO, 1 with PFO plus ASA). No events occurred in patients submitted to transcatheteral closure.