Human blood lipid profiles after dietary supplementation of different omega 3 ethyl esters formulations.

The validity of omega 3 fatty acids (ω3 FAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as dietary supplements has been widely proved. It's well known in fact, that they protect against cardiovascular diseases, reduce the levels of triacylglycerides (TAGs) and cholesteryl esters (CEs) in blood, and have anti-inflammatory activity. For these reasons, in the last few years the production of dietary supplement containing ω3 has increased significantly. In this context, the possibility to obtain ω3 and other high value molecules from alternative sources as fish waste, in accordance with the principles of circular economy, becomes an enormous attractive. In addition, the opportunity of creating new products, with greater health benefits, represents an interesting challenge. The current study was focused on the extraction of ω3 fatty acids and peptides from tuna waste industry, to realize a new dietary supplement. To this purpose, a supercritical fluid extraction (SFE) method was developed to separate, isolate, and enrich the different fractions subsequently used to produce an innovative formulate. The obtained supplement was characterized in terms of fatty acids esterified ester (FAEE) composition by gas chromatography (GC) coupled to both flame ionization detection (FID) and mass spectrometry (MS), and content of heavy metals by inductively coupled plasma-mass spectrometry (ICP-MS). The effects of ω3 supplementation on metabolism and circulating lipid profiles was tested on 12 volunteers and assessed by GC-FID analysis of whole blood collected on paper support (Dried Blood Spot, DBS) at the beginning of the study and after thirty days. The results of plasma fatty acids levels after 30 days showed a significant decrease in the ω6/ω3 ratio, as well as the saturated/polyunsaturated fatty acids (SFA/PUFA) ratio, compared to subjects who took the ω3 ethyl esters unformulated. The novel formulated supplements proved to be extremely interesting and promising products, due to a significant increase in bioavailability, that makes it highly competitive in the current panorama of the nutraceutical industry.

Sagittal kinematics and imbalance of the spine and whole body during walking in late-onset Pompe disease.

Late-onset Pompe disease (LOPD) is characterized by postural abnormalities mainly due to involvement of paraspinal lumbar and abdominal-pelvic muscles. Previous studies quantitatively analyzed static upright posture, spatial-temporal parameters, and kinematics of the lower limbs and trunk, considered as single bone segment. Sagittal plane analysis of the spine and whole body during walking has never been investigated in patients with LOPD. The aim of the study was to evaluate sagittal kinematics and imbalance of the spine and whole body in patients with LOPD by three-dimensional (3-D)-motion analysis using an appropriate marker set protocol and introducing innovative kinematic parameters. Seven siblings with LOPD were assessed by 3-D-stereophotogrammetry using the DB-total protocol, which allows to analyze sagittal alignment of whole body. Fourteen age- and sex-matched healthy subjects were used as controls. LOPD group showed a flattening of the spinal curvatures, with a head and neck posteriorization with respect to sacrum, a significant increase of concavity in Heel-S2-Nasion/C7 angles, a rear-position of upper limbs with respect to pelvis, a shorter pendular activity, and a trend of elbow extension during ambulation. Moreover, a significant increase of excursion range in most of sagittal parameters was found. The present study highlighted a specific pathological postural pattern, resembling "man falling backwards," which reveals a biomechanical compensation strategy of patients with LOPD to maintain the balance against the instability of the spinopelvic region, kinematically verified by increase of the excursion ranges. DB-total kinematic parameters might be useful for functional evaluation and for monitoring response to enzyme replacement therapy, rehabilitation project, and disease progression.NEW & NOTEWORTHY This study is the first to quantitatively characterize the sagittal spine and whole body posture of patients with late-onset Pompe disease during walking, showing a pathological kinematic pattern defined "man falling backwards." 3-D-motion analysis, with a specific marker set (DB-total protocol) introducing new whole body kinematic parameters, may be useful for accurate functional evaluation and monitoring this rare disease.

Truncated Analogues of a G-Quadruplex-Forming Aptamer Targeting Mutant Huntingtin: Shorter Is Better!

Two analogues of the MS3 aptamer, which was previously shown to have an exquisite capability to selectively bind and modulate the activity of mutant huntingtin (mHTT), have been here designed and evaluated in their physicochemical and biological properties. Featured by a distinctive propensity to form complex G-quadruplex structures, including large multimeric aggregates, the original 36-mer MS3 has been truncated to give a 33-mer (here named MS3-33) and a 17-mer (here named MS3-17). A combined use of different techniques (UV, CD, DSC, gel electrophoresis) allowed a detailed physicochemical characterization of these novel G-quadruplex-forming aptamers, tested in vitro on SH-SY5Y cells and in vivo on a Drosophila Huntington's disease model, in which these shorter MS3-derived oligonucleotides proved to have improved bioactivity in comparison with the parent aptamer.

Genotype-Phenotype Correlations in Neurofibromatosis Type 1: Identification of Novel and Recurrent NF1 Gene Variants and Correlations with Neurocognitive Phenotype.

Neurofibromatosis type 1 (NF1) is one of the most common genetic tumor predisposition syndrome, caused by mutations in the NF1. To date, few genotype-phenotype correlations have been discerned in NF1, due to a highly variable clinical presentation. We aimed to study the molecular spectrum of NF1 and genotype-phenotype correlations in a monocentric study cohort of 85 NF1 patients (20 relatives, 65 sporadic cases). Clinical data were collected at the time of the mutation analysis and reviewed for accuracy in this investigation. An internal phenotypic categorization was applied. The 94% of the patients enrolled showed a severe phenotype with at least one systemic complication and a wide range of associated malignancies. Spine deformities were the most common complications in this cohort. We also reported 66 different NF1 mutations, of which 7 are novel mutations. Correlation analysis identified a slight significant inverse correlation between age at diagnosis and delayed acquisition of psychomotor skills with residual multi-domain cognitive impairment. Odds ratio with 95% confidence interval showed a higher prevalence of learning disabilities in patients carrying frameshift mutations. Overall, our results aim to offer an interesting contribution to studies on the genotype-phenotype of NF1 and in genetic management and counselling.

Down Syndrome Fetal Fibroblasts Display Alterations of Endosomal Trafficking Possibly due to SYNJ1 Overexpression.

Endosomal trafficking is essential for cellular homeostasis. At the crossroads of distinct intracellular pathways, the endolysosomal system is crucial to maintain critical functions and adapt to the environment. Alterations of endosomal compartments were observed in cells from adult individuals with Down syndrome (DS), suggesting that the dysfunction of the endosomal pathway may contribute to the pathogenesis of DS. However, the nature and the degree of impairment, as well as the timing of onset, remain elusive. Here, by applying imaging and biochemical approaches, we demonstrate that the structure and dynamics of early endosomes are altered in DS cells. Furthermore, we found that recycling trafficking is markedly compromised in these cells. Remarkably, our results in 18-20 week-old human fetal fibroblasts indicate that alterations in the endolysosomal pathway are already present early in development. In addition, we show that overexpression of the polyphosphoinositide phosphatase synaptojanin 1 (Synj1) recapitulates the alterations observed in DS cells, suggesting a role for this lipid phosphatase in the pathogenesis of DS, likely already early in disease development. Overall, these data strengthen the link between the endolysosomal pathway and DS, highlighting a dangerous liaison among Synj1, endosomal trafficking and DS.

Fighting the Huntington's Disease with a G-Quadruplex-Forming Aptamer Specifically Binding to Mutant Huntingtin Protein: Biophysical Characterization, In Vitro and In Vivo Studies.

A set of guanine-rich aptamers able to preferentially recognize full-length huntingtin with an expanded polyglutamine tract has been recently identified, showing high efficacy in modulating the functions of the mutated protein in a variety of cell experiments. We here report a detailed biophysical characterization of the best aptamer in the series, named MS3, proved to adopt a stable, parallel G-quadruplex structure and show high nuclease resistance in serum. Confocal microscopy experiments on HeLa and SH-SY5Y cells, as models of non-neuronal and neuronal cells, respectively, showed a rapid, dose-dependent uptake of fluorescein-labelled MS3, demonstrating its effective internalization, even in the absence of transfecting agents, with no general cytotoxicity. Then, using a well-established Drosophila melanogaster model for Huntington's disease, which expresses the mutated form of human huntingtin, a significant improvement in the motor neuronal function in flies fed with MS3 was observed, proving the in vivo efficacy of this aptamer.

Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network.

Background and Objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability. Methods: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. Results: A total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3). Discussion: The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability.

POLR3A variants in hereditary spastic paraparesis and ataxia: clinical, genetic, and neuroradiological findings in a cohort of Italian patients.

Mutations in POLR3A are characterized by high phenotypic heterogeneity, with manifestations ranging from severe childhood-onset hypomyelinating leukodystrophic syndromes to milder and later-onset gait disorders with central hypomyelination, with or without additional non-neurological signs. Recently, a milder phenotype consisting of late-onset spastic ataxia without hypomyelinating leukodystrophy has been suggested to be specific to the intronic c.1909 + 22G > A mutation in POLR3A. Here, we present 10 patients from 8 unrelated families with POLR3A-related late-onset spastic ataxia, all harboring the c.1909 + 22G > A variant. Most of them showed an ataxic-spastic picture, two a "pure" cerebellar phenotype, and one a "pure" spastic presentation. The non-neurological findings typically associated with POLR3A mutations were absent in all the patients. The main findings on brain MRI were bilateral hyperintensity along the superior cerebellar peduncles on FLAIR sequences, observed in most of the patients, and cerebellar and/or spinal cord atrophy, found in half of the patients. Only one patient exhibited central hypomyelination. The POLR3A mutations present in this cohort were the c.1909 + 22G > A splice site variant found in compound heterozygosity with six additional variants (three missense, two nonsense, one splice) and, in one patient, with a novel large deletion involving exons 14-18. Interestingly, this patient had the most "complex" presentation among those observed in our cohort; it included some neurological and non-neurological features, such as seizures, neurosensory deafness, and lipomas, that have not previously been reported in association with late-onset POLR3A-related disorders, and therefore further expand the phenotype.

A Translational Approach to Spinal Neurofibromatosis: Clinical and Molecular Insights from a Wide Italian Cohort.

Spinal neurofibromatosis (SNF), a phenotypic subclass of neurofibromatosis 1 (NF1), is characterized by bilateral neurofibromas involving all spinal roots. In order to deepen the understanding of SNF's clinical and genetic features, we identified 81 patients with SNF, 55 from unrelated families, and 26 belonging to 19 families with at least 1 member affected by SNF, and 106 NF1 patients aged >30 years without spinal tumors. A comprehensive NF1 mutation screening was performed using NGS panels, including NF1 and several RAS pathway genes. The main features of the SNF subjects were a higher number of internal neurofibromas (p < 0.001), nerve root swelling (p < 0.001), and subcutaneous neurofibromas (p = 0.03), while hyperpigmentation signs were significantly less frequent compared with the classical NF1-affected cohorts (p = 0.012). Fifteen patients underwent neurosurgical intervention. The histological findings revealed neurofibromas in 13 patients and ganglioneuromas in 2 patients. Phenotypic variability within SNF families was observed. The proportion of missense mutations was higher in the SNF cases than in the classical NF1 group (21.40% vs. 7.5%, p = 0.007), conferring an odds ratio (OR) of 3.34 (CI = 1.33−10.78). Two unrelated familial SNF cases harbored in trans double NF1 mutations that seemed to have a subclinical worsening effect on the clinical phenotype. Our study, with the largest series of SNF patients reported to date, better defines the clinical and genetic features of SNF, which could improve the management and genetic counseling of NF1.

Nanoparticle-Guided Brain Drug Delivery: Expanding the Therapeutic Approach to Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) represent a heterogeneous group of aging-related disorders featured by progressive impairment of motor and/or cognitive functions, often accompanied by psychiatric disorders. NDs are denoted as 'protein misfolding' diseases or proteinopathies, and are classified according to their known genetic mechanisms and/or the main protein involved in disease onset and progression. Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) are included under this nosographic umbrella, sharing histopathologically salient features, including deposition of insoluble proteins, activation of glial cells, loss of neuronal cells and synaptic connectivity. To date, there are no effective cures or disease-modifying therapies for these NDs. Several compounds have not shown efficacy in clinical trials, since they generally fail to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells that greatly limits the brain internalization of endogenous substances. By engineering materials of a size usually within 1-100 nm, nanotechnology offers an alternative approach for promising and innovative therapeutic solutions in NDs. Nanoparticles can cross the BBB and release active molecules at target sites in the brain, minimizing side effects. This review focuses on the state-of-the-art of nanoengineered delivery systems for brain targeting in the treatment of AD, PD and HD.

Quantitative Evaluation of Upright Posture by x-Ray and 3D Stereophotogrammetry with a New Marker Set Protocol in Late Onset Pompe Disease.

BACKGROUND: Late Onset Pompe Disease (LOPD) is a rare myopathy characterized by prevailing weakness of trunk and pelvic girdle muscles that causes motor disabilities. Spinal deformities have been reported unclearly on clinical examination. No study quantitatively assessed upright posture defining specific alterations of LOPD various phenotype. OBJECTIVE: Identify postural abnormalities in a homogeneous group of LOPD patients using 3D Stereophotogrammetry (St) and x-Ray (xR). METHODS: Seven LOPD siblings were recruited. They were assessed by clinical scales and, in upright posture, using xR and 3D-St with a new marker set protocol. Fourteen healthy individuals, age and sex-matched, were used as controls for St-parameters; normative xR-values were found in literature. RESULTS: LOPD patients showed a significant weakness of trunk and tibialis anterior muscles. Statistical analysis of St-parameters showed a larger ankle, knee, elbow, dorsal, S2-C7, heel-S2-C7, heel-S2-nasion angles and a lower sagittal vertical axis (SVA) than controls.xR-analysis highlighted an absence of scoliosis and a lower occipito-cervical, C2-C7 cervical and Cobb dorsal angles, and a trend to lower lumbar lordosis and SVA compared to normal values. Significant correlation was found in dorsal and lumbar angles calculated using xR-markers placed on spiny apophysis, xR-centre of vertebral bodies, Cobb-method and St-markers. CONCLUSION: This is the first quantitative study of postural abnormalities in LOPD patients using 3D-St and xR, highlighting sagittal standing alignment changes, difficult to assess to direct exam.Our new St-protocol showed a high reliability compared to xR. Further studies on larger population of LOPD might confirm the usefulness of these instrumental methods for monitoring disease course.

"One Health" Approach for Health Innovation and Active Aging in Campania (Italy).

This article describes how innovations are exploited in Campania (Italy) to improve health outcomes, quality of life, and sustainability of social and healthcare services. Campania's strategy for digitalization of health and care and for healthy aging is based on a person-centered, life-course, "One Health" approach, where demographic change is considered capable of stimulating a growth dynamic linked to the opportunities of combining the "Silver Economy" with local assets and the specific health needs of the population. The end-users (citizens, patients, and professionals) contribute to the co-creation of products and services, being involved in the identification of unmet needs and test-bed activity. The Campania Reference Site of the European Innovation Partnership on Active and Healthy Aging is a flexible regional ecosystem to address the challenge of an aging population with a life-course approach. The good practices, developed in the context of research and innovation projects and innovative procurements by local stakeholders and collaborations with international networks, have been allowing the transfer of innovative solutions, knowledge, and skills to the stakeholders of such a multi-sectoral ecosystem for health.

Short and long term effects of Nabiximols on balance and walking assessed by 3D-gait analysis in people with Multiple Sclerosis and spasticity.

BACKGROUND: Spasticity in people with Multiple Sclerosis (pwMS) is one of the most disabling symptoms on walking ability and balance. Among the systemic antispastic drugs, Nabiximols showed a good tolerability, safety profile and relevant efficacy. A few studies assessed long-term effects of this drug through clinical scales and instrumental tools, but no study investigated short-term effects. The aim of our study is to quantitatively evaluate the immediate effects of Nabiximols on walking and balance and their maintenance after 4 weeks in pwMS and spasticity. METHODS: pwMS were enrolled and randomized in 2 treatment groups: Sativex (SG) and control (CG) group. All patients were assessed at T0 (before the first Sativex puff), T1(after 45 minutes) and T2 (after 4 weeks of treatment) using clinical scales and 3d-Gait Analysis . Then, the patients treated with Sativex, were divided into 5 subgroups according to Numeric Rating Scale for spasticity (NRSs) and Berg Balance Score (BBS) response: NRSs responder[1] and non-[2]; BBS responders[3] and non-[4]; NRSs-BBS responders[5]. RESULTS: 32 pwMS (22 SG, 10 CG) were recruited. Significant improvements were found between T0 and T1 in SG compared to CG in a few clinical and kinematic parameters. Larger significant differences were found for NRSs and BBS responders' groups versus CG. Eventually, no significant differences were found comparing the results between T1 and T2, suggesting the persistence of the improvements emerged at T1. CONCLUSION: These results quantitatively demonstrated a short time effect of Nabiximols on balance and walking of pwMS, which is mantained after 4 weeks. Patients identified as responder by combination of NRSs and BBS showed the best efficacy. These findings may suggest how to early select the real responders in order to improve the adherence and cost-effectiveness of the therapy.

Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families.

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype-phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

Neuroacanthocytosis Syndromes in an Italian Cohort: Clinical Spectrum, High Genetic Variability and Muscle Involvement.

Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis, progressive degeneration of the basal ganglia and neuromuscular features with characteristic persistent hyperCKemia. The main NA syndromes include autosomal recessive chorea-acanthocytosis (ChAc) and X-linked McLeod syndrome (MLS). A series of Italian patients selected through a multicenter study for these specific neurological phenotypes underwent DNA sequencing of the VPS13A and XK genes to search for causative mutations. Where it has been possible, muscle biopsies were obtained and thoroughly investigated with histochemical assays. A total of nine patients from five different families were diagnosed with ChAC and had mostly biallelic changes in the VPS13A gene (three nonsense, two frameshift, three splicing), while three patients from a single X-linked family were diagnosed with McLeod syndrome and had a deletion in the XK gene. Despite a very low incidence (only one thousand cases of ChAc and a few hundred MLS cases reported worldwide), none of the 8 VPS13A variants identified in our patients is shared by two families, suggesting the high genetic variability of ChAc in the Italian population. In our series, in line with epidemiological data, McLeod syndrome occurs less frequently than ChAc, although it can be easily suspected because of its X-linked mode of inheritance. Finally, histochemical studies strongly suggest that muscle pathology is not simply secondary to the axonal neuropathy, frequently seen in these patients, but primary myopathic alterations can be detected in both NA syndromes.

Novel autophagic vacuolar myopathies: Phenotype and genotype features.

BACKGROUND: Autophagic vacuolar myopathies (AVMs) are an emerging group of heterogeneous myopathies sharing histopathological features on muscle pathology, in which autophagic vacuoles are the pathognomonic morphologic hallmarks. Glycogen storage disease type II (GSDII) caused by lysosomal acid α-glucosidase (GAA) deficiency is the best-characterised AVM. AIMS: This study aimed to investigate the mutational profiling of seven neuromuscular outpatients sharing clinical, myopathological and biochemical findings with AVMs. METHODS: We applied a diagnostic protocol, recently published by our research group for suspected late-onset GSDII (LO-GSDII), including counting PAS-positive lymphocytes on blood smears, dried blood spot (DBS)-GAA, muscle biopsy histological and immunofluorescence studies, GAA activity assay and expression studies on muscle homogenate, GAA sequencing, GAA multiplex ligation-dependent probe amplification (MLPA) and whole exome sequencing (WES). RESULTS: The patients had a limb girdle-like muscular pattern with persistent hyperCKaemia; vacuolated PAS-positive lymphocytes, glycogen accumulation and impaired autophagy at muscle biopsy. Decreased GAA activity was also measured. While GAA sequencing identified no pathogenic mutations, WES approach allowed us to identify for each patient an unexpected mutational pattern in genes cooperating in lysosomal-autophagic machinery, some of which have never been linked to human diseases. CONCLUSIONS: Our data suggest that reduced GAA activity may occur in any condition of impaired autophagy and that WES approach is advisable in all genetically undefined cases of autophagic myopathy. Therefore, deficiency of GAA activity and PAS-positive lymphocytes should be considered as AVM markers together with LC3/p62-positive autophagic vacuoles.

"Borderline" idiopathic CD4+ T-cell lymphocytopenia presenting with atypical progressive multifocal leukoencephalopathy.

Idiopathic CD4+ lymphocytopenia (ICL) is a rare disorder characterized by low counts of CD4+ cells (<300/mm3) in absence of other known causes of immunosuppression. A few cases of progressive multifocal leukoencephalopathy (PML) were reported in association with ICL with variable outcome. We describe the case of a 40 year-old man diagnosed with PML, which showed a monophasic course. Causes of primary and secondary immunodeficiency were ruled out, only a "borderline" ICL was found. This case highlights that a severe immunodepression could not be an absolute prerequisite in developing PML and also points the attention on current definition of ICL.

Understanding the Biological Activities of Vitamin D in Type 1 Neurofibromatosis: New Insights into Disease Pathogenesis and Therapeutic Design.

Vitamin D is a fat-soluble steroid hormone playing a pivotal role in calcium and phosphate homeostasis as well as in bone health. Vitamin D levels are not exclusively dependent on food intake. Indeed, the endogenous production-occurring in the skin and dependent on sun exposure-contributes to the majority amount of vitamin D present in the body. Since vitamin D receptors (VDRs) are ubiquitous and drive the expression of hundreds of genes, the interest in vitamin D has tremendously grown and its role in different diseases has been extensively studied. Several investigations indicated that vitamin D action extends far beyond bone health and calcium metabolism, showing broad effects on a variety of critical illnesses, including cancer, infections, cardiovascular and autoimmune diseases. Epidemiological studies indicated that low circulating vitamin D levels inversely correlate with cutaneous manifestations and bone abnormalities, clinical hallmarks of neurofibromatosis type 1 (NF1). NF1 is an autosomal dominant tumour predisposition syndrome causing significant pain and morbidity, for which limited treatment options are available. In this context, vitamin D or its analogues have been used to treat both skin and bone lesions in NF1 patients, alone or combined with other therapeutic agents. Here we provide an overview of vitamin D, its characteristic nutritional properties relevant for health benefits and its role in NF1 disorder. We focus on preclinical and clinical studies that demonstrated the clinical correlation between vitamin D status and NF1 disease, thus providing important insights into disease pathogenesis and new opportunities for targeted therapy.

The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity.

A mismatch between ß-oxidation and the tricarboxylic acid cycle (TCA) cycle flux in mitochondria produces an accumulation of lipid metabolic intermediates, resulting in both blunted metabolic flexibility and decreased glucose utilization in the affected cells. The ability of the cell to switch to glucose as an energy substrate can be restored by reducing the reliance of the cell on fatty acid oxidation. The inhibition of the carnitine system, limiting the carnitine shuttle to the oxidation of lipids in the mitochondria, allows cells to develop a high plasticity to metabolic rewiring with a decrease in fatty acid oxidation and a parallel increase in glucose oxidation. We found that 3-(2,2,2-trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2), was reported to improve mitochondrial dysfunction in several diseases, such as Huntington's disease (HD). Here, new THP-derived carnitine-lowering agents (TCL), characterized by a high affinity for the OCTN2 with a minimal effect on carnitine synthesis, were developed, and their biological activities were evaluated in both in vitro and in vivo HD models. Certain compounds showed promising biological activities: reducing protein aggregates in HD cells, ameliorating motility defects, and increasing the lifespan of HD Drosophila melanogaster.

Bioactive Phenolic Compounds in the Modulation of Central and Peripheral Nervous System Cancers: Facts and Misdeeds.

Efficacious therapies are not available for the cure of both gliomas and glioneuronal tumors, which represent the most numerous and heterogeneous primary cancers of the central nervous system (CNS), and for neoplasms of the peripheral nervous system (PNS), which can be divided into benign tumors, mainly represented by schwannomas and neurofibromas, and malignant tumors of the peripheral nerve sheath (MPNST). Increased cellular oxidative stress and other metabolic aspects have been reported as potential etiologies in the nervous system tumors. Thus polyphenols have been tested as effective natural compounds likely useful for the prevention and therapy of this group of neoplasms, because of their antioxidant and anti-inflammatory activity. However, polyphenols show poor intestinal absorption due to individual intestinal microbiota content, poor bioavailability, and difficulty in passing the blood-brain barrier (BBB). Recently, polymeric nanoparticle-based polyphenol delivery improved their gastrointestinal absorption, their bioavailability, and entry into defined target organs. Herein, we summarize recent findings about the primary polyphenols employed for nervous system tumor prevention and treatment. We describe the limitations of their application in clinical practice and the new strategies aimed at enhancing their bioavailability and targeted delivery.