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Parkinson’s disease (PD) represents the most common neurodegenerative movement disorder. We recently identified 16 novel genes associated with PD. In this study, we focused the attention on the common and rare variants identified in the lysosomal K+ channel TMEM175. The study includes a detailed clinical and genetic analysis of 400 cases and 300 controls. Molecular studies were performed on patient-derived fibroblasts. The functional properties of the mutant channels were assessed by patch-clamp technique and co-immunoprecipitation. We have found that TMEM175 was highly expressed in dopaminergic neurons of the substantia nigra pars compacta and in microglia of the cerebral cortex of the human brain. Four common variants were associated with PD, including two novel variants rs2290402 (c.-10C > T) and rs80114247 (c.T1022C, p.M341T), located in the Kozak consensus sequence and TM3II domain, respectively. We also disclosed 13 novel highly penetrant detrimental mutations in the TMEM175 gene associated with PD. At least nine of these mutations (p.R35C, p. R183X, p.A270T, p.P308L, p.S348L, p. L405V, p.R414W, p.P427fs, p.R481W) may be sufficient to cause the disease, and the presence of mutations of other genes correlated with an earlier disease onset. In vitro functional analysis of the ion channel encoded by the mutated TMEM175 gene revealed a loss of the K+ conductance and a reduced channel affinity for Akt. Moreover, we observed an impaired autophagic/lysosomal proteolytic flux and an increase expression of unfolded protein response markers in patient-derived fibroblasts. These data suggest that mutations in TMEM175 gene may contribute to the pathophysiology of PD.

Supplementary Results, Methods, Table 1, Figures 1-4 from A Placental Growth Factor Variant Unable to Recognize Vascular Endothelial Growth Factor (VEGF) Receptor-1 Inhibits VEGF-Dependent Tumor Angiogenesis via Heterodimerization

Background KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A-R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. We explored the role of SET, the endogenous inhibitor of SER/THR phosphatase PP2A in KMT2A-R leukemia. Material and Methods The expression of SET was analysed in a large acute myeloid leukemia (AML)- RNA-seq dataset and in primary KMT2A-R samples and aged matched-controls. Stable SET knockdown (KD) was established by RNA interference in three KMT2A wild-type (wt) and four KMT2A-R leukemic cell lines. Gene and protein expression were analysed by RT-qPCR, ChiP, IP and western blot. RNA-seq and phospho-proteomics were employed to evaluate the effect of the SET-PP2A inhibitor FTY720 on global protein phosphorylation and gene expression. The cellular impact of FTY720 was evaluated by analysing proliferation, cell cycle and apoptosis in leukemic cell lines and by colony formation assay in two patient-derived xenograft (PDX). Results SET mRNA was found expressed in blasts from KMT2A-R-patients and in leukemic stem cells. SET protein interacted with both KMT2A wt and fusion proteins. Knockdown of SET inhibited the transcription of KMT2A target genes HOXA9 and HOXA10and abolished the self-renewal of KMT2A-R leukemic cells. Pharmacological inhibition of SET by FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest, apoptosis and increased sensitivity to chemotherapy in KMT2A-R-leukemic models. Phospho-proteomic and western blot analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3b, ARKB, and led to degradation of MYC, supporting the hypothesis of a feedback loop among SET, PP2A and MYC. The RNA-seq indicated that FTY720 reduced the activity of signalling pathways implicated in gene transcription and it compromised the expression of several genes belonging to the KMT2A-R leukemia signature. Conclusions Taken together our results identify SET as a novel player in KMT2A-R leukemia and provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia.

The gene encoding for the protein SE translocation (SET) was identified for the first time 30 years ago as part of a chromosomal translocation in a patient affected by leukemia. Since then, accumulating evidence have linked overexpression of SET, aberrant SET splicing, and cellular localization to cancer progression and development of neurodegenerative tauopathies such as Alzheimer’s disease. Molecular biology tools, such as targeted genetic deletion, and pharmacological approaches based on SET antagonist peptides, have contributed to unveil the molecular functions of SET and its implications in human pathogenesis. In this review, we provide an overview of the functions of SET as inhibitor of histone and non-histone protein acetylation and as a potent endogenous inhibitor of serine–threonine phosphatase PP2A. We discuss the role of SET in multiple cellular processes, including chromatin remodelling and gene transcription, DNA repair, oxidative stress, cell cycle, apoptosis cell migration and differentiation. We review the molecular mechanisms linking SET dysregulation to tumorigenesis and discuss how SET commits neurons to progressive cell death in Alzheimer’s disease, highlighting the rationale of exploiting SET as a therapeutic target for cancer and neurodegenerative tauopathies.

Background: One of the current methods to diagnose prediabetes and predict diabetes incidence is based on 2-h plasma glucose (2-hPG) value following 75-g oral glucose tolerance test. Evidence demonstrates that 1-hour post-load plasma glucose (1-hPG) ≥ 155 mg/dl (8.6 mmol/L) in those with normal glucose tolerance at 2-hPG is highly predictive for T2D incidence. We conducted a health economic analysis to estimate long-term cost-effectiveness of using 1-hPG as compared to 2-hPG to screen and assess diabetes risk. Methods: The main outcome of the study was cost per quality-adjusted life-year (QALY) gained. We used a Monte Carlo-based Markov simulation model to simulate long-term effects of the two screening strategies on clinical and cost-effectiveness outcomes. The base case model included 20.000 simulated patients over 35-years. Transition probabilities were retrieved from landmark studies. Direct medical costs were sourced from the literature and inflated to 20Euros. Results: In the lifetime analysis, 1-hPG was projected to increase the number of years free from disease (2yr/patient) ; to delay the onset of T2D (1yr/patient) ; to reduce the incidence of T2D complications (0.6 Relative Risk/patient) and to increase the QALY gained (0.58/patient) . Though testing the 1-hPG resulted in higher initial costs owing to a larger number of preventive treatments, long-term diabetes and complications costs were reduced leading to -31,225,719.82€ saving over a lifetime as compared to 2-hPG. The incremental cost-effectiveness ratio was -8,214.7€ per each QALY gained for the overall population. Conclusions: Screening prediabetes by using 1h-PG is feasible and cost-effective resulting in QALYs gained and reduced costs. Notwithstanding the higher initial costs of 1-hPG compared to 2-hPG, due to the incremental number of preventive treatments, long-term diabetes and complications costs were reduced expecting an overall cost saving of -8,214.7€ per each QALY gained. Disclosure M.Andellini: None. M.Manco: None. M.Esposito: None. A.Tozzi: None. M.Bergman: None. M.Ritrovato: None.

Levodopa is the standard long-term dopamine replacement therapy to treat Parkinson’s disease (PD) symptoms. With time, levodopa may induce debilitating dyskinesias (LID), the treatment of which represents a large clinically unmet need. However, time-to-LID onset varies between patients, reflecting a possible genetic component. We performed an hypothesis-free whole-exome sequencing (WES)-based screening of time-to-LID onset and attempted replication of previously published candidate gene studies. A WES association analysis was carried out in 134 PD patients in a meta-analytical framework. Replication was attempted in an independent study of 97 PD patients. Variants from previously reported candidate genes (OPRM1, COMT, BDNF) were also specifically examined. We significantly replicated, for the first time, an association of variant rs1799971 in the OPRM1 gene with time-to-LID onset. Furthermore, we identified two novel potentially functional variants, in the MAD2L2 (rs2233019) and MAP7 (rs35350783) genes, which were significantly associated at the discovery stage. In the replication study, the two variants showed direction-consistent effects but did not achieve the replication significance threshold. Our study provides the first WES results for time-to-LID onset, where we replicate association at OPRM1, and suggest new variants in MAD2L2 and MAP7 genes that are significant in discovery, but require larger datasets for replication. The results are being made publicly available to allow for independent external validation.

Previous studies have demonstrated that different curcumin extracts are able to influence cell metabolic activity vitality in human papillary thyroid carcinoma TPC-1 cells. We continued the study using the most effective extract and adding other nutraceuticals such as piperine and vitamin E, in order to define the possible role of these in modulating the genetic expression of cell markers and to understand the effectiveness in modulating the regression of cancer phenotype. Cells were treated with one extract of curcumin (Naturex® Ultimate Botanical Benefits), with Piperine (Piper Longum, A.C.E.F.) and Vitamin E (Dry Vitamin E-Acetate 50% DC, BASF) alone and in combination, dissolved in the culture medium, for 48 h. Treatment with the different nutraceuticals is able to influence cell cycle regulators (cyclin D1, β-catenin, p21, p53) and activators or inhibitors of apoptosis (BAX, pro-caspase3, Bcl-2). They are able to influence cell cycle distribution and metabolic activity vitality. The inhibitory effect of curcumin, piperine and vitamin E on cell proliferation involves different markers, and in particular inhibits β-catenin, cyclinD1 and p53, making them candidates for a possible use in alternative therapies although further studies are needed.

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.

Cerebral cavernous malformations (CCM) are lesions affecting brain capillaries that appear with a mulberry-like morphology. This shape results from the enlarged and tangled microvessels having defective endothelial cell junctions, few surrounding pericytes and dense extracellular collagen-rich matrix. Three genes KRIT1, CCM2 and PDCD10 are linked to disease onset. However, a variable percentage of patients harbour no mutations at these loci, encouraging hypothesis of further genetic factors involved in CCM pathogenesis. Here we present data obtained by transcriptome analysis on endothelial cells isolated by CCM specimens, with the aim to identify dysregulated pathways involved in lesion onset. Lesions belonged to two patients carried neither germline nor somatic mutations at the three CCM genes. By comparison with Human brain microvascular endothelial cells (HBMECs) expression profile, we identified 1325 differentially expressed genes (Bonferroni pValue

The association studies of several immune-diseases with the 3' Regulatory Region 1 (3'RR1) increased interest on the role that the region plays in the immune-regulation. The 3'RR1 is a polymorphic region on human chromosome 14q32, acting as a cis-regulative element on the Immunoglobulin constant-gene locus recently considered as super-enhancer. The human 3'RR1 share large sequences with its paralogous 3'RR2, at high level of similarity. Thus, a focused investigation was necessary to discriminate each one of the duplicated components of the two regions and its specific contribution to the immunologic phenotype. One of the duplicated elements is the hs1.2 enhancer. The 3'RR1 alleles of this enhancer were demonstrated to play a role in autoimmune diseases, including Psoriasis. We sequenced a specific region internal to the 3'RR1 in hs1.2 homozygous subjects, to detect SNPs associated to the main alleles of the enhancer. We identified two alternative nine-SNPs haplotypes strictly linked to the allele *1 and *2 of hs1.2, that could be used as markers to further investigate the region and associations to pathology. Finally, we identified two haplotypes, namely E2A1 and E2A2, that strongly support the hypothesis of a relevant effect of the rs35216181 in the onset of Psoriasis when the *2 allele is present.

Neoplastic transformation is a rare but serious complication of Paget's disease of bone (PDB), occurring in fewer than 1% of individuals with polyostotic disease. Their prognosis is poor, with less than 50% surviving 5 years. In 2016, the genetic alteration of giant cell tumor (GCT) complicating PDB was identified as a founder germline mutation (P937R) in the ZNF687 gene. However, the study population was exclusively of Italian descent, and patients of different ethnic origins were not studied. To fill this gap, herein we performed mutation analysis of ZNF687 in a GCT in the pelvis of a 45-year-old black American woman with polyostotic PDB. The P937R mutation in ZNF687 was found in her tumor but, as expected, the ancestral haplotype that characterizes the Italian GCT/PDB patients was not found. Furthermore, we identified two additional Italian GCT/PDB patients with this ZNF687 mutation, now constituting a cohort of 18 GCT/PDB cases, all harboring the identical mutation. We also searched for ZNF687 mutations in a unique collection of tumor tissues derived from Italian PDB patients, including 28 osteosarcomas (OS/PDB), 8 undifferentiated sarcomas (SRC/PDB), 1 fibrosarcoma (FS/PDB), and 1 chondrosarcoma (CS/PDB). We identified the P937R mutation in one SRC/PDB and a different ZNF687 mutation (R331W) in 1 of 28 pagetic osteosarcomas. Thus, whereas GCT/PDB pathogenesis globally seems to involve the P937R mutation in ZNF687, other neoplasms associated with PDB seem to be less related to mutations in this gene. Finally, we identified the G34W mutation in the H3F3A gene in the maxillary tumor masses of two PDB patients, defining them as conventional GCT rather than GCT/PDB. Thus, combined molecular analysis of H3F3A and ZNF687 is essential to clarify the origin and diagnosis of tumors in PDB. © 2020 American Society for Bone and Mineral Research.

Il dibattito sulla magia naturale nel Rinascimento . tra i pi. vivi e complessi. Il presente libro ha l’obiettivo di sondare i fondamenti della magia naturale di uno dei pi. celebri protagonisti del dibattito filosofico italiano del XVI secolo, Giovan Battista Della Porta (1535-1615). L’A. mostra come Della Porta, figlio della cultura umanistica, prediliga un metodo di studio eclettico, impostando la propria proposta concettuale alla luce di un aristotelismo sfumato, aperto all’albertismo rinascimentale e alle acquisizioni della tradizione della fisica e della cosmologia di Tolomeo. Nella prima parte del volume, l’A. fa esplicito riferimento a numerosi intellettuali napoletani seguaci in vario modo dell’aristotelismo propugnato a Padova nel XVI secolo. Tra di essi, l’A. dedica particolare spazio al logico Francesco Storella, meritevole di aver aperto la strada a una profonda riconsiderazione della possibilit. che possa darsi scienza, anche in senso aristotelico, di quei dati empirici ritenuti rari o irregolari altrimenti appannaggio di spiegazioni “superstiziose”. Lo studio della lezione storelliana, cos. viva a Napoli al tempo della scrittura della prima edizione della Magia naturalis libri IV (1558), aiuta l’A. a inserire il giovane Della Porta nel vivace e fecondo contesto intellettuale napoletano della seconda met. del ‘500. In questo modo, egli pu. gettare nuova luce sul retaggio del peripatetismo napoletano e sul ruolo che esso ha potuto esercitare sul pensiero di Della Porta.

Paget's disease of bone (PDB) is a late-onset disorder frequently caused by mutations in the SQSTM1 gene, leading to hyperactive osteoclasts and resulting in bone pain, deformities, and fractures. However, some more severe forms of PDB--negative for SQSTM1 mutations--have been described, in which the disease degenerates into bone cancers and shows a poor prognosis. Osteosarcoma is the most frequent and aggressive tumor arising in PDB (OS/PDB), with a 5-year survival rate almost nil, but the underlying molecular mechanism is unknown. Here, we investigated an extended pedigree with 11 individuals affected by early onset and polyostotic PDB, mainly interesting the appendicular skeleton. Interestingly, three members also developed secondary osteosarcoma. We performed exome sequencing and identified a 4-bp deletion in the PFN1 gene, resulting in the degradation of the mutant protein. Copy number screening on 218 PDB individuals of our biobank disclosed that four of them (~2%) carry a germline heterozygous deletion of PFN1. The identification of these subjects, who exhibit a particularly severe form of disease, emphasizes the diagnostic value of this genetic screening to identify PDB individuals predisposed to develop osteosarcoma. In fact, we detected allelic imbalance at PFN1 locus also in 8 of 14 (57%) sporadic OS/PDB, further proving its causative role. in vitro experiments also confirmed PFN1 involvement in this form of PDB. Indeed, CRISPR-Cas9-mediated Pfn1 knockout in pre-osteoclasts resulted into enhanced osteoclast differentiation and resorption, with the formation of large osteoclasts never described before in PDB. In addition, Pfn1 lacking pre-osteoblasts lost their differentiation capability and failed to efficiently mineralize bone. Moreover, they acquired features of malignant transformation, including loss of focal adhesions and increased invasion ability. In conclusion, these findings disclose PFN1 haploinsufficiency as the pathological mechanism in OS/PDB. © 2020 American Society for Bone and Mineral Research.

A nutraceutical product can be defined as a substance that has a physiological benefit or provides protection against chronic diseases. The term nutraceutical is a hybrid term derived from the union of “nutrition” and “pharmaceutical”. The list of studied nutraceuticals is constantly changing and reflects ongoing market developments, research and consumer interest. Spices, in addition to giving color and taste to foods, are also important nutraceutical. Spices have been an integral part of human diets and commerce for millennia but recently, the recognition of the link between health and nutrition has strengthened their importance in the food sector and sparked the interest of researchers who increasingly engage in trying to determine the mechanisms of action of spices and the countless beneficial properties attributed to them. Among the many existing spices, turmeric is one of the most studied for its antioxidant, anti-inflammatory, antibacterial and anticancer properties. The purpose of this review is to briefly summarize the fundamental characteristics of turmeric and give an overview of the use of this spice in several diseases.

Teresa Esposito,1,2 Jean Marc Lobaccaro,3 Maria Grazia Esposito,4 Vincenzo Monda,1 Antonietta Messina,1 Giuseppe Paolisso,5 Bruno Varriale,2 Marcellino Monda,1 Giovanni Messina1,6 1Department of Experimental Medicine, Section of Human Physiology and Unit of Dietetics and Sports Medicine, 2Laboratory of Molecular Biology and Genetics, Department of Experimental Medicine, Second University of Naples, Naples, Italy; 3UMR, Clermont Université, Centre de Recherche en Nutrition Humaine d’Auvergne, Aubière Cedex, France; 4Complex Surgery Unit, Evangelic Hospital Villa Betania, 5Department of Scienze Mediche, Chirurgiche, Neurologiche, Metaboliche e dell’Invecchiamento, Second University of Naples, Naples, 6Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy Abstract: The thyroid is one of the metabolism regulating glands. Its function is to determine the amount of calories that the body has to burn to maintain normal weight. Thyroiditides are inflammatory processes that mainly result in autoimmune diseases. We have conducted the present study in order to have a clear picture of both autoimmune status and the control of body weight. We have evaluated the amount of either thyroid hormones, or antithyroid, or anti-microsomal, or anti-peroxidase antibodies (Abs) in patients with high amounts of Abs. In a diet devoid of carbohydrates (bread, pasta, fruit, and rice), free from goitrogenic food, and based on body mass index, the distribution of body mass and intracellular and extracellular water conducted for 3 weeks gives the following results: patients treated as above showed a significant reduction of antithyroid (-40%, P0064). With regard to the body parameters measured in patients who followed this diet, reduction in body weight (-5%, P

Background The thyroid gland is one of the largest endocrine glands in the body. The vast majority of TCs (> 90%) originate from follicular cells and are defined as differentiated thyroid cancers (DTC) and the two histological subtypes are the papillary TC with its variants and the follicular TC. Curcumin possesses a wide variety of biological functions, and thanks to its properties, it has gained considerable attention due to its profound medicinal values (Prasad, Gupta, Tyagi, and Aggarwal, Biotechnol Adv 32:1053–1064, 2014). We have undertaken the present work in order to define the possible role of curcumin in modulating the genetic expression of cell markers and to understand the effectiveness of this nutraceutical in modulating the regression of cancer phenotype. Methods As a template we used the TPC-1 cells treated with the different extracts of turmeric, and examined the levels of expression of different markers (proliferative, inflammatory, antioxidant, apoptotic). Results Treatment with the three different curcumin extracts displays anti-inflammatory, antioxidant properties and it is able to influence cell cycle with slightly different effects upon the extracts. Furthermore curcumin is able to influence cell metabolic activity vitality. Conclusions In conclusion curcumin has the potential to be developed as a safe therapeutic but further studies are needed to verify its antitumor ability in vivo.

Paget's disease of bone (PDB) is a skeletal disorder whose molecular basis are not fully elucidated. However, 10% of patients show a familial PDB and 35% of them carry mutations in the SQSTM1 gene. We recently reported a founder mutation (p.Pro937Arg) in the ZNF687 gene, underlying PDB complicated by Giant Cell Tumor (GCT/PDB) and rarely occurring in PDB patients without neoplastic degeneration. Since 80% of Italian GCT/PDB patients derive from Avellino, we hypothesized that ZNF687 mutation rate was higher in this region than elsewhere. Interestingly, our molecular analysis on 30 PDB patients showed that 33% hosted ZNF687 mutations, with the p.Pro937Arg identified in 8 familial cases. Two novel ZNF687 mutations (p.Pro665Leu and p.Gln784Glu) were detected in 2 sporadic patients. Only 2 subjects were positive for the p.Pro392Leu mutation in SQSTM1. ZNF687 mutated patients showed a severe PDB, with a remarkable number of affected sites. In vitro studies revealed that the ZNF687 mutant osteoclasts appeared as giant-sized with up to 150 nuclei, never described in PDB. Finally, we also confirmed the causality of the p.Pro937Arg mutation in 4 additional GCT/PDB cases deriving from the same geographic area, indicating that PDB and GCT/PDB represent two sides of the same coin.

Clinical studies of large human populations and pharmacological interventions in rodent models have recently suggested that anti-hypertensive drugs that target angiotensin II (Ang II) activity may also reduce loss of bone mineral density. Here, we identified in a genetic screening the Ang II type I receptor (AT1R) as a potential determinant of osteogenic differentiation and, implicitly, bone formation. Silencing of AT1R expression by RNA interference severely impaired the maturation of a multipotent mesenchymal cell line (W20-17) along the osteoblastic lineage. The same effect was also observed after the addition of the AT1R antagonist losartan but not the AT2R inhibitor PD123,319. Additional cell culture assays traced the time of greatest losartan action to the early stages of W20-17 differentiation, namely during cell proliferation. Indeed, addition of Ang II increased proliferation of differentiating W20-17 and primary mesenchymal stem cells and this stimulation was reversed by losartan treatment. Cells treated with losartan also displayed an appreciable decrease of activated (phosphorylated)-Smad2/3 proteins. Moreover, Ang II treatment elevated endogenous transforming growth factor β (TGFβ) expression considerably and in an AT1R-dependent manner. Finally, exogenous TGFβ was able to restore high proliferative activity to W20-17 cells that were treated with both Ang II and losartan. Collectively, these results suggest a novel mechanism of Ang II action in bone metabolism that is mediated by TGFβ and targets proliferation of osteoblast progenitors.

Background Autosomal recessive forms of retinitis punctata albescens (RPA) have been described. RPA is characterized by progressive retinal degeneration due to alteration in visual cycle and consequent deposit of photopigments in retinal pigment epithelium. Five loci have been linked to RPA onset. Among these, the retinaldehyde-binding protein 1 gene, RLBP1, is the most frequently involved and several founder mutations were reported. We report results of a genetic molecular investigation performed on a large Sicilian family in which appears a young woman with RPA. Results The proband is in homozygous condition for a novel RLBP1 single-pair deletion, and her healthy parents, both heterozygous, are not consanguineous. Thenovelc.398delC (p.P133Qfs*258) involves the exon 6 and leads to a premature stop codon, resulting in a truncated protein entirely missing of CRAL-TRIO lipid-binding domain. Pedigree analysis showed other non-consanguineous relatives heterozygous for the same mutation in the family. Extension of mutation research in the native town of the proband revealed its presence also in healthy subjects, in a heterozygous condition. Conclusions A novel RLBP1 truncating mutation was detected in a young girl affected by RPA. Although her parents are not consanguineous, the mutation was observed in a homozygous condition. Being them native of the same small Sicilian town of Fiumedinisi, the hypothesis of a geographical area-related mutation was assessed and confirmed.

Annalisa Panico,1 Giovanni Messina,2,3 Gelsy Arianna Lupoli,1 Roberta Lupoli,1 Marianna Cacciapuoti,1 Fiorenzo Moscatelli,2 Teresa Esposito,3 Ines Villano,3 Anna Valenzano,2 Vincenzo Monda,3 Antonietta Messina,3 Francesco Precenzano,4 Giuseppe Cibelli,2 Marcellino Monda,3 Giovanni Lupoli1 1Department of Clinical Medicine and Surgery, University of Napoli Federico II, Naples, Italy; 2Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy; 3Department of Experimental Medicine, Second University of Naples, Naples, Italy; 4Department of Mental and Physical Health, and Preventive Medicine, Child and Adolescent Neuropsychiatry Unit, Second University of Naples, Naples, Italy Objective: Polycystic ovary syndrome (PCOS) is characterized by phenotypic heterogeneity and has a wide variety of consequences. Approximately half of women with PCOS are overweight or obese, and their obesity may be a contributing factor to PCOS pathogenesis through different mechanisms. The aim of this study was to evaluate if PCOS alone affects the patients’ quality of life and to what extent obesity contributes to worsen this disease. Design: To evaluate the impact of PCOS on health-related quality-of-life (HRQoL), 100 Mediterranean women with PCOS (group A), 50 with a body mass index (BMI) >25kg/m2 (group A1) and 50 with BMI 25 (A1) showed a significant and more marked reduction in scores, suggesting a lower quality of life, compared with controls (B) and with normal-weight PCOS patients (A2). Conclusion: PCOS is a complex disease that alone determines a deterioration of HRQoL. The innovative use of these psychometric questionnaires in this study, in particular the PCOS questionnaire, has highlighted that obesity has a negative effect on HRQoL. It follows that a weight decrease is associated to phenotypic spectrum improvement and relative decrement in psychological distress. Keywords: polycystic ovary syndrome, obesity, normal-weight, health-related quality-of-life, psychological disturbances

The human gastrointestinal tract (GIT) is inhabited by a wide cluster of microorganisms that play protective, structural, and metabolic functions for the intestinal mucosa. Gut microbiota is involved in the barrier functions and in the maintenance of its homeostasis. It provides nutrients, participates in the signaling network, regulates the epithelial development, and affects the immune system. Considering the microbiota ability to respond to homeostatic and physiological changes, some researchers proposed that it can be seen as an endocrine organ. Evidence suggests that different factors can determine changes in the gut microbiota. These changes can be both quantitative and qualitative resulting in variations of the composition and metabolic activity of the gut microbiota which, in turn, can affect health and different disease processes. Recent studies suggest that exercise can enhance the number of beneficial microbial species, enrich the microflora diversity, and improve the development of commensal bacteria. All these effects are beneficial for the host, improving its health status. In this paper, we intend to shed some light over the recent knowledge of the role played by exercise as an environmental factor in determining changes in microbial composition and how these effects could provide benefits to health and disease prevention.

Adipose tissue, defined as white adipose tissue (WAT) and brown adipose tissue (BAT), is a biological caloric reservoir; in response to over-nutrition it expands and, in response to energy deficit, it releases lipids. The WAT primarily stores energy as triglycerides, whereas BAT dissipates chemical energy as heat. In mammals, the BAT is a key site for heat production and an attractive target to promote weight loss. The autonomic nervous system (ANS) exerts a direct control at the cellular and molecular levels in adiposity. The sympathetic nervous system (SNS) provides a complex homeostatic control to specifically coordinate function and crosstalk of both fat pads, as indicated by the increase of the sympathetic outflow to BAT, in response to cold and high-fat diet, but also by the increase or decrease of the sympathetic outflow to selected WAT depots, in response to different lipolytic requirements of these two conditions. More recently, a role has been attributed to the parasympathetic nervous system (PNS) in modulating both adipose tissue insulin-mediated glucose uptake and fatty free acid (FFA) metabolism in an anabolic way and its endocrine function. The regulation of adipose tissue is unlikely to be limited to the autonomic control, since a number of signaling cytokines and neuropeptides play an important role, as well. In this review, we report some experimental evidences about the role played by both the ANS and orexins into different fat pads, related to food intake and energy expenditure, with a special emphasis on body weight status and fat mass (FM) content.

Alessandro Giunta,1,* Alessandra Ventura,1,* Maria Sole Chimenti,2 Luca Bianchi,1 Maria Esposito1 1Department of Dermatology, 2Department of Rheumatology, University of Rome Tor Vergata, Rome, Italy *These authors contributed equally to this manuscript Abstract: Psoriasis is a chronic inflammatory disease affecting up to 3% of the general population, associated with discomfort and impaired quality of life. In recent years, the pathogenic cytokine network of psoriasis has been extensively studied leading to the development of new treatments that provide greater efficacy. Interleukin 17A (IL-17A) has been recognized as a crucial cytokine that mediates immunopathogenesis of psoriasis. Ixekizumab – indicated for the treatment of adults with moderate-to-severe plaque psoriasis – is a subcutaneously administered humanized monoclonal antibody that targets IL-17A. A large percentage of patients affected by psoriasis achieved consistent benefits in terms of disease control and rapid onset of action during clinical trials. Overall, ixekizumab brought clinical improvement and a favorable safety profile in phase III trials. Ixekizumab is characterized by consistent efficacy and rapid onset of response; it is not influenced by previous exposure to biologics and has shown good results in areas that are difficult to treat and in severe clinical variants of psoriasis. Ixekizumab has shown significant improvements in the activity of the disease and in those physical functions that inhibit radiographic progression in patients with concomitant involvement of joints. Our data support ixekizumab as a successful therapeutic option for patients affected by moderate-to-severe plaque-type psoriasis. Keywords: biologic therapies, IL-17, ixekizumab, psoriasis

Neurofibromas are the hallmark lesions in Neurofibromatosis 1 (NF1); these tumors are classified as cutaneous, subcutaneous and plexiform. In contrast to cutaneous and subcutaneous neurofibromas, plexiform neurofibromas can grow quickly and progress to malignancy. Curcumin, a turmeric-derived polyphenol, has been shown to interact with several molecular targets implicated in carcinogenesis. Here, we describe the impact of different dietary patterns, namely Mediterranean diet (MedDiet) compared to the Western diet (WesDiet), both with or without curcumin, on NF1 patients’ health. After six months, patients adopting a traditional MedDiet enriched with 1200 mg curcumin per day (MedDietCurcumin) presented a significant reduction in the number and volume of cutaneous neurofibromas; these results were confirmed in subsequent evaluations. Notably, in one patient, a large cranial plexiform neurofibroma exhibited a reduction in volume (28%) confirmed by Magnetic Resonance Imaging. Conversely, neither unenriched MedDiet nor WesDiet enriched with curcumin exhibited any significant positive effect. We hypothesize that the combination of a polyphenol-rich Mediterranean diet and curcumin was responsible for the beneficial effect observed on NF1. This is, to the best of our knowledge, the first experience with curcumin supplementation in NF1 patients. Our report suggests that an integrated nutritional approach may effectively aid in the management of NF1.

// Giuseppina Divisato 1 , Federica Scotto di Carlo 1, 2 , Laura Pazzaglia 3 , Riccardo Rizzo 4 , Domenico A. Coviello 5 , Maria Serena Benassi 3 , Piero Picci 3 , Teresa Esposito 1, 6 and Fernando Gianfrancesco 1 1 Institute of Genetics and Biophysics Adriano Buzzati-Traverso, National Research Council of Italy, Naples, Italy 2 Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania Luigi Vanvitelli, Caserta, Italy 3 Laboratory of Experimental Oncology, Rizzoli Orthopaedic Institute, Bologna, Italy 4 Institute of Protein Biochemistry, National Research Council of Italy, Naples, Italy 5 Laboratory of Human Genetics, Galliera Hospital, Genova, Italy 6 IRCCS INM Neuromed, Pozzilli, Italy Correspondence to: Fernando Gianfrancesco, email: fernando.gianfrancesco@igb.cnr.it Keywords: bone cancer, GCT, pagetic GCT, ZNF687, H3F3A Received: August 04, 2016 Accepted: May 23, 2017 Published: June 27, 2017 ABSTRACT Giant Cell Tumor of Bone (GCT) is a tumor characterized by neoplastic mesenchymal stromal cells and a high number of osteoclast-like multinucleated giant cells. Rarely, GCT could arise in bones affected by Paget’s disease of bone (GCT/PDB). Although it is already known that GCT/PDB and GCT show a different clinical profile regarding the age-onset and skeletal localization, our deep clinical comparison between the two GCT/PDB and GCT cohorts, permitted us to identify additional differences (e.g. focality, ALP serum levels, the 5-year survival rate and the familial recurrence), strongly suggesting a different molecular basis. Accordingly, driver somatic mutations in H3F3A and IDH2 were described in GCT patients, while we recently identified a germline mutation in ZNF687 as the genetic defect of GCT/PDB patients. Here, we detected H3F3A mutations in our GCT cohort, confirming its molecular screening as the elected diagnostic tool, and then we excluded the two-hit in H3F3A and IDH2 as the trigger event for the GCT/PDB development. Importantly, we also identified an alternative biochemical profile with GCT/PDB not exhibiting the up-regulation of the GCT marker FGFR2IIIc . Finally, our histological analysis also showed a different appearance of the two forms of the tumor, with GCT/PDB showing a higher number of osteoclast-like giant cells (twice), with an abnormal number of nuclei per cell, corroborating its different behaviour in terms of neoplastic properties. We demonstrated that the distinct clinical features of pagetic and conventional GCT are associated with different genetic background, resulting in a specific biochemical and histological behaviour of the tumour.

Posture is human fundamental ability that deals with the scientific and clinical study of body position in space, in order of maintaining balance in both static and dynamic conditions, in relation to the psychic functions, biochemical and somatosensory individual for the maintenance or achievement of health status. The aim of the present study was to examine if a medical device (plantar), called RUGRAN, can improve muscle rehabilitation in pain syndromes muscle-tendon for the correction and stabilization postural. The static pedobarographic evaluation revealed significantly higher values in terms of forefoot peak pressure, total plantar force and total contact area in subject without RUGARN plantar, compared to subjects with RUGARN plantar. This is the first study that investigated the pedobarographic changes in subjects with the RUGARN plantar. The static pedobarographic findings we observed while the subjects were standing revealed no difference of force distribution and contact area between forefoot and rearfoot and this finding did not support the hypothesis that the centre of the body shifts to forward because of excessive adipose tissue causing excessive forefoot loading.

The superior sagittal sinus (SSS) of the mammalian brain is a pain-sensitive intracranial vessel thought to play a role in the pathogenesis of migraine headaches. Here, we aimed to investigate the presence and the potential co-localization of some neurotransmitters in the human SSS. Immunohistochemical and double-labeling immunofluorescence analyses were applied to paraformaldehyde-fixed, paraffin-embedded, coronal sections of the SSS. Protein extraction and Western blotting technique were performed on the same material to confirm the morphological data. Our results showed nerve fibers clustered mainly in large bundles tracking parallel to the longitudinal axis of the sinus, close in proximity to the vascular endothelium. Smaller fascicles of fibers encircled the vascular lumen in a spiral fashion, extending through the subendothelial connective tissue. Isolated nerve fibers were observed around the openings of bridging veins in the sinus or around small vessels extending into the perisinusal dura. The neurotransmitters calcitonin gene related peptide (CGRP), substance P (SP), neuronal nitric oxide synthase (nNOS), vasoactive intestinal polypeptide (VIP), tyrosine hydroxylase (TH), and neuropeptide Y (NPY) were found in parietal nerve structures, distributed all along the length of the SSS. Overall, CGRP- and TH-containing nerve fibers were the most abundant. Neurotransmitters co-localized in the same fibers in the following pairs: CGRP/SP, CGRP/NOS, CGRP/VIP, and TH/NPY. Western blotting analysis confirmed the presence of such neurosubstances in the SSS wall. Overall our data provide the first evidence of the presence and co-localization of critical neurotransmitters in the SSS of the human brain, thus contributing to a better understanding of the sinus functional role.

The basal forebrain cholinergic system is considered as a major component of attentive mediator system. It could be activated by different ingoing inputs, and among them the hypothalamus represents an important source of projections and the orexin neurons, whose cell bodies are present in the lateral hypothalamus, highly contribute to these projections. Recently, the orexin-producing neurons have been considered to act in the basal forebrain promoting arousal and attention. Aim of the present review is trying to explain the putative effects of orexin-producing neurons and their projection to the basal forebrain in order to support the hypothesis that orexin system may contribute to attentional processing toward increased cell activity and cortical acetylcholine (Ach) release. Collectively, the available data seem to support this hypothesis: orexins excite cholinergic neurons increasing acetylcholine release in cerebral cortex contributing to cerebral cortical activation and prefrontal cortex associated with executive system. We have reviewed evidence suggesting that the BF may be a key target through which orexin neurons promote attention.

DNA damage repair mechanisms are vital to maintain genomic integrity. Mutations in genes involved in the DNA damage response (DDR) can increase the risk of developing cancer. In recent years, a variety of polymorphisms in DDR genes have been associated with increased risk of developing acute myeloid leukemia (AML) or of disease relapse. Moreover, a growing body of literature has indicated that epigenetic silencing of DDR genes could contribute to the leukemogenic process. In addition, a variety of AML oncogenes have been shown to induce replication and oxidative stress leading to accumulation of DNA damage, which affects the balance between proliferation and differentiation. Conversely, upregulation of DDR genes can provide AML cells with escape mechanisms to the DDR anticancer barrier and induce chemotherapy resistance. The current review summarizes the DDR pathways in the context of AML and describes how aberrant DNA damage response can affect AML pathogenesis, disease progression, and resistance to standard chemotherapy, and how defects in DDR pathways may provide a new avenue for personalized therapeutic strategies in AML.

Supplemental Digital Content is available in the text, Leukemia is an evolutionary disease and evolves by the accrual of mutations within a clone. Those mutations that are systematically found in all the patients affected by a certain leukemia are called “drivers” as they are necessary to drive the development of leukemia. Those ones that accumulate over time but are different from patient to patient and, therefore, are not essential for leukemia development are called “passengers.” The first studies highlighting a potential cooperating role of phosphatidylinositol 3-kinase (PI3K)/RAS pathway mutations in the phenotype of KMT2A-rearranged leukemia was published 20 years ago. The recent development in more sensitive sequencing technologies has contributed to clarify the contribution of these mutations to the evolution of KMT2A-rearranged leukemia and suggested that these mutations might confer clonal fitness and enhance the evolvability of KMT2A-leukemic cells. This is of particular interest since this pathway can be targeted offering potential novel therapeutic strategies to KMT2A-leukemic patients. This review summarizes the recent progress on our understanding of the role of PI3K/RAS pathway mutations in initiation, maintenance, and relapse of KMT2A-rearranged leukemia.