Terre di Confine

Narrativa: Il libro presenta il viaggio iniziatico del protagonista attraverso le Terre di Confine tra la realtà e la fantasia, tra lucidità e pazzia, tra il mondo materiale ed il mondo spirituale. Un fantasy eroico che affronta temi di critica sociale, intrecciati a concetti di esoterismo occidentale ed orientale. Il protagonista, sul quale grava un profondo senso di mancanza, vive una condizione di intenso disagio psicologico. Il viaggio attraverso i mondi rivelerà il perchè di questo senso di inadeguatezza e gli fornirà le conoscenze necessarie per svolgere la missione a cui è destinato. Per ottenere la comprensione di ciò che l’attende dovrà riscoprire tutto ciò che dava per scontato, vivere nuove esperienze in un mondo a lui sconosciuto, ed infine intraprendere un difficile viaggio attraverso mondi fratelli che patiscono sofferenze occulte, mondi il cui destino è legato l’uno all’altro. Uno di questi è il nostro mondo natio. Un viaggio entusiasmante alla scoperta di esseri mitici, civiltà perdute, dei dimenticati, ed amicizie fraterne, un viaggio che culmina nell’abbraccio della grande Manenawa

Hutchinson Gilford Progeria Syndrome: A Therapeutic Approach via Adenoviral Delivery of CRISPR/cas Genome Editing System

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare human genetic disease caused by mutations in the LMNA gene. LMNA codes for structural components of the nuclear lamina. Alterations of nuclear lamina lead to a very variable class of diseases known as laminopathies. In detail, HGPS manifests a severe premature ageing phenotype due to the accumulation of a dominant negative form of lamin-A called progerin. With current treatments, the life expectancy of HGPS patients does not exceed their second decade. Death is usually due to cardiovascular complications. Recently, a new technology for mammals in vivo gene editing has been developed: the clustered regularly interspaced short palindromic repeats/Cas protein (CRISPR/Cas) system. The CRISPR/Cas technology permits to edit the genome at specific loci. Even if the CRSIPR/Cas constructs are transiently administered to the target cells, the genome editing is permanent. The advantages of the combination of non-integrating transient vectors in combination with the CRISPR/Cas constructs could give rise to a secure approach for the treatment of disease of genetic origin, especially those caused by dominant negative mutations, such as HGPS. A potential application of non-integrating transient vectors carrying CRISPR/Cas constructs for the treatment of HGPS will be discussed in detail

Targeted sequencing of BRAF by MinION in archival Formalin-Fixed Paraffin-Embedded specimens allows to discriminate between Hairy Cell Leukemia and Hair Cell Leukemia Variant

Targeted sequencing of BRAF by MinION in archival Formalin-Fixed Paraffin-Embedded specimens allows to discriminate between Hairy Cell Leukemia and Hair Cell Leukemia Varian

Anaplastic Thyroid Carcinoma: A ceRNA Analysis Pointed to a Crosstalk between SOX2

It has been suggested that cancer stem cells (CSC) may play a central role in oncogenesis, especially in undifferentiated tumours. Anaplastic thyroid carcinoma (ATC) has characteristics suggestive of a tumour enriched in CSC. Previous studies suggested that the stem cell factor SOX2 has a preeminent hierarchical role in determining the characteristics of stem cells in SW1736 ATC cell line. In detail, silencing SOX2 in SW1736 is able to suppress the expression of the stem markers analysed, strongly sensitizing the line to treatment with chemotherapeutic agents. Therefore, in order to further investigate the role of SOX2 in ATC, a competing endogenous RNA (ceRNA) analysis was conducted in order to isolate new functional partners of SOX2. Among the interactors, of particular interest are genes involved in the biogenesis of miRNAs (DICER1, RNASEN, and EIF2C2), in the control cell cycle (TP53, CCND1), and in mitochondrial activity (COX8A). The data suggest that stemness, microRNA biogenesis and functions, p53 regulatory network, cyclin D1, and cell cycle control, together with mitochondrial activity, might be coregulated

Identification of Novel Wsf1 Mutations in a Sicilian Child with Wolfram Syndrome

Wolfram Syndrome (WS) is a rare hereditary disease with autosomal recessive inheritance with incomplete penetrance. It is characterized by diabetes mellitus associated with progressive optic atrophy. The diagnosis is essentially clinical and mutation analysis is used to confirm the diagnosis. In the present study we describe the clinical and molecular features of a diabetic child carrying two novel WFS1 mutations. The Sicilian proband and his non-affected family were studied. Ophthalmologic examination included: visual acuity determination and funduscopy, optical coherent tomography, retinal fluorangiography, perimetry and electroretinogram. Molecular methods: automatic sequencing of PCR amplified WFS1 gene fragments and qRT-PCR analysis of WFS1 transcripts. 3 WSF1 mutations have been identified in the proband. One allele carries 2 paternally inherited mutations (c.1332 C>G and c.1631C>G) in exon-8, never annotated before, in heterozygosis with one “de novo” classic mutation (c.505 G>A) in exon-5. In addition, we report an unexpected molecular feature: higher WFS1 mRNA levels in the proband compared to the father

Hypoxia inducible factor-1 alpha expression is increased in infected positive HPV16 DNA oral squamous cell carcinoma and positively associated with HPV16 E7 oncoprotein

<p>Abstract</p> <p>Background</p> <p>There is increasing evidence for the role of High Risk (HR) Human PapillomaVirus (HPV) in the pathogenesis of Oral Squamous Cell Carcinoma (OSCC). The E6 and E7 oncogenes from HR HPVs are responsible for the deregulation of p53 and pRB proteins involved in cell cycle and apoptotic pathways. In cell lines experiments, the HPV E7 protein seems to be able to enhance Hypoxia Inducible Factor-1 alpha (HIF-1α) activity, normally involved in the response to hypoxia and able to enhance angiogenesis.</p> <p>Results</p> <p>We studied tumor specimens from 62 OSCC; a higher prevalence of tumors in TNM stage II and also in pT2 class between OSCC infected positive HPV16 DNA than non-infected ones was observed. HIF-1α positivity was detected throughout the analysed fields, not associated with areas of necrosis and also observed in cells immediately adjacent to blood vessels. A significant increase in mean values of the HIF-1α labeling indexes was observed for pT1-T2, as well for stage I-II, in the infected positive HPV16 DNA tumors than non-infected ones. HIF-1α and HPV16 E7 labeling indexes showed a significantly positive correlation which suggested a positive association between HPV16 E7 and HIF-1α expression.</p> <p>Conclusions</p> <p>In our specimens HIF-1α immunoreactivity hints for an O₂-independent regulatory mechanism in infected positive HPV16 DNA tumors, especially for pT1-T2 and stage I-II tumors, suggesting a very early involvement in the development of HPV-induced OSCC. HIF-1α and HPV16 E7 labeling indexes suggest also a positive association between the two proteins in infected positive HPV16 DNA OSCC.</p

Natriuretic peptide system expression in murine and human submandibular salivary glands: a study of the spatial localisation of ANB, BNP, CNP and their receptors

The natriuretic peptide (NP) system comprises of three ligands, the Atrial Natriuretic Peptide (ANP), Brain Natriuretic peptide (BNP) and C-type Natriuretic peptide (CNP), and three natriuretic peptide receptors, NPRA, NPRB and NPRC. Here we present a comprehensive study of the natriuretic peptide system in healthy murine and human submandibular salivary glands (SMGs). We show CNP is the dominant NP in mouse and human SMG and is expressed together with NP receptors in ducts, autonomic nerves and the microvasculature of the gland, suggesting CNP autocrine signalling may take place in some of these glandular structures. These data suggest the NP system may control salivary gland function during homeostasis through the regulation of electrolyte re-absorption, neural stimulation and/or blood vessel wall contraction/relaxation. We also show abnormal expression of NPRA in the stroma of a subset of human SMGs resected from patients diagnosed with oral squamous cell carcinoma (OSCC) of non-salivary gland origin. This finding warrants further research to investigate a possible correlation between early OSCC invasion and NPRA overexpression

Genetic deletion of α7 nicotinic acetylcholine receptors induces an age-dependent Alzheimer's disease-like pathology.

The accumulation of amyloid-beta peptide (Aβ) and the failure of cholinergic transmission are key players in Alzheimer's disease (AD). However, in the healthy brain, Aβ contributes to synaptic plasticity and memory acting through α7 subtype nicotinic acetylcholine receptors (α7nAChRs). Here, we hypothesized that the α7nAChR deletion blocks Aβ physiological function and promotes a compensatory increase in Aβ levels that, in turn, triggers an AD-like pathology. To validate this hypothesis, we studied the age-dependent phenotype of α7 knock out mice. We found that α7nAChR deletion caused an impairment of hippocampal synaptic plasticity and memory at 12 months of age, paralleled by an increase of Amyloid Precursor Protein expression and Aβ levels. This was accompanied by other classical AD features such as a hyperphosphorylation of tau at residues Ser 199, Ser 396, Thr 205, a decrease of GSK-3β at Ser 9, the presence of paired helical filaments and neurofibrillary tangles, neuronal loss and an increase of GFAP-positive astrocytes. Our findings suggest that α7nAChR malfunction might precede Aβ and tau pathology, offering a different perspective to interpret the failure of anti-Aβ therapies against AD and to find novel therapeutical approaches aimed at restoring α7nAChRs-mediated Aβ function at the synapse

LTP and memory impairment caused by extracellular A\u3b2 and Tau oligomers is APP-dependent

The concurrent application of subtoxic doses of soluble oligomeric forms of human amyloid-beta (oA\u3b2) and Tau (oTau) proteins impairs memory and its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued by these findings, we investigated whether oA\u3b2 and oTau share a common mechanism when they impair memory and LTP in mice. We found that as already shown for oA\u3b2, also oTau can bind to amyloid precursor protein (APP). Moreover, efficient intra-neuronal uptake of oA\u3b2 and oTau requires expression of APP. Finally, the toxic effect of both extracellular oA\u3b2 and oTau on memory and LTP is dependent upon APP since APP-KO mice were resistant to oA\u3b2- and oTau-induced defects in spatial/associative memory and LTP. Thus, APP might serve as a common therapeutic target against Alzheimer's Disease (AD) and a host of other neurodegenerative diseases characterized by abnormal levels of A\u3b2 and/or Tau