Next-generation sequencing revealing TP53 mutation as potential genetic driver in dermal deep-seated melanoma arising in giant congenital nevus in adult patients: A unique case report and review of the literature

Melanoma in giant congenital nevus (M-GCN) is a rare and potentially lethal neoplasm. In children, M-GCN appears as a dermal/deep-seated melanoma (DDM-GCN) with histopathologic features difficult to distinguish from proliferative nodules (PNs-GCN). DDM-GCN in adults is an anecdotal entity and only 8 cases have been described and genetically characterized. We report the first case of DDM-GCN in a 34-year-old man characterized with a large-panel next-generation sequence (NGS) highlighting a TP53 mutation with a UV-signature (C>T substitution) in DDM but not in PNs-GCN and GCN. Curiously, DDM showed an aberrant p16 overexpression without detection of CDKN2A mutation at NGS. In line with previous studies, it supports a different pathway in children and adults: UV-induced mutations may be involved in the latter not only by CDKN2A but also by TP53 mutations, with a potentially confusing overexpression of p16 protein. While these data need to be confirmed in larger cases series, our results show that NGS could be an additional genetic diagnostic tool in DDM-GCN.     

Autoimmune encephalitis and CSF anti-AMPA GluR3 antibodies in childhood: a case report and literature review

Neurological Sciences - Acute autoimmune encephalitis is a severe neurological disorder presenting with altered level of consciousness, confusion, irritability, headache, vomiting, and in some...     

Dendritic cells modulate c‐kit expression on the edge between activation and death

Dendritic cells (DCs) are key players in immunity and tolerance. Some DCs express c‐kit, the receptor for stem cell factor (SCF), nevertheless c‐kit functional role and the regulation of its expression in DCs are incompletely defined. We recently demonstrated that autocrine SCF sustains a pro‐survival circuit, and that SCF increases phospho‐AKT in c‐kit+ mouse bone marrow‐derived DCs (BMdDCs). Herein we observed that CpG and PolyI:C, two stimuli mimicking bacterial and viral nucleic acids respectively, strongly inhibited c‐kit expression by BMdDCs and spleen DCs in vitro and in vivo. Experiments in IFNARI^?/? mice showed that IFN‐I pathway was required for c‐kit down‐regulation in cDC1s, but only partially supported it in cDC2s. Furthermore, CpG and PolyI:C strongly inhibited c‐kit mRNA expression. In agreement with the reduced c‐kit levels, SCF pro‐survival activity was impaired. Thus in the presence of exogenously provided SCF, either PolyI:C or CpG induced spleen DC death in 2 days, while at earlier times IL‐6 and IL‐12 production were slightly increased. In contrast, SCF improved survival of unstimulated spleen DCs expressing high c‐kit levels. Our studies suggest that c‐kit down‐modulation is a previously neglected component of DC response to CpG and PolyI:C, regulating DC survival and ultimately tuning immune response.     

Anomalous Sorption Kinetics of Self-Interacting Particles by a Spherical Trap

In this paper we propose a computational framework for the investigation of the correlated motion between positive and negative ions exposed to the attraction of a bubble surface that mimics the (oscillating) cell membrane. Specifically we aim to investigate the role of surface traps with substances freely diffusing around the cell. The physical system we want to model is an anchored gas drop submitted to a diffusive flow of charged surfactants (ions). When the diffusing surfactants meet the surface of the bubble, they are reversibly adsorbed and their local concentration is accurately measured. The correlated diffusion of surfactants is described by a Poisson-Nernst-Planck (PNP) system, in which the drift term is given by the gradient of a potential which includes both the effect of the bubble and the Coulomb interaction between the carriers. The latter term is obtained from the solution of a self-consistent Poisson equation. For very short Debye lengths one can adopt the so called Quasi-Neutral limit which drastically simplifies the system, thus allowing for much faster numerical simulations. The paper has four main objectives. The first one is to present a PNP model that describes ion charges in presence of a trap. The second one is to provide benchmark tests for the validation of simplified multiscale models under current development [1]. The third one is to explore the relevance of the term describing the interaction among the apolar tails of the anions. The last one is to quantitatively explore the validity of the Quasi-Neutral limit by comparison with detailed numerical simulation for smaller and smaller Debye lengths. In order to reach these goals, we propose a simple and efficient Alternate Direction Implicit method for the numerical solution of the non-linear PNP system, which guarantees second order accuracy bothin space and time, without requiring solution of nonlinear equation at each time step. New semi-implicit scheme for a simplified PNP system near quasi neutrality is also proposed.     

Amyotrophic lateral sclerosis linked to a novel SOD1 mutation with muscle mitochondrial dysfunction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative motor neuron disorder. Mutations in Cu,Zn superoxide dismutase (SOD1) cause approximately 20% of familial ALS. One of the possible mechanisms whereby they induce disease is mitochondrial dysfunction in motor neurons. Here we describe a patient with ALS and muscle mitochondrial oxidative defect associated with a novel SOD1 mutation. Direct sequencing of SOD1 gene revealed a heterozygous mutation in codon 22 substituting a highly conserved amino acid, from glutamine to arginine (Q22R). Muscle biopsy showed a neurogenic pattern associated with cytochrome c oxidase (COX) deficiency in several muscle fibers. Western blot analysis demonstrated a reduction in SOD1 content in the cytoplasmic and mitochondrial fractions. These results suggest that a minute quantity of mutant SOD1 protein contributes to a mitochondrial toxicity also in muscle tissue.