Identification of Epigenetic Mechanisms Regulating NCX3 in in Vivo Model of Brain Ischemic Preconditioning

Variations of the isoform 3 expression of the sodium / calcium exchanger play an important role in the response to neuronal damage after an ischemic insult. I found that the transcription factor (GATA binding protein) 3 GATA3 activates the transcription of ncx3 in rat cortical cultures. In fact, the overexpression of GATA3, obtained as a result of transient transfection of the plasmid containing the GATA3 cDNA in neurons, leads to a significant increase in the luciferase activity of the ncx3 promoter, in parallel with an increase in mRNA and protein expression of ncx3. In contrast, the transfection of a siRNA capable of reducing the protein expression of GATA3 by about 60% causes a reduction of the luciferase activity of the ncx3 promoter and a decrease in the ncx3 mRNA. The site-specific mutagenesis of the binding sequence of GATA3 on the ncx3 promoter demonstrates that the mechanism by which GATA3 activates NCX3 is site-specific. More important, in vivo, GATA3 recruitment to the ncx3 gene was increased in the temporoparietal cortex of rats subjected to Preconditioning (PC) followed by transient middle cerebral artery occlusion (tMCAO), with an increase of histone 3 lysine 3 trimethylation of the ncx3 promoter region. Interestingly, in the same experimental conditions histone acetylation on ncx3 promoter was unmodified. Furthermore, Re-ChIP experiments demonstrated that GATA3 forms a functional complex with the histone lysine methyl transferase KMT2A on the ncx3 gene during PC+tMCAO. Therefore, increasing KMT2A expression or activity might represent a new possible strategy in stroke intervention

Low-Thrust Optimal Escape Trajectories from Lagrangian Points and Quasi-Periodic Orbits in a High-Fidelity Model

L'abstract è presente nell'allegato / the abstract is in the attachmen

Fast and accurate estimation of fuel-optimal trajectories to Near-Earth Asteroids

This paper proposes an improved method for the preliminary evaluation of minimum-propellant trajectories to Near-Earth Asteroids (NEAs). The method applies to missions from Earth to asteroids with small eccentricity and inclination. A planar and a plane-change problem can be distinguished. In the planar problem, the solution assumes that multiple burn arcs are performed in correspondence of the apsides of the target asteroid in order to change the initial spacecraft orbit (i.e., Earth’s orbit) into the target one. The number of arcs is established once the time of flight is given (1 burn at each apsis per revolution, 1 revolution per year can be assumed). The length and propellant consumption of each arc to attain the required changes of semi-major axis and eccentricity are computed by a procedure based on Edelbaum’s approximation, which is well-suited to the problem at hand, as eccentricity changes are expected to be small for feasible missions. No numerical integration is required, but only the numerical solution of a three-unknown algebraic system is needed, making the procedure extremely fast. Plane change is taken into account assuming a constant out-of-plane thrust angle during each burn. A previous simple formulation used an averaged thrust effect over one revolution and neglected the fact that plane changes are more effective at the nodes. Several improvements are here introduced, which greatly increase the method accuracy. The influences of the eccentricity change, the angle between the asteroid line of nodes and line of apsides, and the expected length of the arc are considered: In fact, when the eccentricity is small, the thrust arc can be performed at the nodes where the inclination is efficiently changed, with little penalty in the planar maneuver. An efficient plane change is also performed when the angle between the asteroid line of nodes and line of apsides is small and/or the length of the arc is large, because, in this case, the node is comprised in the apsidal burn. A simple corrective formula accounts for this effect. The new method shows remarkable accuracy. The results comparison with solutions obtained with an indirect optimization method for a set of more than 60 NEAs shows a 0.95 correlation coefficient in the propellant masses. The estimation error is below 10% for 75% of the targets, below 15% for 95% of the targets, and always below 20%

TCGA Molecular Subgroups in Endometrial Undifferentiated/Dedifferentiated Carcinoma

We aimed to classify undifferentiated/dedifferentiated carcinoma (UDC/DDC) according to the four TCGA molecular subgroups of endometrial cancer: microsatellite-instable/hypermutated (MSI), POLE-mutant/ultramutated (POLE), copy-number-low/p53-wild-type (p53wt), and copy-number-high/p53-abnormal (p53abn), through a systematic review and meta-analysis. Electronic databases were searched from January 2013 to July 2019 for studies assessing the TCGA classification in endometrial UDC/DDC series. Pooled prevalence of each TCGA subgroup on the total UDC/DDCs was calculated. Three studies with 73 patients were included. Pooled prevalence of the TCGA subgroups were: 12.4% for the POLE subgroup, 44% for the MSI subgroup, 18.6% for the p53abn subgroup, 25% for the p53wt group. All TCGA groups are represented in UDC/DDC, with a predominance of the MSI group, indicating a biological heterogeneity. Hypermutated/ultramutated cancers constitute the majority of UDC/DDC, suggesting a crucial difference with other high-risk histologies of endometrial carcinoma

resveratrol treatment reduces the vulnerability of sh sy5y cells and cortical neurons overexpressing sod1 g93a to thimerosal toxicity through sirt1 dream pdyn pathway

Abstract In humans, mutation of glycine 93 to alanine of Cu++/Zn++ superoxide dismutase type-1 (SOD1-G93 A) has been associated to some familial cases of Amyotrophic Lateral Sclerosis (ALS). Several evidence proposed the involvement of environmental pollutants that like mercury could accelerate ALS symptoms. SH-SY5Y cells stably transfected with SOD1 and G93 A mutant of SOD1 constructs were exposed to non-toxic concentrations (0.01 μM) of ethylmercury thiosalicylate (thimerosal) for 24 h. Interestingly, we found that thimerosal, in SOD1-G93 A cells, but not in SOD1 cells, reduced cell survival. Furthermore, thimerosal-induced cell death occurred in a concentration dependent-manner and was prevented by the Sirtuin 1 (SIRT1) activator Resveratrol (RSV). Moreover, thimerosal decreased the protein expression of transcription factor Downstream Regulatory Element Antagonist Modulator (DREAM), but not DREAM gene. Interestingly, DREAM reduction was blocked by co-treatment with RSV, suggesting the participation of SIRT1 in determining this effect. Immunoprecipitation experiments in SOD1-G93 A cells exposed to thimerosal demonstrated that RSV increased DREAM deacetylation and reduced its polyubiquitination. In addition, RSV counteracted thimerosal-enhanced prodynorphin (PDYN) mRNA, a DREAM target gene. Furthermore, cortical neurons transiently transfected with SOD1-G93 A construct and exposed to thimerosal (0.5 μM/24 h) showed a reduction of DREAM and an up-regulation of the prodynorphin gene. Importantly, both the treatment with RSV or the transfection of siRNA against prodynorphin significantly reduced thimerosal-induced neurotoxicity, while DREAM knocking-down potentiated thimerosal-reduced cell survival. These results demonstrate the particular vulnerability of SOD1-G93 A neuronal cells to thimerosal and that RSV via SIRT1 counteracts the neurodetrimental effect of this toxicant by preventing DREAM reduction and prodynorphin up-regulation

Mandibular coronoid process tumor resembling a mandibular condyle: A case report

Abnormal elongation of mandibular coronoid process, often defined as coronoid hyperplasia, is a rare condition, which is frequently associated with limited mouth opening. In some cases, the enlarged coronoid pushes the zygoma forward causing facial asymmetry. This case report describes a 16-year-old boy whose chief complaint was a progressive difficulty and deviation in mouth opening, together with a deformity appearing at maximum opening at the zygomatic area. The diagnosis was Unilateral Accessory Mandibular Condyle at coronoid process, without reduction of the mouth opening capacity. A coronoidectomy was carried out by means of piezoelectric surgery, instead of a coronoidotomy which is usually performed in these cases, due to a suspect of ramus neoplasm. Keywords: Coronoid hyperplasia, Accessory condyle, Temporomandibular disorder, Piezoelectric surgery, Adolescen

Hashimoto Thyroiditis in Primary Thyroid Non-Hodgkin Lymphoma

OBJECTIVES: To assess the prevalence of Hashimoto thyroiditis (HT) in primary thyroid lymphoma (PTL) and whether it differs between mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL). METHODS: Electronic databases were searched for studies assessing HT prevalence in PTL, based on antithyroid antibodies, clinical history, or pathology. Pooled prevalence of HT and its association with histotype (MALT or DLBCL) were calculated. RESULTS: Thirty-eight studies with 1,346 PTLs were included. Pooled prevalence results were 78.9% (any HT evidence), 65.3% (antithyroid antibodies), 41.7% (clinical history), and 64% (pathology). HT prevalence was significantly higher in MALT lymphoma than in DLBCL (P = .007) and in mixed DLBCL/MALT than in pure DLBCL (P = .002). CONCLUSIONS: Overall, 78.9% of patients with PTL have any HT evidence, but only half of these had been clinically followed. The difference in HT prevalence suggests that a subset of DLBCL may not derive from MALT lymphoma

Stroke by inducing HDAC9-dependent deacetylation of HIF-1 and Sp1, promotes TfR1 transcription and GPX4 reduction, thus determining ferroptotic neuronal death

: Background: The inhibition of histone deacetylase 9 (HDAC9) represents a promising druggable target for stroke intervention. Indeed, HDAC9 is overexpressed in neurons after brain ischemia where exerts a neurodetrimental role. However, mechanisms of HDAC9-dependent neuronal cell death are not yet well established. Methods: Brain ischemia was obtained in vitro by primary cortical neurons exposed to glucose deprivation plus reoxygenation (OGD/Rx) and in vivo by transient middle cerebral artery occlusion. Western blot and quantitative real-time polymerase chain reaction were used to evaluate transcript and protein levels. Chromatin immunoprecipitation was used to evaluate the binding of transcription factors to the promoter of target genes. Cell viability was measured by MTT and LDH assays. Ferroptosis was evaluated by iron overload and 4-hydroxynonenal (4-HNE) release. Results: Our results showed that HDAC9 binds to hypoxia-inducible factor 1 (HIF-1) and specificity protein 1 (Sp1), two transcription activators of transferrin 1 receptor (TfR1) and glutathione peroxidase 4 (GPX4) genes, respectively, in neuronal cells exposed to OGD/Rx. Consequently, HDAC9 induced: (1) an increase in protein level of HIF-1 by deacetylation and deubiquitination, thus promoting the transcription of the pro-ferroptotic TfR1 gene; and (2) a reduction in Sp1 protein levels by deacetylation and ubiquitination, thus resulting in a down-regulation of the anti-ferroptotic GPX4 gene. Supporting these results, the silencing of HDAC9 partially prevented either HIF-1 increase and Sp1 reduction after OGD/Rx. Interestingly, silencing of the neurodetrimental factors, HDAC9, HIF-1, or TfR1 or the overexpression of the prosurvival factors Sp1 or GPX4 significantly reduced a well-known marker of ferroptosis 4-HNE after OGD/Rx. More important, in vivo, intracerebroventricular injection of siHDAC9 reduced 4-HNE levels after stroke by preventing: (1) HIF-1 and TfR1 increase and thus the augmented intracellular iron overload; and (2) a reduction of Sp1 and its target gene GPX4. Conclusions: Collectively, results obtained suggest that HDAC9 mediates post-traslational modifications of HIF-1 and Sp1 that, in turn, increases TfR1 and decreases GPX4 expression, thus promoting neuronal ferroptosis in in vitro and in vivo models of stroke

Sinonasal mucosal melanoma extended to nose bridge: A one-time reconstruction treatment report

Sinonasal mucosal melanoma is a rare and highly aggressive tumour. This tumour often carries a poor prognosis because of local invasion and early distant metastasis. It's, in fact, an aggressive, fortunately rare, disease. It's more common among population in their seventies, with a prolonged course due to innocuous symptoms. We report a case of sinonasal mucosal melanoma in a 56-years old male who presented with a brownish sinonasal mass involving right nasal fossa, swelling and spontaneous epistaxis. We report this case for the one-time reconstruction treatment performed by our team