MARCATORI SPECIFICI NELLE IBD E PERSONALIZZAZIONE DELLE STRATEGIE TERAPEUTICHE ATTRAVERSO L¿APPROCCIO PROTEOMICO

Inflammatory bowel diseases (IBD) are chronic and relapsing inflammatory conditions of the gastrointestinal tract including Crohn\u2019s disease (CD) and ulcerative colitis (UC). Pathogenic mechanisms of IBDs, etiology and behavior, are not fully understood. They are characterized by a great extent of heterogeneity, in terms of phenotypic presentation and response to different therapies. These aspects lead to a great variability of the efficacy of different therapeutic strategies inducing patient to suffer and imply enormous costs for healthcare systems. In severe IBD and in corticosteroid-dependent or \u2013resistant cases, the use of biological drugs, targeted towards TNF (infliximab, adalimumab) or \u3b14\u3b27-mediated lymphocyte adhesion (vedolizumab) is indicated. However, 20-40% of patients do not respond to biological agents, leading to an increase of direct and indirect costs and unnecessary exposure of patients to possible adverse events. Nowadays, the diagnostic and prognostic tools for IBD and the outcome of therapy are largely based on evaluation of clinical symptoms in combination with endoscopy, histology, radiology and non-specific biomarkers from serum or stools. There are no reliable clinical or molecular predictors of response to anti-TNF or anti-leukocyte adhesion drugs. The aim of the project is to promote personalized medicine in IBD, using serum proteomic profiling, to identify potential molecular markers that may predict the behavior of the disease and the response vs. failure of anti-TNF or anti-leukocyte adhesion treatment strategies in IBD patients. After obtaining written informed consent, we prospectively enrolled all the consecutive IBD patients afferent to Gastroenterology and Digestive Endoscopy Unit of IRCCS Policlinico San Donato. All diagnoses must have been previously confirmed by clinical, endoscopic and histologic criteria. Age and sex matched healthy controls were also be enrolled. Clinical data, such as, disease, medication and family medical history were collected; disease location, extension and behavior were classified according to Montreal classification, whereas clinical activity was evaluated using clinical scores, i.e. Harvey-Bradshaw Index (HBI) as appropriate. Patients underwent blood collection for serum. Successively, we obtained Protein Matrix Assisted Laser Desorption Ionization (MALDI) profiling from the collected sera. A total of 40 sera from healthy control and 32 sera from male adult patients affected by CD were analyzed. Before MALDI analysis, the samples underwent immunodeplection in order to eliminate the high abundant protein fractions from the serum. From MALDI analysis, we obtain best separating peaks between different conditions, which represent characteristic serum profiles. The best separating peaks were compared along different groups. Healthy controls versus responder and non responder were compared first, to identify the best peaks able to define control samples and disease samples. To identify the best peaks able to define differences between responders and non responders, these two groups were compared at I infusion and at II infusion time. Finally, total MALDI spectra from controls, responders and non responders were compared together at I infusion and at II second infusion time. This comparison showed one particular peak (corresponding to 3155, 98 m/z) that was changed in all samples and normalized at control level after treatment. This finding could indicate that this peak is typical of the disease. In conclusion specific protein profiles appear to be associated with the absence of response to anti-TNF in CD patients and one single peak is differentially expressed in controls, CD responder to anti-TNF and non-responder; thus, further investigations are required in order to identify the protein that the peak corresponds to

Dynamic regulation of Ero1 and peroxiredoxin 4 localization in the secretory pathway

In the early secretory compartment (ESC), a network of chaper- ones and enzymes assists oxidative folding of nascent proteins. Ero1 flavoproteins oxidize protein disulfide isomerase (PDI), gen- erating H2O2 as a byproduct. Peroxiredoxin 4 (Prx4) can utilize luminal H2O2 to oxidize PDI, thus favoring oxidative folding while limiting oxidative stress. Interestingly, neither ER oxidase contains known ER retention signal(s), raising the question of how cells pre- vent their secretion. Here we show that the two proteins share sim- ilar intracellular localization mechanisms. Their secretion is pre- vented by sequential interactions with PDI and ERp44, two resident proteins of the ESC-bearing KDEL-like motifs. PDI binds preferentially Ero1 , whereas ERp44 equally retains Ero1 and Prx4. The different binding properties of Ero1 and Prx4 increase the robustness of ER redox homeostasis

On topological spin excitations on a rigid torus

We study Heisenberg model of classical spins lying on the toroidal support, whose internal and external radii are $r$ and $R$, respectively. The isotropic regime is characterized by a fractional soliton solution. Whenever the torus size is very large, $R\to\infty$, its charge equals unity and the soliton effectively lies on an infinite cylinder. However, for R=0 the spherical geometry is recovered and we obtain that configuration and energy of a soliton lying on a sphere. Vortex-like configurations are also supported: in a ring torus ($R>r$) such excitations present no core where energy could blow up. At the limit $R\to\infty$ we are effectively describing it on an infinite cylinder, where the spins appear to be practically parallel to each other, yielding no net energy. On the other hand, in a horn torus ($R=r$) a singular core takes place, while for $R<r$ (spindle torus) two such singularities appear. If $R$ is further diminished until vanish we recover vortex configuration on a sphere.Comment: 11 pages, 9 figure

Thermo-mechanical behavior of surface acoustic waves in ordered arrays of nanodisks studied by near infrared pump-probe diffraction experiments

The ultrafast thermal and mechanical dynamics of a two-dimensional lattice of metallic nano-disks has been studied by near infrared pump-probe diffraction measurements, over a temporal range spanning from 100 fs to several nanoseconds. The experiments demonstrate that, in these systems, a two-dimensional surface acoustic wave (2DSAW), with a wavevector given by the reciprocal periodicity of the array, can be excited by ~120 fs Ti:sapphire laser pulses. In order to clarify the interaction between the nanodisks and the substrate, numerical calculations of the elastic eigenmodes and simulations of the thermodynamics of the system are developed through finite-element analysis. At this light, we unambiguously show that the observed 2DSAW velocity shift originates from the mechanical interaction between the 2DSAWs and the nano-disks, while the correlated 2DSAW damping is due to the energy radiation into the substrate.Comment: 13 pages, 10 figure

Ex vivo experimental study on the Thulium laser system : new horizons for interventional endoscopy (with videos)

BACKGROUND AND STUDY AIMS: The Thulium laser system (TLS) is an emerging interventional tool adopted in many surgical specialties. Its 2.0-\u3bcm wavelength allows precise coagulation (0.2\u200a-\u200a0.4\u200amm in depth) and cutting, limiting the possibilities of collateral injuries. We tested the impact of the TLS for gastric endoscopic submucosal dissection (ESD) and per oral endoscopic myotomy (POEM) ex vivo in pigs. MATERIALS AND METHODS: Ex vivo porcine stomach and esophagus models underwent 2 POEMs, and 3 ESDs (mean diameter 3.5\u200acm) with TLS using a 272-\ub5m and a 365-\ub5m thick optical fibers. Both continuous and pulsed laser emission were evaluated. Subsequent histopathological analysis was performed by an expert GI pathologist on the whole porcine models. RESULTS: Complete POEMs and gastric ESDs were successfully performed in all cases in 30 to 70 and 15 to 20 minutes. Both optical fibers were equally effective and precise. The best power output for mucosal incision was 25 to 30\u200aW during ESD and 25\u200aW for POEM using continuous laser emission. During submucosal dissection and tunneling the favorite power output was 20\u200aW and 15 to 20\u200aW, respectively, operating in continuous mode. No transmural perforation occurred throughout the operations and histopathology confirmed the absence of accidental muscular layer damage. CONCLUSIONS: The TLS stands out as a precise and manageable instrument in ex vivo models. This technique appears to be a promising tool for advanced interventional endoscopy

Magnetoplasmonic design rules for active magneto-optics

Light polarization rotators and non-reciprocal optical isolators are essential building blocks in photonics technology. These macroscopic passive devices are commonly based on magneto-optical Faraday and Kerr polarization rotation. Magnetoplasmonics - the combination of magnetism and plasmonics - is a promising route to bring these devices to the nanoscale. We introduce design rules for highly tunable active magnetoplasmonic elements in which we can tailor the amplitude and sign of the Kerr response over a broad spectral range

Experimental and theoretical analysis of Landauer erasure in nanomagnetic switches of different sizes

The authors acknowledge support by the European Union (FPVII (2007-2013) under G.A. n.318287 LANDAUER, and by MIUR-PRIN 2010–11 Project 2010ECA8P3 “DyNanoMag.”. M.P. and P.V. acknowledge funding from the Spanish Ministry of Economy and Competitiveness (Project No. MAT2012-36844); M.P. acknowledges support by Spanish Ministry of Economy and Competitiveness (grant BES-2013-063690).Bistable nanomagnetic switches are extensively used in storage media and magnetic memories, associating each logic state to a different equilibrium orientation of the magnetization. Here we consider the issue of the minimum energy required to change the information content of nanomagnetic switches, a crucial topic to face fundamental challenges of current technology, such as power dissipation and limits of scaling. The energy dissipated during a reset operation, also known as “Landauer erasure”, has been accurately measured at room temperature by vectorial magneto-optical measurements in arrays of elongated Permalloy nanodots. Both elliptical and rectangular dots were analysed, with lateral sizes ranging from several hundreds to a few tens of nanometers and thickness of either 10 nm or 5 nm. The experimental results show a nearly linear decrease of the dissipated energy with the dot volume, ranging from three to one orders of magnitude above the theoretical Landauer limit of kBT×ln(2). These experimental findings are corroborated by micromagnetic simulations showing that the significant deviations from the ideal macrospin behavior are caused by both inhomogeneous magnetization distribution and edge effects, leading to an average produced heat which is appreciably larger than that expected for ideal nanoswitches.PostprintPeer reviewe