Poly(HPMA)-based copolymers with biodegradable side chains able to self-assemble into nanoparticles

Poly(N-(2-Hydroxypropyl) methacrylamide) (poly(HPMA)) is gaining pharmaceutical attention in replacement to PEG as a hydrophilic stabilizer for polymer nanoparticles (NPs) devoted to systemic administration.[1] This is due to its biocompatibility, prolonged circulation time and, compared to PEG, to the avoidance of allergic reactions and of the accelerated blood clearance effect.[2, 3] In this work, a lipophilic HPMA-based macromonomer with a predetermined and controllable structure is synthesized for the first time attaching a short oligo(caprolactone) chain obtained via Ring Opening Polymerization (ROP) to the HPMA using a succinic acid unit as a spacer. This biodegradable monomer (hereinafter HPMA-CL) was then used to synthesize well-defined amphiphilic block copolymers comprising a hydrophilic poly(HPMA) block and a hydrophobic poly(HPMA-CL) segment via Reversible Addition-Fragmentation Transfer (RAFT) polymerization. The combination of ROP and RAFT allows the production of a library of polymers with a predetermined and controlled structure that are able to self-assemble in water into biodegradable NPs with different size. In particular, such NPs are designed to degrade in aqueous environment into completely water soluble poly(HPMA), with a molecular weight that is below the critical threshold for the renal excretion. This is a very important feature since it allows to avoid polymer accumulation into the body once the NPs are injected.[4] The degradation time is a function of the number of caprolactone units in the HPMA-CL macromonomer and of its degree of polymerization in the NP forming copolymer. Then, the polymer structure can be adjusted to obtain the desired degradation time. Finally, the possibility for such nanoparticles to physically incorporate and mediate the release of a lipophilic antineoplastic drug was evaluated in the case of Trabectedin. The formulation proved to be biocompatible and to sustainedly release the drug for up to 24 hours. Please click Additional Files below to see the full abstract

Primary Intraocular Lymphoma: The Masquerade Syndrome

This chapter aims to provide a complete knowledge over the primary intraocular lymphoma (PIOL) and a correct clinical approach towards this rare condition, to avoid delays in diagnosis, which is considered the most important prognostic factor. A PIOL arises with no specific symptoms and could mimic both inflammatory and non-inflammatory ocular conditions. Also known as reticulum cell sarcoma in the past, PIOL is an ocular malignant condition, with a strong bond with primary central system lymphoma (PCNSL). This linkage is underlined by the fact that approximately 30% of the patients with PIOL have also PCNSL at presentation, while 45–90% will develop PCSNL in the following months. A correct diagnosis is currently achieved by the means of many different techniques: cytology, flow cytometry, immunohistochemistry, molecular analysis, and cytokines assay. Treatment of this condition has been completely revolutionized with the introduction of monoclonal antibodies directed against specific proteins present on the surface of lymphomatous cells

Structure and stability of 7-mercapto-4-methylcoumarin self-assembled monolayers on gold: an experimental and computational analysis

Self-assembled monolayers (SAM) of 7-mercapto-4-methylcoumarin (MMC) on a flat gold surface were studied by molecular dynamics (MD) simulations, reference-free grazing incidence X-ray fluorescence (GIXRF) and X-ray photoelectron spectroscopy (XPS), to determine the maximum monolayer density and to investigate the nature of the molecule/surface interface. In particular, the protonation state of the sulfur atom upon adsorption was analyzed, since some recent literature presented evidence for physisorbed thiols (preserving the S-H bond), unlike the common picture of chemisorbed thiyls (losing the hydrogen). MD with a specifically tailored force field was used to simulate either thiol or thiyl monolayers with increasing number of molecules, to determine the maximum dynamically stable densities. This result was refined by computing the monolayer chemical potential as a function of the density with the bennet acceptance ratio method, based again on MD simulations. The monolayer density was also measured with GIXRF, which provided the absolute quantification of the number of sulfur atoms in a dense self-assembled monolayer (SAM) on flat gold surfaces. The sulfur core level binding energies in the same monolayers were measured by XPS, fitting the recorded spectra with the binding energies proposed in the literature for free or adsorbed thiols and thiyls, to get insight on the nature of the molecular species present in the layer. The comparison of theoretical and experimental SAM densities, and the XPS analysis strongly support the picture of a monolayer formed by chemisorbed, dissociated thiyls

Analysis of multi-year near-surface ozone observations at the WMO/GAW "Concordia" station (75°06′S, 123°20′E, 3280 m a.s.l. – Antarctica)

Abstract This work focuses on the near-surface O3 variability over the eastern Antarctic Plateau. In particular, eight years (2006–2013) of continuous observations at the WMO/GAW contributing station "Concordia" (Dome C–DMC: 75°06′S, 123°20′E, 3280 m) are presented, in the framework of the Italian Antarctic Research Programme (PNRA). First, the characterization of seasonal and diurnal O3 variability at DMC is provided. Then, for the period of highest data coverage (2008–2013), we investigated the role of specific atmospheric processes in affecting near-surface summer O3 variability, when O3 enhancement events (OEEs) are systematically observed at DMC (average monthly frequency peaking up to 60% in December). As deduced by a statistical selection methodology, these OEEs are affected by a significant interannual variability, both in their average O3 values and in their frequency. To explain part of this variability, we analyzed OEEs as a function of specific atmospheric variables and processes: (i) total column of O3 (TCO) and UV-A irradiance, (ii) long-range transport of air masses over the Antarctic Plateau (by Lagrangian back-trajectory analysis – LAGRANTO), (iii) occurrence of "deep" stratospheric intrusion events (by using the Lagrangian tool STLEFLUX). The overall near-surface O3 variability at DMC is controlled by a day-to-day pattern, which strongly points towards a dominating influence of processes occurring at "synoptic" scales rather than "local" processes. Even if previous studies suggested an inverse relationship between OEEs and TCO, we found a slight tendency for the annual frequency of OEEs to be higher when TCO values are higher over DMC. The annual occurrence of OEEs at DMC seems related to the total time spent by air masses over the Antarctic plateau before their arrival to DMC, suggesting the accumulation of photochemically-produced O3 during the transport, rather than a more efficient local production. Moreover, the identification of recent (i.e., 4-day old) stratospheric intrusion events by STEFLUX suggested only a minor influence (up to 3% of the period, in November) of "deep" events on the variability of near-surface summer O3 at DMC

Adult autologous mesenchymal stem cells for the treatment of suspected non-infectious inflammatory diseases of the canine central nervous system: safety, feasibility and preliminary clinical findings

Non-infectious inflammatory diseases of the canine central nervous system (CNS) are common idiopathic disorders grouped under the term meningoencephalomyelitis of unknown origin (MUO). Ante mortem diagnosis is achieved via assessment of clinical signs, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis, but the definitive diagnosis needs histopathological examination. MUO are mostly considered as autoimmune CNS disorders, so that suppressing the immune reaction is the best management method for patients. Mesenchymal stem cells (MSCs) are under investigation to treat autoimmune and degenerative disorders due to their immunomodulatory and regenerative properties. This study aims to verify the safety, feasibility, and efficacy of MSCs treatment in canine idiopathic autoimmune inflammatory disorders of the CNS

Persistent and transient olfactory deficits in COVID-19 are associated to inflammation and zinc homeostasis

IntroductionThe Coronavirus Disease 2019 (COVID-19) is mainly a respiratory syndrome that can affect multiple organ systems, causing a variety of symptoms. Among the most common and characteristic symptoms are deficits in smell and taste perception, which may last for weeks/months after COVID-19 diagnosis owing to mechanisms that are not fully elucidated. MethodsIn order to identify the determinants of olfactory symptom persistence, we obtained olfactory mucosa (OM) from 21 subjects, grouped according to clinical criteria: i) with persistent olfactory symptoms; ii) with transient olfactory symptoms; iii) without olfactory symptoms; and iv) non-COVID-19 controls. Cells from the olfactory mucosa were harvested for transcriptome analyses. Results and discussionRNA-Seq assays showed that gene expression levels are altered for a long time after infection. The expression profile of micro RNAs appeared significantly altered after infection, but no relationship with olfactory symptoms was found. On the other hand, patients with persistent olfactory deficits displayed increased levels of expression of genes involved in the inflammatory response and zinc homeostasis, suggesting an association with persistent or transient olfactory deficits in individuals who experienced SARS-CoV-2 infection

Heart-Kidney Biomarkers in Patients Undergoing Cardiac Stress Testing

We examined association of inducible myocardial perfusion defects with cardiorenal biomarkers, and of diminished left ventricular ejection fraction (LVEF) with kidney injury marker plasma neutrophil gelatinase-associated lipocalin (NGAL). Patients undergoing nuclear myocardial perfusion stress imaging were divided into 2 groups. Biomarkers were analyzed pre- and poststress testing. Compared to the patients in the low ischemia group (n = 16), the patients in the high ischemia group (n = 18) demonstrated a significantly greater rise in cardiac biomarkers plasma BNP, NT-proBNP and cTnI. Subjects were also categorized based on pre- or poststress test detectable plasma NGAL. With stress, the group with no detectable NGAL had a segmental defect score 4.2 compared to 8.2 (P = .06) in the detectable NGAL group, and 0.9 vs. 3.8 (P = .03) at rest. BNP rose with stress to a greater degree in patients with detectable NGAL (10.2 vs. 3.5 pg/mL, P = .03). LVEF at rest and with stress was significantly lower in the detectable NGAL group; 55.8 versus 65.0 (P = .03) and 55.1 vs. 63.8 (P = .04), respectively. Myocardial perfusion defects associate with biomarkers of cardiac stress, and detectable plasma NGAL with significantly lower LVEF, suggesting a specific heart-kidney link

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson