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ObjectiveTo investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a history of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment.MethodsA phase 2, exploratory, randomized, double-blind, placebo-controlled, 15-center study is described. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy (change from baseline to week 11 of Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and of the revised 15-item Myasthenia Gravis Quality of Life scale), pharmacokinetics, pharmacodynamics, and immunogenicity.ResultsOf the 35 screened patients, 24 were enrolled and randomized: 12 received efgartigimod and 12 placebo. Efgartigimod was well-tolerated in all patients, with no serious or severe adverse events reported, no relevant changes in vital signs or ECG findings observed, and no difference in adverse events between efgartigimod and placebo treatment. All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement.ConclusionsEfgartigimod was safe and well-tolerated. The correlation between reduction of levels of pathogenic IgG autoantibodies and disease improvement suggests that reducing pathogenic autoantibodies with efgartigimod may offer an innovative approach to treat MG.Classification of evidenceThis study provides Class I evidence that efgartigimod is safe and well-tolerated in patients with gMG.

We report a simple one‐pot method for the rapid preparation of sub‐10 nm pure hexagonal (v‐phase) NaYF4‐based upconverting nanoparticles (UCNPs). Using Therminol® 66 as a co‐solvent, monodisperse UCNPs could be obtained in unusually short reaction times. By varying the reaction time and reaction temperature, it was possible to control precisely the particle size and crystalline phase of the UCNPs. The upconversion (UC) luminescence properties of the nanocrystals were tuned by varying the concentrations of the dopants (Nd3+ and Yb3+ sensitizer ions and Er3+ activator ions). The size and phase‐purity of the as‐synthesized core and core-shell nanocrystals were assessed by using complementary transmission electron microscopy, dynamic light scattering, X‐ray diffraction, and small‐angle X‐ray scattering studies. In‐depth photophysical evaluation of the UCNPs was pursued by using steady‐state and time‐resolved luminescence spectroscopy. An enhancement in the UC intensity was observed if the nanocrystals, doped with optimized concentrations of lanthanide sensitizer/activator ions, were further coated with an inert/active shell. This was attributed to the suppression of surface‐related luminescence quenching effects.

Currently, there is a widespread interest to use neodymium containing upconverting nanophosphors (UCNPs) for bioimaging applications. The infatuation of these nanoparticles derives from their capacity for excitation in the biologically transparent window (700-1000 nm), exceptional ability to convert near infrared radiation into visible light (upconversion), which prevents autofluorescence and over-heating effect of biological tissues and capability for deep tissue, high contrast imaging related to minimum autofluorescence in this spectral range [1]. Despite the fast progress in lanthanide-doped upconversion nanoparticles, the preparation of ultrasmall, monodisperse and hydrophilic UCNPs that display intense luminescence is still a challenging issue. Only a few examples of ultrasmall and hydrophilic UCNPs have been reported [2-3]. Here, we report the elaboration, synthesis and surface modification of sub-10 nm UCNPs with an excitation wavelength of 795 nm, which are composed of a host lattice of crystalline NaYF4 doped with Nd3+ and Yb3+ as sensitizers, and Er3+,Ho3+ or Tm3+ as emitter ions. Established strategies for synthesizing UCNPs yield mainly hydrophobic particles[1]. We report the conversion of these into hydrophilic, colloidally-stable, and biocompatible by using mainly ligand exchange strategies, and the influence of the coating on the UCNPs’ photophysical properties. This study will also allow establishing information about biodistribution, pharmacokinetics and formation of protein corona for ultrasmall UCNPs.

Currently, there is a widespread interest to use neodymium containing upconverting nanophosphors (UCNPs) for bioimaging applications. The fascination of these nanoparticles derives from their capacity for excitation in the biologically transparent window (650-950 nm), exceptional ability to convert near infrared radiation into visible light (upconversion), which prevents autofluorescence and over-heating effect of biological tissues, capability for deep tissue, and high contrast imaging [1]. Despite the fast progress in lanthanide-doped upconversion nanoparticles, the preparation of ultrasmall, monodisperse and hydrophilic UCNPs that display intense luminescence is still a challenging issue. Only a few examples of ultrasmall and hydrophilic UCNPs have been reported [2-3]. Established strategies for synthesizing UCNPs yield mainly hydrophobic particles[1]. Here, we report the, synthesis and surface modification of sub-10 nm UCNPs with an excitation wavelength of 795 nm, which are composed of a host lattice of crystalline hexagonal phased NaYF4 doped with Nd3+ and Yb3+ as sensitizers, and Er3+, Ho3+ or Tm3+ as emitter ions. Surface passivation by coating with a shell of active and also inert host material is used to enhance the overall upconversion efficiency. We also report the conversion of these into hydrophilic, colloidally-stable, and biocompatible by using mainly ligand exchange strategies and the influence of the coating on the UCNPs’ photophysical properties will also be discussed. Finally, this study will also allow establishing information about biodistribution, pharmacokinetics and formation of protein corona for ultrasmall UCNPs.

In order to make more reasonable international comparisons between graguate outcome studies, two main stylized facts of the Italian setting are spelled out: the rapid ageing of the population and the scarcity of youths; the scarcity of highly qualified manpower. Secondly, a very compact comparison is carried out on the characteristics of pre- and post-reform graduates and on the strengths and weaknesses of the Italian higher education system. This paper, after a short introduction, in paragraph 1. synthetically describes the study structure of the Italian higher education system and the main features of the Bologna Process reform in Italy. In paragraph 2 a short description is presented of the AlmaLaurea graduate surveys used for the analysis and the AlmaLaurea broad model. Paragraph 3 offers an account of the main characteristics of bachelor-level graduates, especially in terms of socio-biographic background and course of study. Some evidence on graduates’ international mobility is put forward in paragraph 4. In paragraph 5 the main features of the available evidence on employment and further studies of bachelors are presented, while paragraph 6 is devoted to the presentation of the main evidence concerning the professional success of bachelors. Paragraph 7 outlines the major conclusions that can be drawn, at this stage, on the open debate on the impact of the reform. The appendix displays basic data analysed in the previous paragraphs.

Historically, senescence has been considered a safe program in response to multiple stresses in which cells undergo irreversible growth arrest. This process is characterized by morphological and metabolic changes, heterochromatin formation, and secretion of inflammatory components, known as senescence-associated secretory phenotype (SASP). However, recent reports demonstrated that anti-cancer therapy itself can stimulate a senescence response in tumor cells, the so-called therapy-induced senescence (TIS), which may represent a temporary bypass pathway that promotes drug resistance. In this context, several studies have shown that EGFR blockage, by TKIs or moAbs, promotes TIS by increasing IL-1 cytokine production, thus pushing cells into a “pseudo-senescent” state. Today, senotherapeutic agents are emerging as a potential strategy in cancer treatment thanks to their dual role in annihilating senescent cells and simultaneously preventing their awakening into a resistant and aggressive form. Here, we summarize classic and recent findings about the cellular processes driving senescence and SASP, and we provide a state-of-the-art of the anti-cancer strategies available so far that exploits the activation and/or blockade of senescence-based mechanisms.

Salicylate and benzoate sunscreen agents have been encapsulated by the green, fast and robust ultrasound technique in tannin microcapsules (TMCs). The generated TMCs, obtained without use of cross linking agents, were fully characterised, including encapsulation efficiencies with respect to the encapsulated actives. Release kinetics of TMCs have been studied mimicking skin conditions. Body cream base samples containing specific concentrations of microcapsules filled with sunscreen actives were prepared and showed synergistic effects in terms of UV-protection abilities generated by the interplay between sunscreen actives and natural tannin polyphenols. The synergistic effect exerted by the tannin and the controlled active release allows to reduce the amount of synthetic sunscreens needed, and does thus contribute to the development of more sustainable and environmentally benign UV-protection systems.

Objectives: Evidences from either small series or spontaneous reporting are accumulating that SARS-CoV-2 involves the Nervous Systems. The aim of this study is to provide an extensive overview on the major neurological complications in a large cohort of COVID-19 patients. Methods: Retrospective, observational analysis on all COVID-19 patients admitted from February 23rd to April 30th, 2020 to ASST Papa Giovanni XXIII, Bergamo, Italy for whom a neurological consultation/neurophysiological assessment/neuroradiologic investigation was requested. Each identified neurologic complication was then classified into main neurologic categories. Results: Of 1760 COVID-19 patients, 137 presented neurologic manifestations that manifested after COVID-19 symptoms in 98 pts and was the presenting symptom in 39. Neurological manifestations were classified as: (a) cerebrovascular disease [53 pts (38.7%)] including 37 ischemic and 11 haemorrhagic strokes, 4 transient ischemic attacks, 1 cerebral venous thrombosis; (b) peripheral nervous system diseases [31 (22.6%)] including 17 Guillain–Barrè syndromes; (c) altered mental status [49 (35.8%)] including one necrotizing encephalitis and 2 cases with RT-PCR detection of SARS-Cov-2 RNA in CSF; (d) miscellaneous disorders, among whom 2 patients with myelopathy associated with Ab anti-SARS-CoV-2 in CSF. Patients with peripheral nervous system involvement had more frequently severe ARDS compared to patients with cerebrovascular disease (87.1% vs 42%; difference = 45.1% 95% CI 42.0–48.2; χ2= 14.306; p < 0.0002) and with altered mental status (87.1% vs 55.6%; difference = 31.5% 95% CI 27.5–37.5%; χ2= 7.055; p < 0.01). Conclusion: This study confirms that involvement of nervous system is common in SARS-CoV-2 infection and offers clinicians useful information for prevention and prompt identification in order to set the adequate therapeutic strategies.

ERBB3, also known as HER3, is a tyrosine kinase transmembrane receptor of the ERBB family. Upon binding to neuregulin 1 (NRG1), ERBB3 preferentially dimerizes with HER2 (ERBB2), in turn inducing aggressive features in several cancer types. The analysis of a dataset of breast cancer patients unveiled that higher ERBB3 mRNA expression correlates with shorter relapse-free survival in basal-like breast cancers, despite low ERBB3 expression in this breast cancer subtype. Administration of neuregulin 1 beta (NRG1β) significantly affected neither cellular proliferation nor the basal migratory ability of basal-like/triple-negative quasi-normal MCF10A breast cells, cultured in mono-layer conditions. Furthermore, no significant regulation in cell morphology or in the expression of basal/myoepithelial and luminal markers was observed upon stimulation with NRG1β. In non-adherent conditions, NRG1β administration to MCF10A cells did not significantly influence cell survival; however, it robustly induced cell growth as spheroids (3D growth). Intriguingly, a remarkable upregulation of ERBB3 and ERBB2 protein abundance was observed in 3D compared to 2D cell cultures, and NRG1β-induced 3D cell growth was efficiently prevented by the anti-HER2 monoclonal antibody pertuzumab. Similar results were obtained by the analysis of basal-like/triple-negative breast cancer cellular models, MDA-MB-468 and MDA-MB-231 cells, in which NRG1β induced anchorage-independent cell growth that in turn was prevented or reduced by the simultaneous administration of anti-HER2 neutralizing antibodies. Finally, the ability of pertuzumab in suppressing NRG1β-induced 3D growth was also evaluated and confirmed in MCF10A engineered with HER2-overexpression. We suggest that the NRG1/ERBB3/ERBB2 pathway promotes the anchorage-independent growth of basal-like breast cancer cells. Importantly, we provide evidence that ERBB2 neutralization, in particular by pertuzumab, robustly inhibits this process. Our results pave the way towards the development of novel anticancer strategies for basal-like breast cancer patients based on the interception of the NRG1/ERBB3/ERBB2 signaling axis.

Background EGFR targeting is currently the main treatment strategy for metastatic colorectal cancer (mCRC). Results of different clinical trials show that patients with wild-type KRAS and BRAF benefit from anti-EGFR monoclonal antibodies (moAbs) cetuximab (CTX) or panitumumab. Unfortunately, despite initial response, patients soon became refractory. Tumor heterogeneity and multiple escaping routes have been addressed as the main culprit, and, behind genomic alterations already described, changes in signaling pathways induced by drug pressure are emerging as mechanisms of acquired resistance. We previously reported an association between reduced sensitivity to CTX and increased expression of IL-1. However, how IL-1 mediates CTX resistance in mCRC is still unclear. Methods Under CTX treatment, the upregulation of IL-1R1 expression and a senescence program in sensitive colorectal cancer (CRC) cell lines is examined over time using qPCR, immunoblotting, and immunofluorescence. Results In sensitive CRC cells, IL-1 appeared responsible for a CTX-mediated G0 phase arrest. On the contrary, CTX-resistant CRC cells (CXR) maintained high mRNA levels of IL-1R1 and a post-senescence reprogramming, as indicated by increased SNAIL expression. Interestingly, treatment of CXR cells with a recombinant decoy, able to sequester the soluble form of IL-1, pushed CTX-resistant CRC cells back into a stage of senescence, thus blocking their proliferation. Our model suggests a trans-regulatory mechanism mediated by IL-1 on EGFR signaling. By establishing senescence and regulating EGFR activity and expression, IL-1 exposure ultimately bestows resistance. Conclusions To sum up, our findings point to the combined blockage of IL-1R and EGFR as a promising therapeutical approach to restore sensitivity to EGFR-targeting monoclonal antibodies.

Stepwise self-assembly processes using new lanthanide metalloligands (Ln-MLs) and silver salts have been successfully applied to isolate 4f-4d heterometallic coordination networks of four different structural types. In particular, the new lanthanide tetrakis-chelate complexes NEt4[Ln(L1)4] [HL1 = 1,3-bis(4'-cyanophenyl)-1,3-propanedione; Ln = Eu (1a), La (1b), Nd (1c), Tb (1d)] and NEt4[Ln(L2)4] (HL2 = 1,3-bis(4'-pyridyl)-1,3-propanedione; Ln = Eu (1e), Nd (1f)] have been synthesized, characterized, and reacted with different silver salts. The use of NEt4[Ln-(L1)4] allowed then to isolate and characterize i) neutral onedimensional ladder-like species of formula [Ln(L1)4Ag] [Ln = Eu (2a), La(2b), Nd(2c), Tb(2d)] and ii) their supramolecular isomers [Ln(L1)4Ag] [Ln = Eu (3a), La (3b), Nd (3c), Tb (3d)] showing a very unstable 2D network structure, iii) the cationic 2D species [Ln(L1)4Ag2]X [Ln = Eu, X = PF6-, CF3SO3-, ClO4- (4a-4c); Ln = Tb, Nd, La X = PF6 - (4d-4f)], and, only for lanthanum, iv) a fourth 2D species of formula [La(L1)4(H2O)Ag] (5) and SQL topology. Of the eight nitrile groups on the MLs potentially coordinating, only a partial number is used for networking with Ag(I), that is, only two in families 2 and 3 and four in family 4 and in network 5. Finally, the four structural types are rationalized in terms of a new "pincer-like" secondary building unit (SBU) consisting of a silver cation coordinating two central carbon atoms (γ carbon) of two different diketonate ligands on the same ML. Therefore, it is shown that compounds 5, 4, and 2-3 contain, respectively, none, one, or two of such pincer-like SBUs. The luminescence properties of the Ln-MLs and some of their polymeric species have been also investigated in solution and in the solid state.

We report here the synthesis of a new thio-aza macrocyclic chemosensor based on the 2,5-diphenyl[1,3,4]oxadiazole in which two thioether groups were inserted in a macrocycle with the aim to make it suitable for the coordination of soft and heavy metal ions. In acetonitrile solution, the fluorescence of the chemosensor changes upon addition of different metal ions, such as Cu(II), Zn(II), Cd(II), Pb(II), Hg(II) and Ag(I), that form a not fluorescent ML species and a fluorescent M2L species characterized also via NMR experiments. The hosting of the chemosensor inside the PluS Nanoparticles leads to a high water solubility, allowing to perform the metal detection without the use of additional solvents and also induced an higher selectivity towards Ag(I) and Hg(II). Moreover, it was demonstrated for the first time the possibility to control the stoichiometry of the formed complex upon changing the number of ligands per nanoparticles. To our opinion, this possibility can give an additional tool for the tuning of the affinity and selectivity of the chemosensor that could be of great interest for the design of more and more efficient systems.

none 9 no A systematic study of a series of diaza-18-crown-6 8-hydroxyquinoline (DCHQ) chemosensors, devoted to Mg(II) ion detection, was performed. Functionalization of DCHQ by peripheral substituents allowed the development of novel all-solid-state optodes via inclusion inside PVC-based polymeric films. The influence on the DCHQ-based optode response of the lipophilic sites functionalization and of the nature of the plasticizer, was investigated. Fluorimetric studies on optodes sensitivity towards a number of different metal cations (Ca2+, Na+, K+, Li+, Co2+, Cd2+, Pb2+, Cu2+, Hg2+, Zn2+) and NH4+were carried out. The results demonstrated the suitability of the DCHQ optodes to perform fast monitoring (

Background Video-assisted thoracoscopic extended thymectomy (VATET) is well established in the treatment of myasthenia gravis; however, patient selection remains controversial. Perioperative management protocol is lacking, and concerns regarding post-operative myasthenic crisis still remain. We performed a retrospective observational study evaluating the impact of the introduction of a protocol in the perioperative management of patients with myasthenia gravis who underwent VATET. Methods The perioperative management protocol was developed by a team of neurologists and anesthesiologists who reviewed the literature and their previous experience on myasthenia gravis patients. Respiratory, clinical, and neurological patient features were included in the protocol evaluation. A retrospective review of patients who underwent VATET before and after introduction to the protocol was finally performed. Results The medical records of 66 patients (pre-protocol group) and 44 patients (protocol group) were available for the study. In the pre-protocol group, 17 patients (26%) were admitted to intensive care unit (ICU) during the post-operative period, while three patients (6.8%) of the protocol group met the criteria for ICU post-operative admission. This resulted in a reduction of 73.5% of patients admitted to ICU (P = 0.023) and in an 80% (P = 0.002) reduction of the use neuromuscular blocking agents. Two post-operative myasthenic crises preceded by bulbar symptoms (1.8%) were identified in the pre-protocol group patients. Conclusions Although the application of our protocol results in a substantial reduction in the recovery of patients in the ICU and in hospital costs, there was no substantial difference in mortality and morbidity between patients admitted to the surgical ward or to ICU.

This review aims to give an overview on the state of the art in the precise context of metal complexes-based ECL dyes directly adsorbed on, included in or interacting with nanoparticles of various nature. Electrogenerated chemiluminescence, or electrochemiluminescence (ECL), is the process through which species generated at electrodes undergo homogeneous high-energy electron transfer reactions to give excited states that emit light. When stable ECL probes such as ruthenium coordination complexes are used, this process can be performed several times, free of the interferences typical of photoluminescence such as the excitation light, providing a clear and stable signal suitable for highly sensitive assays. The ECL emission is initiated and controlled by the electrode potential and immobilization of the ECL probes on the electrode surface allows one to reduce the consumption of expensive reagents, simplifies the experimental design, and creates regenerable sensing devices. The organization of the electrode surface is thus the key point to optimize the device performance. Nanoparticles have proved their potential as tools to organize the ECL probes, to increase the active area and to improve the electrochemical properties of the interface. There is an extended research devoted on one hand to optimize the materials, and on the other hand to explore the wide horizon of possibilities that arise from the combination of nanoparticles and ECL probes, co-reagents, (bio)markers and other functional moieties. The results discussed in this review clearly show that the use of nanoparticles aimed to obtain signal enhancement represents one of the most interesting research lines for the development of the ECL technique. The activity in this field is so dynamic that outstanding results could reasonably be expected in the near future.

Recent studies demonstrated that 2MM-67, a new 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinone, analog of recently published compounds is able to induce apoptotic cell death in HT-29, a colon carcinoma cell line. The cells treated with the proapoptotic agent (500 nM) showed arrest in G2/M phase and increased expression of p21 protein. Moreover it was observed a significant reduction of mitochondrial potential (Δψm), enhanced expression of Bax and, finally, a marked induction of effector caspases. The aim of this work was to assess cellular magnesium levels during 2MM-67-induced apoptosis and if they correlate to Δψm decrease and to an increase in ROS production, characteristic feature of mitochondrion-mediated apoptosis. Intracellular free and total magnesium were evaluated in flow cytometry, respectively by the commercial probe MagFluo4-AM (Kd=4.7 mM), and the new synthesized DCHQ7 (Kd=8.3 μM), while ROS production was assessed by DiClFDA and Dihydrohetidine. Our results indicate that 2MM-67 treatment in HT29 cells can result in rapid declines in intracellular free and total magnesium concomitant with the decrease in mitochondrial membrane potential and the increase of ROS production.