Towards formal models and languages for verifiable Multi-Robot Systems

Incorrect operations of a Multi-Robot System (MRS) may not only lead to unsatisfactory results, but can also cause economic losses and threats to safety. These threats may not always be apparent, since they may arise as unforeseen consequences of the interactions between elements of the system. This call for tools and techniques that can help in providing guarantees about MRSs behaviour. We think that, whenever possible, these guarantees should be backed up by formal proofs to complement traditional approaches based on testing and simulation. We believe that tailored linguistic support to specify MRSs is a major step towards this goal. In particular, reducing the gap between typical features of an MRS and the level of abstraction of the linguistic primitives would simplify both the specification of these systems and the verification of their properties. In this work, we review different agent-oriented languages and their features; we then consider a selection of case studies of interest and implement them useing the surveyed languages. We also evaluate and compare effectiveness of the proposed solution, considering, in particular, easiness of expressing non-trivial behaviour.Comment: Changed formattin

Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) Patients: A Retrospective Analysis of Eligibility Criteria for CAR-T Cell Therapy

Patients (pts) with diffuse large B-cell lymphoma (DLBCL) refractory to second-line therapy or relapsed after an autologous stem cell transplant (ASCT) have a very poor clinical outcome with a median overall survival (OS) of 5 and 8-10 months, respectively. Autologous anti-CD19 chimeric antigen receptor (CD19 CAR) T cells have been associated with sustained complete remissions and long-term survivals in a large proportion of pts with R/R DLBCL by the two pivotal clinical trials Zuma1 and Juliet. This has led to the rapid approval by FDA and then by EMA of CAR-T cells for the third-line treatment of R/R DLBCL. Despite being a potentially revolutionary treatment for pts with advanced disease, the costs are much greater than any previously approved cancer therapy and this may become a substantial economic challenge for the health care system. The definition of inclusion and exclusion criteria capable of identifying more precisely pts who can successfully undergo CAR-T cell therapy, minimizing the severity of the toxicity, still remains a matter of discussion. Moreover, some eligible pts run the risk of becoming ineligible because of poor disease control. Indeed, one of the major obstacles to the successful use of CAR-T cells is the 4-5 week period so far required for the manufacturing and transfer of CAR-T cells. To address this issue, we have examined data of R/R DLBCL pts managed between 2010 and 2018 at our Center in order to: 1) better identify the characteristics and outcome of a cohort of R/R DLBCL pts potentially eligible, according to the approval criteria, for CAR-T cell therapy; 2) define factors influencing CAR-T cell eligibility; 3) make a realistic estimate of pts eligible for CAR-T cells. In this retrospective real-life cohort of R/R DLBCLs, 82/480 pts (17%) were R/R tosecond-line treatment including ASCT. Considering Juliet's inclusion/exclusion criteria for CAR-T cell therapy, only 50 pts (10.4%) would be eligible for CAR-T cells. Our analysis suggests that elevated LDH plus ECOG ≥2 have to be considered the two most significant features of very rapid disease progression. These variables should be taken in account in order to better select DLBCL pts potentially eligible to CAR-T therapy

Correction: Conformational features of 4-(N)-squalenoyl-gemcitabine in solution: a combined NMR and molecular dynamics investigation

Correction for 'Conformational features of 4-(N)-squalenoyl-gemcitabine in solution: a combined NMR and molecular dynamics investigation' by Ceruti Maurizio et al., New J. Chem., 2015, 39, 3484–3496

Assembly and functional analysis of an S/MAR based episome with the cystic fibrosis transmembrane conductance regulator gene

Improving the efficacy of gene therapy vectors is still an important goal toward the development of safe and efficient gene therapy treatments. S/MAR (scaffold/matrix attached region)-based vectors are maintained extra-chromosomally in numerous cell types, which is similar to viral-based vectors. Additionally, when established as an episome, they show a very high mitotic stability. In the present study we tested the idea that addition of an S/MAR element to a CFTR (cystic fibrosis transmembrane conductance regulator) expression vector, may allow the establishment of a CFTR episome in bronchial epithelial cells. Starting from the observation that the S/MAR vector pEPI-EGFP (enhanced green fluorescence protein) is maintained as an episome in human bronchial epithelial cells, we assembled the CFTR vector pBQ-S/MAR. This vector, transfected in bronchial epithelial cells with mutated CFTR, supported long term wt CFTR expression and activity, which in turn positively impacted on the assembly of tight junctions in polarized epithelial cells. Additionally, the recovery of intact pBQ-S/MAR, but not the parental vector lacking the S/MAR element, from transfected cells after extensive proliferation, strongly suggested that pBQ-S/MAR was established as an episome. These results add a new element, the S/MAR, that can be considered to improve the persistence and safety of gene therapy vectors for cystic fibrosis pulmonary disease

Polyethylene Glycol Epirubicin-Loaded Transcatheter Arterial Chemoembolization Procedures Utilizing a Combined Approach with 100 and 200 μm Microspheres: A Promising Alternative to Current Standards

PURPOSE:To report clinical effectiveness, toxicity profile, and prognostic factors of combined 100 μm ± 25 and 200 μm ± 50 epirubicin-loaded polyethylene glycol (PEG) microsphere drug-eluting embolic transcatheter arterial chemoembolization protocol in patients with hepatocellular carcinoma. MATERIALS AND METHODS: In this prospective, single-center, single-arm study with 18 months of follow-up, 36 consecutive patients (mean age 69.9 y ± 10.8; 26 men, 10 women; 54 naïve lesions) were treated. Embolization was initiated with 100 μm ± 25 microspheres, and if stasis (10 heart beats) was not achieved, 200 μm ± 50 microspheres were administered. Each syringe (2 mL) of PEG microsphere was loaded with 50 mg of epirubicin. Results were evaluated using Modified Response Evaluation Criteria In Solid Tumors with multidetector computed tomography/magnetic resonance imaging at 1, 3-6, 9-12, and 15-18 months. Toxicity profile was assessed by laboratory testing before and after the procedure. Complications were recorded. Postembolization syndrome (PES) was defined as onset of fever/nausea/pain after the procedure. Patient/lesion characteristics and treatment results were correlated with predicted outcome using regression analysis. Child-Pugh score was A in 86.1% of patients (31/36) and B in 13.9% (5/36). RESULTS: In 10 of 21 lesions, < 2 cm in diameter (47.5%) stasis was achieved with 100 μm ± 25 microspheres only, whereas all other lesions required adjunctive treatment with 200 μm ± 50 microspheres. Reported adverse events were grade 1 acute liver bile duct injury (3/39 cases, 7.7%) and PES (grade 2; 3/39 cases, 7.7%). Complete response (CR) at 1, 3-6, 9-12, and 15-18 months was 61.1%, 65.5%, 63.63%, and 62.5%. Objective response (CR + partial response) at 1, 3-6, 9-12, and 15-18 months was 83.3%, 65.85%, 63.63%, and 62.5%. No single factor (laboratory testing, etiology, patient status, hepatic status, tumor characteristics, administration protocol) predicted outcomes except for albumin level at baseline for CR (P < .05, odds ratio = 1.09). CONCLUSIONS: The combined microsphere sizing strategy was technically feasible and yielded promising results in terms of effectiveness and toxicity

Emergency total thyroidectomy due to non traumatic disease. Experience of a surgical unit and literature review

<p>Abstract</p> <p>Background</p> <p>Acute respiratory failure due to thyroid compression or invasion of the tracheal lumen is a surgical emergency requiring urgent management. The aim of this paper is to describe a series of six patients treated successfully in the emergency setting with total thyroidectomy due to ingravescent dyspnoea and asphyxia, as well as review related data reported in literature.</p> <p>Methods</p> <p>During 2005-2010, of 919 patients treated by total thyroidectomy at our Academic Hospital, 6 (0.7%; 4 females and 2 men, mean age: 68.7 years, range 42-81 years) were treated in emergency. All the emergency operations were performed for life-threatening respiratory distress. The clinical picture at admission, clinical features, type of surgery, outcomes and complications are described. Mean duration of surgery was 146 minutes (range: 53-260).</p> <p>Results</p> <p>In 3/6 (50%) a manubriotomy was necessary due to the extension of the mass into the upper mediastinum. In all cases total thyroidectomy was performed. In one case (16.7%) a parathyroid gland transplantation and in another one (16.7%) a tracheotomy was necessary due to a condition of tracheomalacia. Mean post-operative hospital stay was 6.5 days (range: 2-10 days). Histology revealed malignancy in 4/6 cases (66.7%), showing 3 primitive, and 1 secondary tumors. Morbidity consisted of 1 transient recurrent laryngeal palsy, 3 transient postoperative hypoparathyroidism, and 4 pleural effusions, treated by medical therapy in 3 and by drains in one. There was no mortality.</p> <p>Conclusion</p> <p>On the basis of our experience and of literature review, we strongly advocate elective surgery for patients with thyroid disease at the first signs of tracheal compression. When an acute airway distress appears, an emergency life-threatening total thyroidectomy is recommended in a high-volume centre.</p

Bisphenols and Male Reproductive Health: From Toxicological Models to Therapeutic Hypotheses

Bisphenols, and in particular bisphenol A (BPA), have been widely used for the production of plastic manufacts in the last 50 years. Currently, BPA is present in a variety of daily use polycarbonate plastics and epoxy resins, and dietary ingestion is considered the main route of human exposure. Accordingly, BPA is the chemical pollutant with the widest exposure in humans, involving nearly 90% of general population, according to recent studies. Concerns about BPA effects on human health date back to 1930s, when severe impact on male sexual development was suggested. Now, the acknowledged biological effects of BPA are various. In regard to human fertility, BPA has been shown to disrupt hormone signaling even at low concentrations. Results from human epidemiological studies have reported BPA interference with follicle stimulating hormone, inhibin B, estradiol, testosterone levels, and sexual function in male subjects. Moreover, recent studies have reported an association between BPA levels and reduced sperm concentration, motility, normal morphology, sperm DNA damage, and altered epigenetic pattern, resulting in trans-generational legacy of BPA effects. In this review, the recognized effects of BPA on male reproductive health are described, from the most recent issues on experimental models to epidemiological data. In addition, the very recent interest about the use of nutraceutical remedies to counteract BPA effects are discussed

Sublingual Administration of Sildenafil Oro-dispersible Film: New Profiles of Drug Tolerability and Pharmacokinetics for PDE5 Inhibitors

Objective: Type 5 phosphodiesterase inhibitors (PDE5i) are efficient drugs used for treatment of erectile dysfunction (ED); however, a large discontinuation rate due to major side effects is reported. The aim of this study was to evaluate the possible improvement of sildenafil (Sild) pharmacokinetics associated to the sublingual administration of the new available oro-dispersible film (ODF), compared to both the oro-dispersible tablet (ODT) and the film-coated tablet (FCT) as original per os formulation.Methods:In vitro disaggregation test, dissolution test, and permeation test in specific devices to estimate the trans-mucosal absorption. In vivo analysis of serum Sild levels, by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), was performed in 20 patients with psychogenic ED receiving alternatively per os FCT or sublingual ODT or ODF, at an equal dosage (50 mg). Pharmacokinetic parameters of Sild and adverse drug reactions experienced after the dosing of each formulation were compared.Results:In vitro, ODF showed the highest time to disaggregation and an increased rate of permeation compared to both ODT and FCT (P = 0.017 and P = 0.008, respectively). In vivo, compared to both FCT and ODT, ODF showed a faster increase of serum Sild levels (serum levels at 15 min from dosing, respectively: 2.24 ± 1.4 ng/ml FCT, 0.5 ± 0.3 ng/ml ODT, and 13.5 ± 9.1 ng/ml ODF; P &lt; 0.01 and P &lt; 0.05 vs. ODF) together with a higher drug bioavailability within 60 min from dosing (relative AUC60min vs. FCT, respectively: 100.0 ± 44.9% FCT, 183.8 ± 75.4% ODT, and 304.2 ± 156.0% ODF). A trend toward lower peak serum levels was observed for ODF. Finally, ODF showed a lower prevalence of headache compared to FCT (1 vs. 35%; P &lt; 0.05) and improved pattern of flushing and nasal congestion.Conclusion: Sublingual Sild ODF improves the drug tolerability through a likely modified pharmacokinetic, suggesting a possible implication also in the clinical efficacy profile. Sublingual administration of oro-dispersible formulations may represent a strategy to ameliorate the adherence to therapy with PDE5i, particularly in patients discouraged by side effects

An innovative protocol to select the best growth phase for astaxanthin biosynthesis in H. pluvialis.

H. pluvialis is a green unicellular microalgae and it is the first producer of natural astaxanthin in the world if subjected to stress conditions such as high light, high salinity and nutrient starvation. Astaxanthin is a powerful antioxidant used in many fields, such as aquaculture, pharmaceutical, food supplements and cosmetic. To obtain a large amount of astaxanthin, researcher focused on the optimisation of H. pluvialis growth. H. pluvialis has four different size growth stage (macrozooids, microzooids, palmelloid and “red non-motile astaxanthin accumulated encysted”), and astaxanthin production occur in the last phase. Recent studies shown that non-motile cells can produce more astaxanthin than motile cells if subjected to light stress. For these reasons, the aim of this study is to find a new and innovative methodology to select and recovery H. pluvialis in his last growth phase thanks to an electrophoretic run, and optimize, in this way, astaxanthin production