Nanotechnology Addressing Cutaneous Melanoma: The Italian Landscape

Cutaneous melanoma is one of the most aggressive solid tumors, with a low survival for the metastatic stage. Currently, clinical melanoma treatments include surgery, chemotherapy, targeted therapy, immunotherapy and radiotherapy. Of note, innovative therapeutic regimens concern the administration of multitarget drugs in tandem, in order to improve therapeutic efficacy. However, also, if this drug combination is clinically relevant, the patient’s response is not yet optimal. In this scenario, nanotechnology-based delivery systems can play a crucial role in the clinical treatment of advanced melanoma. In fact, their nano-features enable targeted drug delivery at a cellular level by overcoming biological barriers. Various nanomedicines have been proposed for the treatment of cutaneous melanoma, and a relevant number of them are undergoing clinical trials. In Italy, researchers are focusing on the pharmaceutical development of nanoformulations for malignant melanoma therapy. The present review reports an overview of the main melanoma-addressed nanomedicines currently under study in Italy, alongside the state of the art of melanoma therapy. Moreover, the latest Italian advances concerning the pre-clinical evaluation of nanomedicines for melanoma are described

Long-term cardiac sequelae in patients referred into a diagnostic post-COVID-19 pathway: the Different Impacts on the Right and Left Ventricles

Most patients who had COVID-19 are still symptomatic after many months post infection, but the long-term outcomes are not yet well-defined. The aim of our prospective/retrospective study was to define the cardiac sequelae of COVID-19 infection. This monocentric cohort study included 160 consecutive patients who had been discharged from the ward or from the outpatient clinic after a diagnosis of COVID-19 and subsequently referred for a follow up visit. Clinical features data about the acute phase along with information about the follow up visit, including ECG and Echocardiographic parameters, were recorded. At an average follow-upfollow up of 5 months, echocardiography showed morpho-functional changes characteristics of both right (RV) and left (LV) ventricles, such as RV dilation, increased pressure in the pulmonary circulation, and biy-ventricular systolic-diastolic dysfunction. When examined using multivariate analysis, independent of age, sex, and co-morbidities, RV and LV changes were significantly associated with chest High Resolution computed tomography score and hemodynamic Instability (HI) and with C-reactive protein, respectively. Our results suggest that COVID-19 may impact RV and LV differently. Notably, the extent of the pneumonia and HI may affect RV, whereas the inflammatory status may influence LV. A long-term follow-up is warranted to refine and customize the most appropriate therapeutic strategies

Muon reconstruction performance of the ATLAS detector in proton–proton collision data at √s = 13 TeV

This article documents the performance of the ATLAS muon identification and reconstruction using the LHC dataset recorded at √s = 13 TeV in 2015. Using a large sample of J/ψ→μμ and Z→μμ decays from 3.2 fb−1 of pp collision data, measurements of the reconstruction efficiency, as well as of the momentum scale and resolution, are presented and compared to Monte Carlo simulations. The reconstruction efficiency is measured to be close to 99% over most of the covered phase space (|η| 2.2, the pT resolution for muons from Z→μμ decays is 2.9 % while the precision of the momentum scale for low-pT muons from J/ψ→μμ decays is about 0.2%

Design and validation of a pericentromeric BAC clone set aimed at improving diagnosis and phenotype prediction of supernumerary marker chromosomes

BACKGROUND: Small supernumerary marker chromosomes (sSMCs) are additional, structurally abnormal chromosomes, generally smaller than chromosome 20 of the same metaphase spread. Due to their small size, they are difficult to characterize by conventional cytogenetics alone. In regard to their clinical effects, sSMCs are a heterogeneous group: in particular, sSMCs containing pericentromeric euchromatin are likely to be associated with abnormal outcomes, although exceptions have been reported. To improve characterization of the genetic content of sSMCs, several approaches might be applied based on different molecular and molecular-cytogenetic assays, e.g., fluorescent in situ hybridization (FISH), array-based comparative genomic hybridization (array CGH), and multiplex ligation-dependent probe amplification (MLPA). To provide a complementary tool for the characterization of sSMCs, we constructed and validated a new, FISH-based, pericentromeric Bacterial Artificial Chromosome (BAC) clone set that with a high resolution spans the most proximal euchromatic sequences of all human chromosome arms, excluding the acrocentric short arms. RESULTS: By FISH analysis, we assayed 561 pericentromeric BAC probes and excluded 75 that showed a wrong chromosomal localization. The remaining 486 probes were used to establish 43 BAC-based pericentromeric panels. Each panel consists of a core, which with a high resolution covers the most proximal euchromatic ~0.7 Mb (on average) of each chromosome arm and generally bridges the heterochromatin/euchromatin junction, as well as clones located proximally and distally to the core. The pericentromeric clone set was subsequently validated by the characterization of 19 sSMCs. Using the core probes, we could rapidly distinguish between heterochromatic (1/19) and euchromatic (11/19) sSMCs, and estimate the euchromatic DNA content, which ranged from approximately 0.13 to more than 10 Mb. The characterization was not completed for seven sSMCs due to a lack of information about the covered region in the reference sequence (1/19) or sample insufficiency (6/19). CONCLUSIONS: Our results demonstrate that this pericentromeric clone set is useful as an alternative tool for sSMC characterization, primarily in cases of very small SMCs that contain either heterochromatin exclusively or a tiny amount of euchromatic sequence, and also in cases of low-level or cryptic mosaicism. The resulting data will foster knowledge of human proximal euchromatic regions involved in chromosomal imbalances, thereby improving genotype–phenotype correlations

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

A first-in-class Wiskott-Aldrich syndrome protein activator with anti-tumor activity in hematologic cancers

Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization

Paediatric recurrent pericarditis: Appropriateness of the standard of care and response to IL1-blockade

Objective: To analyse, in a cohort of paediatric patients with recurrent pericarditis (RP) undergoing anti-IL-1 treatment: the agent and dosing used as first line treatment, the long-term efficacy of IL1-blockers, the percentage of patients achieving a drug-free remission, the presence of variables associated with drug-free remission. Study design: Data were collected from patients' charts. Annualized relapse rate (ARR) was used for evaluation of treatment efficacy, bivariate logistic regression analysis for variables associated with drug-free remisison. Results: 58 patients, treated between 2008 and 2018, were included in the study (mean follow-up 2.6 years). 14/56 patients non-responsive to first line drugs were under-dosed. 57 patients were treated with anakinra: the ARR before and during daily treatment was 3.05 and 0.28, respectively (p<0.0001); an increase to 0.83 was observed after the reduction/withdrawal of treatment (p<.0001). The switch from anakinra to canakinumab (5 patients) was associated to an increase of the ARR (0.49 vs 1.46), but without statistical significance (p=0.215). At last follow-up only 9/58 patients had withdrawn all treatments. With the limits of a retrospective study and the heterogeneity between the patients enrolled in the study, a shorter duration of treatment with anakinra was the only variable associated with drug-free remission. Conclusion: This study shows that most of the pediatric patients with RP needing IL-1 blockade received an inadequate treatment with first line agents. The effectiveness of anakinra is supported by this study, but few patients achieved drug free-remission. The different rate of response to anakinra and canakinumab may suggest a possible role of IL1α in the pathogenesis of RP

Factors influencing liberation from mechanical ventilation in coronavirus disease 2019: multicenter observational study in fifteen Italian ICUs

Background: A large proportion of patients with coronavirus disease 2019 (COVID-19) develop severe respiratory failure requiring admission to the intensive care unit (ICU) and about 80% of them need mechanical ventilation (MV). These patients show great complexity due to multiple organ involvement and a dynamic evolution over time; moreover, few information is available about the risk factors that may contribute to increase the time course of mechanical ventilation. The primary objective of this study is to investigate the risk factors associated with the inability to liberate COVID-19 patients from mechanical ventilation. Due to the complex evolution of the disease, we analyzed both pulmonary variables and occurrence of non-pulmonary complications during mechanical ventilation. The secondary objective of this study was the evaluation of risk factors for ICU mortality. Methods: This multicenter prospective observational study enrolled 391 patients from fifteen COVID-19 dedicated Italian ICUs which underwent invasive mechanical ventilation for COVID-19 pneumonia. Clinical and laboratory data, ventilator parameters, occurrence of organ dysfunction, and outcome were recorded. The primary outcome measure was 28 days ventilator-free days and the liberation from MV at 28 days was studied by performing a competing risks regression model on data, according to the method of Fine and Gray; the event death was considered as a competing risk. Results: Liberation from mechanical ventilation was achieved in 53.2% of the patients (208/391). Competing risks analysis, considering death as a competing event, demonstrated a decreased sub-hazard ratio for liberation from mechanical ventilation (MV) with increasing age and SOFA score at ICU admission, low values of PaO2/FiO2 ratio during the first 5 days of MV, respiratory system compliance (CRS) lower than 40 mL/cmH2O during the first 5 days of MV, need for renal replacement therapy (RRT), late-onset ventilator-associated pneumonia (VAP), and cardiovascular complications. ICU mortality during the observation period was 36.1% (141/391). Similar results were obtained by the multivariate logistic regression analysis using mortality as a dependent variable. Conclusions: Age, SOFA score at ICU admission, CRS, PaO2/FiO2, renal and cardiovascular complications, and late-onset VAP were all independent risk factors for prolonged mechanical ventilation in patients with COVID-19. Trial registration: NCT04411459

High Risk of Secondary Infections Following Thrombotic Complications in Patients With COVID-19

Background. This study’s primary aim was to evaluate the impact of thrombotic complications on the development of secondary infections. The secondary aim was to compare the etiology of secondary infections in patients with and without thrombotic complications. Methods. This was a cohort study (NCT04318366) of coronavirus disease 2019 (COVID-19) patients hospitalized at IRCCS San Raffaele Hospital between February 25 and June 30, 2020. Incidence rates (IRs) were calculated by univariable Poisson regression as the number of cases per 1000 person-days of follow-up (PDFU) with 95% confidence intervals. The cumulative incidence functions of secondary infections according to thrombotic complications were compared with Gray’s method accounting for competing risk of death. A multivariable Fine-Gray model was applied to assess factors associated with risk of secondary infections. Results. Overall, 109/904 patients had 176 secondary infections (IR, 10.0; 95% CI, 8.8–11.5; per 1000-PDFU). The IRs of secondary infections among patients with or without thrombotic complications were 15.0 (95% CI, 10.7–21.0) and 9.3 (95% CI, 7.9–11.0) per 1000-PDFU, respectively (P = .017). At multivariable analysis, thrombotic complications were associated with the development of secondary infections (subdistribution hazard ratio, 1.788; 95% CI, 1.018–3.140; P = .043). The etiology of secondary infections was similar in patients with and without thrombotic complications. Conclusions. In patients with COVID-19, thrombotic complications were associated with a high risk of secondary infections