The Use of Empirical Methods for Testing Granular Materials in Analogue Modelling

The behaviour of a granular material is mainly dependent on its frictional properties, angle of internal friction, and cohesion, which, together with material density, are the key factors to be considered during the scaling procedure of analogue models. The frictional properties of a granular material are usually investigated by means of technical instruments such as a Hubbert-type apparatus and ring shear testers, which allow for investigating the response of the tested material to a wide range of applied stresses. Here we explore the possibility to determine material properties by means of different empirical methods applied to mixtures of quartz and K-feldspar sand. Empirical methods exhibit the great advantage of measuring the properties of a certain analogue material under the experimental conditions, which are strongly sensitive to the handling techniques. Finally, the results obtained from the empirical methods have been compared with ring shear tests carried out on the same materials, which show a satisfactory agreement with those determined empirically

Plasma membrane gamma-glutamyltransferase activity facilitates the uptake of vitamin C in melanoma cells.

Adequate cellular transport of ascorbic acid (AA) and its oxidation product dehydroascorbate (DHA) is assured through specific carriers. It was shown that vitamin C is taken up as DHA by most cell types, including cancer cells, via the facilitative GLUT transporters. Thus, AA oxidation to DHA can be considered a mechanism favoring vitamin C uptake and intracellular accumulation. We have investigated whether such an AA-oxidizing action might be provided by plasma membrane g-glutamyltransferase (GGT), previously shown to function as an autocrine source of prooxidants. The process was studied using two distinct human metastatic melanoma clones. It was observed that the Me665/2/60 clone, expressing high levels of membrane GGT activity, was capable of effecting the oxidation of extracellular AA, accompanied by a marked increase of intracellular AA levels. The phenomenon was not observed with Me665/2/21 cells, possessing only traces of membrane GGT. On the other hand, AA oxidation and stimulation of cellular uptake were indeed observed after transfection of 2/21 cells with cDNA coding for GGT. The mechanism of GGTmediated AA oxidation was investigated in acellular systems, including GGT and its substrate glutathione. The process was observed in the presence of redox-active chelated iron(II) and of transferrin or ferritin, i.e., two physiological iron sources. Thus, membrane GGT activity—often expressed at high levels in human malignancies—can oxidize extracellular AA and promote its uptake efficiently

Immunotherapy for early triple negative breast cancer: research agenda for the next decade

Breast cancer; Drug development; ImmunoeditingCàncer de mama; Desenvolupament de medicaments; ImmunoedicióCáncer de mama; Desarrollo de fármacos; InmunoediciónFor decades, the systemic treatment of localized triple negative breast cancer (TNBC) has exclusively relied on chemotherapy. Recent advancements, however, are rapidly reshaping the treatment algorithms for this disease. The addition of pembrolizumab to neoadjuvant chemotherapy has indeed shown to significantly improve event-free survival for stage II–III TNBC, leading to its establishment as new standard of care in this setting. This landmark advancement has however raised several important scientific questions. Indeed, we desperately need strategies to identify upfront patients deriving benefit from the addition of immunotherapy. Moreover, the best integration of pembrolizumab with further recent advancements (capecitabine, olaparib) is yet to be defined. Lastly, extensive efforts are needed to minimize the impact on patients of immune-related adverse events and financial toxicity. The next decade of clinical research will be key to overcome these challenges, and ultimately learn how to optimally integrate immunotherapy in the treatment landscape of TNBC.Supported by an American-Italian Cancer Foundation Post-Doctoral Research Fellowship

Application of the floristic-vegetational indexes system for the evaluation of the environmental quality of a semi-natural area of the Po Valley (Piacenza, Italy)

The floristic-vegetational indexes proposed by Taffetani and Rismondo (2009) and updated by Rismondo et al. (2011) were used to assess the environmental quality of a semi-natural located on the outskirts of Piacenza (Emilia Romagna, Italy), the site of a closed landfill of Municipal Solid Waste (MSW). This method was created and perfected to analyze the ecological functionality of afro-ecosystem and permits simp and rapid measurement of the ecological characteristics and grade of dynamic evolution of then phtocoenoses. These indexes were applied to the vegetation of the different sectors that make up the study area ad from the results obtained t was possible to identify those with the worst environmental quality and to formulate some proposes for action aimed at improving them environmentally. In particular an interruption in the evolution of the landfill vegetation was found, due to the chemical-physical characteristics of the cover sol which is compacted and of limited depth. The application of the Taffetani and Rismondo (2009) indexes to a real case has also allowed evaluation of their practicality and the information content obtained

Relationship between hospital volume and short-term outcomes: A nationwide population-based study including 75,280 rectal cancer surgical procedures

There is growing interest on the potential relationship between hospital volume (HV) and outcomes as it might justify the centralization of care for rectal cancer surgery. From the National Italian Hospital Discharge Dataset, data on 75,280 rectal cancer patients who underwent elective major surgery between 2002 and 2014 were retrieved and analyzed. HV was grouped into tertiles: low-volume performed 1-12, while high-volume hospitals performed 33+ procedures/year. The impact of HV on in-hospital mortality, abdominoperineal resection (APR), 30-day readmission, and length of stay (LOS) was assessed. Risk factors were calculated using multivariate logistic regression. The proportion of procedures performed in low-volume hospitals decreased by 6.7 percent (p<0.001). The rate of in-hospital mortality, APR and 30-day readmission was 1.3%, 16.3%, and 7.2%, respectively, and the median LOS was 13 days. The adjusted risk of in-hospital mortality (OR = 1.49, 95% CI = 1.25-1.78), APR (OR 1.10, 95%CI 1.02-1.19), 30-day readmission (OR 1.49, 95%CI 1.38-1.61), and prolonged LOS (OR 2.29, 95%CI 2.05-2.55) were greater for low-volume hospitals than for high-volume hospitals. This study shows an independent impact of HV procedures on all short-term outcome measures, justifying a policy of centralization for rectal cancer surgery, a process which is underwa

Antibody–drug conjugates: smart chemotherapy delivery across tumor histologies

Antibody-drug conjugates; Enfortumab vedotin; Smart chemotherapyConjugats anticossos-medicament; Enfortumab vedotin; Quimioteràpia intel·ligentConjugados anticuerpos-fármaco; Enfortumab vedotin; Quimioterapia inteligenteAs distinct cancer biomarkers have been discovered in recent years, a need to reclassify tumors by more than their histology has been proposed, and therapies are now tailored to treat cancers based on specific molecular aberrations and immunologic markers. In fact, multiple histology-agnostic therapies are currently adopted in clinical practice for treating patients regardless of their tumor site of origin. In parallel with this new model for drug development, in the past few years, several novel antibody–drug conjugates (ADCs) have been approved to treat solid tumors, benefiting from engineering improvements in the conjugation process and the introduction of novel linkers and payloads. With the recognition that numerous surface targets are expressed across various cancer histologies, alongside the remarkable activity of modern ADCs, this drug class has been increasingly evaluated as suitable for a histology-agnostic expansion of indication. For illustration, the anti-HER2 ADC trastuzumab deruxtecan has demonstrated compelling activity in HER2-overexpressing breast, gastric, colorectal, and lung cancer. Examples of additional novel and potentially histology-agnostic ADC targets include trophoblast cell-surface antigen 2 (Trop-2) and nectin-4, among others. In the current review article, the authors summarize the current approvals of ADCs by the US Food and Drug Administration focusing on solid tumors and discuss the challenges and opportunities posed by the multihistological expansion of ADCs.Paulo Tarantino reports personal fees from AstraZeneca outside the submitted work. Roberto Carmagnani Pestana reports consulting fees from Bayer and honoraria from Pfizer, Merck, Bayer, and Servier outside the submitted work. Shanu Modi reports grants and nonfinancial support from Daiichi-Sankyo, Genentech, Novartis, Synta Pharmaceuticals, Seattle Genetics, Macrogenics, Carrick Pharmaceuticals, and Eli Lilly outside the submitted work. Aditya Bardia reports institutional grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics Inc, Mersana, Innocrin, and Biotheranostics Inc; consulting fees from Biotheranostics Inc, Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics Inc, Spectrum Pharma, Taiho, Sanofi, Daiichi Pharma, AstraZeneca, Puma, Phillips, and Eli Lilly; and meeting support from Biotheranostics Inc, Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics Inc, Spectrum Pharma, Taiho, Sanofi, and Phillips outside the submitted work. Sara M. Tolaney reports consulting fees from Novartis, Eli Lilly, Pfizer, Merck, AstraZeneca, Eisai, Puma, Genentech, Immunomedics Inc, Nektar, Tesaro, Daiichi-Sankyo, Athenex, Bristol Myers Squibb, and Nanostring outside the submitted work. Javier Cortes reports grants from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH-Servier Affaires, Bayer Healthcare, Eisai, F Hoffman-LaRoche, Guardant Health, MSD, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London; intellectual property for MedSIR; consulting fees from Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceuticals, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Bioasis, and Clovis Oncology; and honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, and Daiichi-Sankyo outside the submitted work. Jean-Charles Soria was formerly employed at AstraZeneca and is now employed by Amgen; owns stock in AstraZeneca, Gritstone Bio, and Relay Therapeutics; and serves on the Board of Directors for Hookipa Pharmaceuticals outside the submitted work. Giuseppe Curigliano reports a grant from Merck; consulting fees from Roche, Pfizer, Novartis, Seattle Genetics, Lilly, Ellipses Pharma, Foundation Medicine, Samsung, Daichii-Sankyo, and Exactsciences; honoraria from Pfizer, Novartis, Seattle Genetics, and Daichii-Sankyo; and meeting support from Foche and Pfizer outside the submitted work. Chiara Corti made no disclosures

Cleavage of chromogranin A N-terminal domain by plasmin provides a new mechanism for regulating cell adhesion

It has been proposed that chromogranin A (CgA), a protein secreted by many normal and neoplastic neuroendocrine cells, can play a role as a positive or a negative modulator of cell adhesion. The mechanisms that regulate these extracellular functions of CgA are unknown. We show here that plasmin can regulate the anti/pro-adhesive activity of CgA by proteolytic cleavage of the N-terminal domain. Limited proteolytic processing decreased its anti-adhesive activity and induced pro-adhesive effects in fibronectin or serum-dependent fibroblast adhesion assays. Cleavage of Lys(77)-Lys(78) dibasic site in CgA(1-115) was relatively rapid and associated with an increase of pro-adhesive effect. In contrast, antibodies against the region 53-90 enhanced the anti-adhesive activity of CgA and CgA(1-115). Structure-activity relationship studies showed that the conserved region 47-64 (RILSILRHQNLLKELQDL) is critical for both pro- and anti-adhesive activity. These findings suggest that CgA might work on one hand as a negative modulator of cell adhesion and on the other hand as a precursor of positive modulators, the latter requiring proteolytic processing for activation. Given the importance of plasminogen activation in tissue invasion and remodeling, the interplay between CgA and plasmin could provide a novel mechanism for regulating fibroblast adhesion and function in neuroendocrine tumors

Failure to rescue as a source of variation in hospital mortality after rectal surgery: The Italian experience

INTRODUCTION: Failure to rescue (FTR) patients from postoperative complications could contribute to the variability in surgical mortality seen among hospitals with different volumes. We sought to examine the impact of complications and FTR on mortality following rectal surgery. METHODS: The National Italian Hospital Discharge Dataset allowed to identify 75,280 patients who underwent rectal surgery between 2002 and 2014. Hospital volume was stratified into tertiles. Rates of major complications, FTR from complications and mortality following rectal surgery were compared. RESULTS: During the study period, both the incidence of complications (2002, 23.7% versus 2014, 21.2%), and FTR decreased overtime (2002, 6.9% versus 2014, 3.8%) (both P\u202f<\u202f0.001). The complication rate was 24.4% in low-, 21.6% in intermediate- and 20.4% in high-volume hospitals (P\u202f<\u202f0.001). Complications were less common in minimally invasive surgery (MIS) versus open cases (18.2% versus 23.2%; P\u202f<\u202f0.001). The most frequent complications included prolonged ileus or small bowel obstruction (5.3%), and anemia requiring blood transfusions (5.3%). The rate of FTR was 5.5%, 5.6% and 3.7% for low-, intermediate- and high-volume hospitals, respectively (P\u202f<\u202f0.001). FTR after MIS was 2.6% vs. 5.5% after open surgery (P\u202f<\u202f0.001). After accounting for patient and hospital characteristics, patients treated at low-volume hospitals were 23% more likely to die after a complication, compared to patients at high-volume hospitals (OR 1.23, 95%CI 1.13-1.33). CONCLUSIONS: Hospital volume is the strongest predictor of complication and FTR. The reduction in mortality in high-volume hospitals could be determined by the better ability to rescue patients. These findings support the centralization policy of rectal cancer treatment

Remote Technology-Based Training Programs for Children with Acquired Brain Injury: A Systematic Review and a Meta-Analytic Exploration

Introduction. Multidisciplinary rehabilitation interventions are considered to be a need for children with acquired brain injury (ABI), in order to remediate the important sequelae and promote adjustment. Technology-based treatments represent a promising field inside the rehabilitation area, as they allow delivering interventions in ecological settings and creating amusing exercises that may favor engagement. In this work, we present an overview of remote technology-based training programs (TP) addressing cognitive and behavioral issues delivered to children with ABI and complement it with the results of a meta-analytic exploration. Evidence Acquisition. We performed the review process between January and February 2019. 32 studies were included in the review, of which 14 were further selected to be included in the meta-analysis on TP efficacy. Evidence Synthesis. Based on the review process, the majority of TP addressing cognitive issues and all TP focusing on behavioral issues were found to be effective. Two meta-analytic models examining the means of either cognitive TP outcomes or behavioral TP outcomes as input outcome yielded a nonsignificant effect size for cognitive TP and a low-moderate effect size for behavioral TP. Additional models on outcomes reflecting the greatest beneficial effects of TP yielded significant moderate effect sizes for both types of TP. Nevertheless, consistent methodological heterogeneity was observed, pointing to cautious interpretation of findings. A subgroup analysis on visuospatial skill outcomes showed a smaller yet significant effect size of cognitive TP, with low heterogeneity, providing a more reliable estimation of overall cognitive TP effects. Conclusions. Promising results on remote cognitive and behavioral TP efficacy emerged both at the review process and at the meta-analytic investigation. Nevertheless, the high heterogeneity that emerged across studies prevents us from drawing definite conclusions. Further research is needed to identify whether specific training characteristics and population subgroups are more likely to be associated with greater training efficacy

Metabolic Syndrome and All-Cause and Cardiovascular Mortality in an Italian Elderly Population: The Progetto Veneto Anziani (Pro.V.A.) Study

OBJECTIVE—The purpose of this study was to explore the association of metabolic syndrome and each of its components with all-cause and cardiovascular mortality in a general Italian elderly population