Patterns of Natural Killer Cell Immune-Reconstitution and Immunological Memory in Patients Affected by Hematologic Malignancies and Undergoing Haploidentical Hematopoietic Stem Cell Transplantation

Haploidentical hematopoietic stem cell transplantation (h-HSCT) represents a promising therapeutic approach to cure patients affected by hematologic malignancies. Despite the positive results in terms of overall/disease free survival and reduced tumor relapse, the HLA mismatch between donor and recipient has not been yet fully exploited and the clinical outcome of h-HSCT patients is still hampered by life-threatening side effects, including relapse and viral infections. In this context, immune cell reconstitution (IR) is certainly key in determining a positive h-HSCT clinical outcome. We demonstrated that Natural Killer (NK) cells represent the first innate lymphocytes recovering after h-HSCT, thus highlighting their role in ensuring a prompt alloreactivity early after the transplant as well as a rapid protection against opportunistic viral infections. We characterized the predominant and temporary expansion, early after h-HSCT, of a donor-derived unconventional subset of CD56dimCD16neg (unCD56dim) NK cells that is poorly represented in healthy donors. The expression of the inhibitory CD94/NKG2A receptor on all unCD56dim NK cells is associated, at least in part, with NK cell impairment. Indeed, only masking CD94/NKG2A, we observed a recovery of the cytolytic capacity of this NK cell subset. Thus, this inhibitory receptor could represent a potential immunotherapeutic target to improve NK cell alloreactivity after h-HSCT, ensuring a prompt graft versus leukemia (GvL) effect and preventing disease relapse. However, given the NK cell impairment and the late recovery of adaptive immune cells are responsible for a prolonged immunodeficiency, the increased risk in developing opportunistic infections is high early after h-HSCT. Among them, the human Cytomegalovirus (HCMV) infection/reactivation represents one of the major causes of morbidity and mortality after h-HSCT. In turn, HCMV infection/reactivation can greatly impact NK cell maturation and effector-functions, by providing a rapid expansion of mature, long-lived and hyper-functional NK cells showing memory-like (ml) properties, with unknown origin and unspecific phenotype. With the aim to investigate the impact of HCMV infection/reactivation on NK cell IR after h-HSCT, we identified a subset of NK cells showing a peculiar CD158b1b2jposNKG2AnegNKG2CposNKp30low phenotype that is expanded only in h-HSCT patients experiencing HCMV reactivation. Interestingly, this latter NK cell population showing memory-like functional features is maintained even after the resolution of the infection and its frequency positively correlates with HCMV viral load and with the numbers of reactivation events. A deeper analysis of our putative ml-NK cell molecular fingerprint revealed that these cells are characterized by an impaired effector-functions, although retaining the capability to produce IFN-γ at transcriptional level. These findings show in a human setting in vivo the expansion and the kinetic of those NK cells that "remember" the HCMV challenge in patients experiencing viral reactivation. Our data are important to better understand the ability of NK cells to control this life-threatening infection after h-HSCT as well as to exploit their alloreactive responses against tumor burden

Supported Gold Nanoparticles for Alcohols Oxidation in Continuous-Flow Heterogeneous Systems

Gold nanoparticles (AuNPs) were anchored on alkynyl carbamate-functionalized support materials having the suitable features for application as catalysts in continuous-flow packed bed reactors. The functionalization step was carried out by grafting with the di-functional organosilane [3-(2-propynylcarbamate)propyl]triethoxysilane (PPTEOS) three commercial micrometer-sized oxide supports, i.e. silica, alumina, and titania. The alkynyl-carbamate moieties were capable to straightforwardly reduce the gold precursor HAuCl4 yielding the supported AuNPs systems Au/SiO2@Yne, Au/Al2O3@Yne, and Au/TiO2@Yne. A comparison among the three materials revealed that silica allowed the highest organic functionalization (12 wt%) as well as the highest gold loading (3.7 wt%). Moreover, TEM investigation showed only for Au/SiO2@Yne the presence of homogeneously distributed, spherically shaped AuNPs (av. diameter 15 nm). Au/SiO2@Yne is an efficient catalyst, both in batch and flow conditions, in the oxidation of a large variety of alcohols, using H2O2 as oxidizing agent, at a temperature of 90 \ub0C. Furthermore, under flow conditions, the catalyst worked for over 50 h without any significant decrease in the catalytic activity. The catalytic activity of the three catalysts was evaluated and compared in the oxidation of 1-phenylethanol as a model substrate. We found that the flow approach plays a strategic role in preserving the physical and chemical integrity of the solid catalysts during its use, with remarkable consequences for the reaction conversion (from 2% in batch to 80 % in flow) in the case of Au/TiO2@Yne

Hydrogeological effects of dredging navigable canals through lagoon shallows. A case study in Venice

For the first time a comprehensive investigation has been carried out to quantify the possible effects of dredging a navigable canal on the hydrogeological system underlying a coastal lagoon. The study is focused on the Venice Lagoon, Italy, where the port authority is planning to open a new 10m deep and 3km long canal to connect the city passenger terminal to the central lagoon inlet, thus avoiding the passage of large cruise ships through the historic center of Venice. A modeling study has been developed to evaluate the short (minutes), medium (months), and long (decades) term processes of water and pollutant exchange between the shallow aquifer system and the lagoon, possibly enhanced by the canal excavation, and ship wakes. An in-depth characterization of the lagoon subsurface along the channel has supported the numerical modeling. Piezometer and sea level records, geophysical acquisitions, laboratory analyses of groundwater and sediment samples (chemical analyses and ecotoxicity testing), and the outcome of 3-D hydrodynamic and computational fluid dynamic (CFD) models have been used to set up and calibrate the subsurface multi-model approach. The numerical outcomes allow us to quantify the groundwater volume and estimate the mass of anthropogenic contaminants (As, Cd, Cu, Cr, Hg, Pb, Se) likely leaked from the nearby industrial area over the past decades, and released into the lagoon from the canal bed by the action of depression waves generated by ships. Moreover, the model outcomes help to understand the effect of the hydrogeological layering on the propagation of the tidal fluctuation and salt concentration into the shallow brackish aquifers underlying the lagoon bottom.Facultad de Ciencias Naturales y MuseoCentro de Investigaciones Geológica

The early expansion of anergic NKG2Apos/CD56dim/CD16neg natural killer cells represents a therapeutic target in haploidentical haematopoietic stem cell transplantation

Natural Killer cells are the first lymphocyte population to reconstitute early after non myelo-ablative and T cell-replete haploidentical hematopoietic stem cell transplantation with post-transplant infusion of cyclophosphamide. The present study characterizes the transient and predominant expansion starting from the 2nd week after haploidentical hematopoietic stem cell transplantation of a donor-derived unconventional subset of NKp46neg-low/CD56dim/CD16neg natural killer cells expressing remarkable high levels of CD94/NKG2A. Both transcription and phenotypic profiles indicated that unconventional NKp46neg-low/CD56dim/CD16neg natural killer cells are a distinct natural killer cell subpopulation with features of late stage differentiation, yet retaining proliferative capability and functional plasticity to generate conventional NKp46pos/CD56bright/CD16pos natural killer cells in response to interleukin-15 plus interleukin-18. While present at low frequency in healthy donors, unconventional NKp46neg-low/CD56dim/CD16neg natural killer cells are greatly expanded in the following 7 weeks after haploidentical hematopoietic stem cell transplantation and express high levels of the activating receptors NKGD and NKp30 as well as of the lytic granules Granzyme-B and Perforin. Nonetheless, NKp46neg-low/CD56dim/CD16neg natural killer cells displayed a markedly defective cytotoxicity that could be reversed by blocking the inhibitory receptor CD94/NKG2A. These data open new important perspectives to better understand the ontogenesis/homeostasis of human natural killer cells and to develop a novel immune-therapeutic approach that targets the inhibitory NKG2A check point, thus unleashing natural killer cell alloreactivity early after haploidentical hematopoietic stem cell transplantation

Hydrogeological effects of dredging navigable canals through lagoon shallows. A case study in Venice

For the first time a comprehensive investigation has been carried out to quantify the possible effects of dredging a navigable canal on the hydrogeological system underlying a coastal lagoon. The study is focused on the Venice Lagoon, Italy, where the port authority is planning to open a new 10m deep and 3km long canal to connect the city passenger terminal to the central lagoon inlet, thus avoiding the passage of large cruise ships through the historic center of Venice. A modeling study has been developed to evaluate the short (minutes), medium (months), and long (decades) term processes of water and pollutant exchange between the shallow aquifer system and the lagoon, possibly enhanced by the canal excavation, and ship wakes. An in-depth characterization of the lagoon subsurface along the channel has supported the numerical modeling. Piezometer and sea level records, geophysical acquisitions, laboratory analyses of groundwater and sediment samples (chemical analyses and ecotoxicity testing), and the outcome of 3-D hydrodynamic and computational fluid dynamic (CFD) models have been used to set up and calibrate the subsurface multi-model approach. The numerical outcomes allow us to quantify the groundwater volume and estimate the mass of anthropogenic contaminants (As, Cd, Cu, Cr, Hg, Pb, Se) likely leaked from the nearby industrial area over the past decades, and released into the lagoon from the canal bed by the action of depression waves generated by ships. Moreover, the model outcomes help to understand the effect of the hydrogeological layering on the propagation of the tidal fluctuation and salt concentration into the shallow brackish aquifers underlying the lagoon bottom.Facultad de Ciencias Naturales y MuseoCentro de Investigaciones Geológica

Colorectal neoplastic emergencies in immunocompromised patients: preliminary result from the Web-based International Register of Emergency Surgery and Trauma (WIRES-T trial)

Association of advanced age, neoplastic disease and immunocompromission (IC) may lead to surgical emergencies. Few data exist about this topic. Present study reports the preliminary data from the WIRES-T trial about patients managed for colorectal neoplastic emergencies in immunocompromised patients. The required data were taken from a prospective observational international register. The study was approved by the Ethical Committee with approval n. 17575; ClinicalTrials.gov Identifier: NCT03643718. 839 patients were collected; 753 (80.7%) with mild-moderate IC and 86 (10.3%) with severe. Median age was 71.9 years and 73 years, respectively, in the two groups. The causes of mild-moderate IC were reported such malignancy (753-100%), diabetes (103-13.7%), malnutrition (26-3.5%) and uremia (1-0.1%), while severe IC causes were steroids treatment (14-16.3%); neutropenia (7-8.1%), malignancy on chemotherapy (71-82.6%). Preoperative risk classification were reported as follow: mild-moderate: ASA 1-14 (1.9%); ASA 2-202 (26.8%); ASA 3-341 (45.3%); ASA 4-84 (11.2%); ASA 5-7 (0.9%); severe group: ASA 1-1 patient (1.2%); ASA 2-16 patients (18.6%); ASA 3-41 patients (47.7%); ASA 4-19 patients (22.1%); ASA 5-3 patients (3.5%); lastly, ASA score was unavailable for 105 cases (13.9%) in mild-moderate group and in 6 cases (6.9%) in severe group. All the patients enrolled underwent urgent/emergency surgery Damage control approach with open abdomen was adopted in 18 patients. Mortality was 5.1% and 12.8%, respectively, in mild-moderate and severe groups. Long-term survival data: in mild-moderate disease-free survival (median, IQR) is 28 (10-91) and in severe IC, it is 21 (10-94). Overall survival (median, IQR) is 44 (18-99) and 26 (20-90) in mild-moderate and severe, respectively; the same is for post-progression survival (median, IQR) 29 (16-81) and 28, respectively. Univariate and multivariate analyses showed as the only factor influencing mortality in mild-moderate and severe IC is the ASA score. Colorectal neoplastic emergencies in immunocompromised patients are more frequent in elderly. Sigmoid and right colon are the most involved. Emergency surgery is at higher risk of complication and mortality; however, management in dedicated emergency surgery units is necessary to reduce disease burden and to optimize results by combining oncological and acute care principles. This approach may improve outcomes to obtain clinical advantages for patients like those observed in elective scenario. Lastly, damage control approach seems feasible and safe in selected patients

Acute diverticulitis in immunocompromised patients: evidence from an international multicenter observational registry (Web-based International Register of Emergency Surgery and Trauma, Wires-T)

Background: Immunocompromised patients with acute diverticulitis are at increased risk of morbidity and mortality. The aim of this study was to compare clinical presentations, types of treatment, and outcomes between immunocompromised and immunocompetent patients with acute diverticulitis. Methods: We compared the data of patients with acute diverticulitis extracted from the Web-based International Registry of Emergency Surgery and Trauma (WIRES-T) from January 2018 to December 2021. First, two groups were identified: medical therapy (A) and surgical therapy (B). Each group was divided into three subgroups: nonimmunocompromised (grade 0), mildly to moderately (grade 1), and severely immunocompromised (grade 2). Results: Data from 482 patients were analyzed—229 patients (47.5%) [M:F = 1:1; median age: 60 (24–95) years] in group A and 253 patients (52.5%) [M:F = 1:1; median age: 71 (26–94) years] in group B. There was a significant difference between the two groups in grade distribution: 69.9% versus 38.3% for grade 0, 26.6% versus 51% for grade 1, and 3.5% versus 10.7% for grade 2 (p < 0.00001). In group A, severe sepsis (p = 0.027) was more common in higher grades of immunodeficiency. Patients with grade 2 needed longer hospitalization (p = 0.005). In group B, a similar condition was found in terms of severe sepsis (p = 0.002), quick Sequential Organ Failure Assessment score > 2 (p = 0.0002), and Mannheim Peritonitis Index (p = 0.010). A Hartmann’s procedure is mainly performed in grades 1–2 (p < 0.0001). Major complications increased significantly after a Hartmann’s procedure (p = 0.047). Mortality was higher in the immunocompromised patients (p = 0.002). Conclusions: Immunocompromised patients with acute diverticulitis present with a more severe clinical picture. When surgery is required, immunocompromised patients mainly undergo a Hartmann’s procedure. Postoperative morbidity and mortality are, however, higher in immunocompromised patients, who also require a longer hospital stay

Textbook outcome in urgent early cholecystectomy for acute calculous cholecystitis: results post hoc of the S.P.Ri.M.A.C.C study

Introduction: A textbook outcome patient is one in which the operative course passes uneventful, without complications, readmission or mortality. There is a lack of publications in terms of TO on acute cholecystitis. Objetive: The objective of this study is to analyze the achievement of TO in patients with urgent early cholecystectomy (UEC) for Acute Cholecystitis. and to identify which factors are related to achieving TO. Materials and methods: This is a post hoc study of the SPRiMACC study. It ́s a prospective multicenter observational study run by WSES. The criteria to define TO in urgent early cholecystectomy (TOUEC) were no 30-day mortality, no 30-day postoperative complications, no readmission within 30 days, and hospital stay ≤ 7 days (75th percentile), and full laparoscopic surgery. Patients who met all these conditions were taken as presenting a TOUEC. Outcomes: 1246 urgent early cholecystectomies for ACC were included. In all, 789 patients (63.3%) achieved all TOUEC parameters, while 457 (36.6%) failed to achieve one or more parameters and were considered non-TOUEC. The patients who achieved TOUEC were younger had significantly lower scores on all the risk scales analyzed. In the serological tests, TOUEC patients had lower values for in a lot of variables than non-TOUEC patients. The TOUEC group had lower rates of complicated cholecystitis. Considering operative time, a shorter duration was also associated with a higher probability of reaching TOUEC. Conclusion: Knowledge of the factors that influence the TOUEC can allow us to improve our results in terms of textbook outcome

Proceedings of the Fifth Italian Conference on Computational Linguistics CLiC-it 2018

On behalf of the Program Committee, a very warm welcome to the Fifth Italian Conference on Computational Linguistics (CLiC-­‐it 2018). This edition of the conference is held in Torino. The conference is locally organised by the University of Torino and hosted into its prestigious main lecture hall “Cavallerizza Reale”. The CLiC-­‐it conference series is an initiative of the Italian Association for Computational Linguistics (AILC) which, after five years of activity, has clearly established itself as the premier national forum for research and development in the fields of Computational Linguistics and Natural Language Processing, where leading researchers and practitioners from academia and industry meet to share their research results, experiences, and challenges