Enhancement of anti-leukemia activity of NK cells in vitro and in vivo by inhibition of leukemia cell-induced NK cell damage

Acute myeloid leukemia (AML) cells induce, in vitro, NK cell abnormalities (NKCAs) including apoptosis and activating receptor down-regulation. The potential negative impact of AML cells on the therapeutic efficacy of NK cell-based strategies prompted us to analyze the mechanisms underlying NKCAs and to develop approaches to protect NK cells from NKCAs. NKCA induction by the AML leukemia cells target a subpopulation of peripheral blood NK cells and is interleukin-2 independent but is abrogated by a long-term culture of NK (LTNK) cells at 37°C. LTNK cells displayed a significantly enhanced ability to damage AML cells in vitro and inhibited the subcutaneous growth of ML-2 cells grafted into CB17 SCID mice. Actinomycin D restored the susceptibility of LTNK cells to NKCAs while TAPI-0, a functional analog of the tissue inhibitor of metalloproteinase (TIMP) 3, inhibits ML-2 cell-induced NKCAs suggesting that the generation of NK cell resistance to NKCAs involves RNA transcription and metalloproteinase (MPP) inactivation. This conclusion is supported by the reduced susceptibility to AML cell-induced NKCAs of LTNK cells in which TIMP3 gene and protein are over-expressed. This information may contribute to the rational design of targeted strategies to enhance the efficacy of NK cell-based-immunotherapy of AML with haploidentical NK cells

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Studio e ottimizzazione del riciclo di CFRP tramite processo di pirogassificazione

I compositi rinforzati con fibre di carbonio (CFRC) stanno sempre più sostituendo i materiali convenzionali in applicazioni che necessitano di alte prestazioni meccaniche, grazie alla loro leggerezza e alle eccellenti proprietà meccaniche. Dato l'enorme incremento della loro produzione e delle loro applicazioni, uno dei principali problemi risiede nel loro smaltimento, sia a fine vita che degli scarti e sfridi di lavorazione. Inoltre, la produzione di fibre di carbonio (CF) necessita di un elevato fabbisogno energetico (183-286 MJ/kg), pertanto la possibilità di recupero dei compositi in ottica di riutilizzo delle CF sembra essere un'opzione promettente in termini di sostenibilità ed economia circolare. Nell’ottica di identificare una metodologia per recuperare e riciclare questi materiali, il lavoro della presente tesi di laurea sperimentale, svolto in collaborazione con Leonardo SpA, è stato quello di studiare e ottimizzare il processo di pirogassificazione su CRFP aeronautici

A Methodology to Define the Level of Safety of Public Transport Bus Stops, Based on the Concept of Risk

SRM is the Public Transport (PT) Authority of Bologna, managing PT 37 Mkm/year service contract and taking also care of the safety of the whole bus stops network, consisting of 6.700 stops. Most of bus stops have been established more than 30 years ago. During decades, PT network, number of users and road characteristics changed a lot and some bus stops are now less safe than before. A specific instrument was therefore needed in order to define a list of priority, also on the basis of what foreseen by the Regulation on service quality (ISO 13816). In 2010 a survey on all the PT stops was carried out, collecting about 120 information each (concerning geometric features as user waiting area conditions, user\u27s accessibility, road characteristics, GPS location, etc) and pictures. A database was fed by all these information. At the same time, an algorithm able to calculate the Level of Safety of bus stops was defined, starting from the concept of Risk as a combination of Probability and Damage. The algorithm can now assign a mark from 1 (worst) to 10 (best) to bus stops, on the basis of all collected data and of external factors such as vehicular traffic, vehicles speed, number of users per day at the bus stop, number of buses per day. Also the statistic data of car accidents occurred close to stops in the last 8 years were taken into account. Finally, a sort of catalogue of possible and standardized measures was produced in order to make a stop safer or to build a new safe bus stop. This catalogue can be also used to identify the maintenance works to be done to allow a bus stop to reach a predefined condition or mark. These features are now included in a specific software owned by the Authority, who is committed to spread information among administrations and operators

Patterns of mortality after pancreatoduodenectomy: A root cause, day-to-day analysis

Background: Mortality is consistently reported as an outcome metric in pancreatic surgery. Given its heterogeneity, better characterization of it might provide crucial insights for clinical practice. This study aimed to analyze the timeline and sequence of events that lead to death after pancreatoduodenectomy to identify possible distinct pathways of mortality.Methods: All consecutive pancreatoduodenectomy cases from 2010 to 2020 were retrospectively analyzed. A day-to-day appraisal of the postoperative course of each fatality was performed and visualized graphically. The graphical analysis allowed for pattern identification. The respective predictors were explored through logistic regression. Results: Out of 2065 pancreatoduodenectomy patients, in-hospital mortality was 3.1%. With graphical analysis, 3 patterns were identified. Pattern A deaths (71.4%, n = 45) occurred after a median of 43 days (14-260), following pancreas-specific complications such as postoperative pancreatic fistula, postpancreatectomy hemorrhage, and delayed gastric emptying. Pattern B deaths (15.9%, n = 10) occurred after a median of 18 days (1-55), succeeding a critical status in the early postoperative course, mainly related to elevated surgical complexity. Patients with pattern C (12.7%) died after a median of 8 days, mostly for unknown cause after an uneventful postoperative course. The predictors of each pattern were distinctive.Conclusion: Mortality after pancreatoduodenectomy occurs through 3 distinct pathways. This knowledge could spawn an additional endpoint of value to clinicians and hospitals, delivering a supplementary tool for comparison between centers and diversified patient populations, and it might facilitate the identification of the best targets for improvement. Further studies are needed to validate this tripartite reclassification.(c) 2022 Elsevier Inc. All rights reserved

Delayed Perihematomal Hypoperfusion is associated with Poor Outcome in Intracerebral Hemorrhage

Background: we aimed to characterize the temporal evolution and prognostic significance of perihematomal perfusion in acute intracerebral hemorrhage (ICH). Methods: single center prospective cohort of patients with primary spontaneous ICH receiving computed tomography perfusion (CTP) within 6 h from onset (T0) and at 7 days (T7). Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT) were measured in the manually outlined perihematomal low-density area. Poor functional prognosis (modified Rankin Scale 3-6) at 90 days was the outcome of interest and predictors were explored with multivariable logistic regression. Results: a total of 150 patients were studied, of whom 52 (34.7%) had a mRS 3-6 at 90 days. Perihematomal perfusion decreased from T0 to T7 in all patients but the magnitude of CBF and CBV reduction was larger in patients with unfavorable outcome (median CBF change -7.8 vs. -6.0 mL/100g/min, p<0.001 and median CBV change -0.5 vs. -0.4 mL/100g, p=0.010 respectively). This finding remained significant after adjustment for confounders (odds ratio [OR] for 1mL/100g/min CBF reduction: 1.33, 95% confidence interval [CI] (1.15-1.55), p<0.001; OR for 0.1 mL/100g CBV reduction 1.67, 95% CI 1.18-2.35, p=0.004). The presence of CBF<20 mL/100g/min at T7 was then demonstrated as an independent predictor of poor functional outcome (adjusted OR: 2.45, 95% CI 1.08-5-54, p=0.032). Conclusion: perihemorrhagic hypoperfusion becomes more severe in the days following acute ICH and is independently associated with poorer outcome. Understanding the underlying biological mechanisms responsible for delayed decrease in perihematomal perfusion is a necessary step towards outcome improvement in patients with ICH

Epilepsy features in ARID1B-related Coffin-Siris syndrome

Objective. Coffin-Siris syndrome (CSS) is a rare congenital malformation syndrome, caused by mutations in the ARID1B gene in over half of the cases. While the clinical characteristics of the syndrome have been increasingly described, a detailed evaluation of the epileptic phenotype in patients with ARID1B alterations and CSS has not been approached yet. We report seven patients with ARID1B-related CSS, focusing on epilepsy and its electroclinical features. Methods. The evolution of epilepsy and EEG findings of children with CSS are described and compared with patients previously reported in the literature. Results. The patients described here reveal common features, consistent with those of patients previously described in the literature. Significance. The epilepsy phenotype of CSS due to ARID1B pathogenic variants may be described as focal epilepsy with seizures, variable in frequency, arising from motor areas, with onset in the first years of life and susceptibility to fever, and interictal perisylvian (centrotemporal) epileptiform abnormalities that are enhanced during sleep with possible evolution to an EEG pattern of continuous spike and wave during sleep (without documented developmental regression). Additional information emerging from other patients is needed to confirm this definition