Studi per un patrimonio accessibile: le Strade Nuove e il sistema dei Palazzi dei Rolli a Genova.

In 2006, part of Genoa\u2019s old town entered the UNESCO World Heritage list, counting 42 palaces, 5 main streets and 4 squares. The urban fabric has a multilayered, medieval lay-out, the interest of which lies partly in the building density, significant differences in elevation and the homogeneity of the surfaces. What makes this old town unique and worthy of the highest cultural recognition is also the very reason why it is not accessible to parts of the general public and visitors. The municipality of Genoa, with the collaboration of the University, is studying hard at how to improve accessibility to the old town, which is now difficult to reach, with access often being denied. Drafting the Plan for the Elimination of Architectural Barriers (P.E.B.A.), therefore, presents a challenge for the city and the administration. About 300 buildings in the UNESCO site and the adjacent urban spaces are currently the object of study in order to discover what potential and criticalities can arise from an ever broader fruition. This knowledge base will be the first step in a larger work, to cover the entire old town, and of which the project that the municipality of Genoa is undertaking, is a part; the objective is to promote citizens\u2019 autonomy and create an inclusive design

I SECAP e la valutazione della vulnerabilità nei confronti del rischio climatico - elaborazione di una metodologia semplificata per i Comuni Liguri

più strategico all’interno di processi e strumenti di pianificazione urbana, come evidenzia l’esperienza dei Piani d’Azione per l’Energia Sostenibile ed il Clima (SECAP). Tali strategie differiscono però metodologicamente per un aspetto cruciale: se le prime non sono necessariamente situ-specifiche, le seconde dipendono strettamente dal contesto per cui vengono progettate. Perciò risulta di grande rilievo la definizione di un solido apparato conoscitivo in grado di fornire adeguate informazioni quali-quantitative per l’identificazione dei pericoli climatici per il Comune e per la valutazione della relativa vulnerabilità. La possibilità di sviluppare azioni di adattamento è dunque commisurata alla capacità di rappresentazione ed analisi della realtà comunale: in questo senso la disponibilità di risorse è strettamente connessa a dimensioni e complessità della struttura stessa dell’ente locale, così come lo sono la reperibilità dei dati e la possibilità di popolare i diversi indicatori. Anche il JRC suggerisce di ricorrere ad un indicator-based vulnerability assessment per i Comuni più piccoli, in sostituzione dei modelli specificatamente elaborati per le maggiori realtà urbane. In riferimento all’area ligure nell’ambito di una collaborazione tra Università di Genova ed IRE, si decide di proporre una metodologia semplificata che consenta di ridurre il numero di indicatori da popolare andando incontro alle esigenze dei comuni più piccoli, tramite l’identificazione dei pericoli climatici prevalenti e l’individuazione di specifiche proxy che consentano di valutare i principali impatti a scala locale

IL-18 and VEGF-A trigger type 2 innate lymphoid cell accumulation and pro-tumoral function in chronic myeloid leukemia

Chronic Myeloid Leukemia (CML) is a hematologic malignancy associated to an unregulated growth of myeloid cells in Bone Marrow (BM) and Peripheral Blood (PB), characterized by the BCR-ABL1 translocation. Given the known cytokine impairment in the leukemic niche of CML, we investigated the impact of this microenvironmental dysregulation on Innate Lymphoid Cells (ILCs), whose role in cancer has recently emerged. Three ILC subsets are identified based on transcriptional profiles and cytokine secretion. We observed that IL-18 and VEGF-A are increased in CML patients' sera and that ILC2s are enriched in CML PB and BM. We found that IL-18 drives ILC2 proliferation and that CML ILC2s highly express CXCR4 and CXCR7 BM-homing receptors, potentially explaining their enrichment in PB and BM, respectively. Next, we showed that ILC2s are hyper-activated through a tumor-derived VEGF-A-dependent mechanism, which leads to higher IL-13 secretion. In response to IL-13, leukemic cells increase their clonogenic capacity. Finally, we discovered that the pro-tumoral axis involving VEGF-A, IL-18 and ILC2s was disrupted upon Tyrosine Kinase Inhibitors' (TKIs) treatment, normalizing the levels of all these players in CML patients responding to therapy. Overall, our study uncovers the involvement of ILC2s in CML progression, mediated by VEGF-A and IL-18

Prediction of spontaneous onset of labor at term (PREDICT study): Research protocol

Background Recent studies have shown that elective induction of labor versus expectant management after 39 weeks of pregnancy result in lower incidence of perinatal complications, while the proportion of cesarean deliveries remains stable, or even decreases. Still, evidence regarding collateral consequences of the potential increase of induction of labor procedures is still lacking. Also, the results of these studies must be carefully interpreted and thoroughly counter-balanced with women’s thoughts and opinions regarding the active management of the last weeks of pregnancy. Therefore, it may be useful to develop a tool that aids in the decision-making process by differentiating women who will spontaneously go into labor from those who will require induction. Objective To develop a predictive model to calculate the probability of spontaneous onset of labor at term. Methods We designed a prospective national multicentric observational study including women enrolled at 39 weeks of gestation, carrying singleton pregnancies. After signing an informed consent form, several clinical, ultrasonographic, biophysical and biochemical variables will be collected by trained staff. If delivery has not occurred at 40 weeks of pregnancy, a second visit and evaluation will be performed. Prenatal care will be continued according to current hospital guidelines. Once recruitment is completed, the information gathered will be used to develop a logistic regression-based predictive model of spontaneous onset of labor between 39 and 41 weeks of gestation. A secondary exploration of the data collected at 40 weeks, as well as a survival analysis regarding time-to-delivery outcomes will also be performed. A total sample of 429 participants is needed for the expected number of events. Conclusion This study aims to develop a model which may help in the decision-making process during follow-up of the last weeks of pregnancy. Trial registration NCT05109247 (clinicaltrials.gov)

Human primed ILCPs support endothelial activation through NF-κB signaling

Innate lymphoid cells (ILCs) represent the most recently identified subset of effector lymphocytes, with key roles in the orchestration of early immune responses. Despite their established involvement in the pathogenesis of many inflammatory disorders, the role of ILCs in cancer remains poorly defined. Here we assessed whether human ILCs can actively interact with the endothelium to promote tumor growth control, favoring immune cell adhesion. We show that, among all ILC subsets, ILCPs elicited the strongest upregulation of adhesion molecules in endothelial cells (ECs) in vitro, mainly in a contact-dependent manner through the tumor necrosis factor receptor- and RANK-dependent engagement of the NF-κB pathway. Moreover, the ILCP-mediated activation of the ECs resulted to be functional by fostering the adhesion of other innate and adaptive immune cells. Interestingly, pre-exposure of ILCPs to human tumor cell lines strongly impaired this capacity. Hence, the ILCP-EC interaction might represent an attractive target to regulate the immune cell trafficking to tumor sites and, therefore, the establishment of an anti-tumor immune response

UHPLC-MS/MS Analysis of Cannabidiol and Its Metabolites in Serum of Patients with Resistant Epilepsy Treated with CBD Formulations

Cannabidiol (CBD) is a promising therapeutic agent with analgesic, myorelaxant, and anti-epileptic actions. Recently, a purified form of CBD (Epidiolex®) has been approved by the European Medicines Agency (EMA) for the treatment of two highly-refractory childhood-onset epilepsies (Dravet and Lennox-Gastaut syndrome). Given the interindividual response and the relationship between the dose administered and CBD blood levels, therapeutic drug monitoring (TDM) is a valuable support in the clinical management of patients. We herein report for the first time a newly developed and validated method using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS/MS) to evaluate CBD and its metabolites (i.e., cannabidiol-7-oic acid (7-COOH-CBD), 7-hydroxycannabidiol (7-OH-CBD), 6-α-hydroxycannabidiol (6-α–OH–CBD) and 6-β-hydroxycannabidiol (6-β–OH–CBD)) in serum samples. The method reached the sensitivity needed to detect minimal amounts of analytes under investigation with limits of quantification ranging from 0.5 to 20 ng/mL. The validation results indicated in this method were accurate (average inter/intra-day error, <15%), precise (inter/intra-day imprecision, <15%), and fast (8 min run time). The method resulted to be linear in the range of 1–10,000 ng/mL for CBD-COOH, 1–500 ng/mL for 7-OH-CBD and CBD and 1–25 ng/mL for 6-α–OH–CBD and 6-β–OH–CBD. Serum levels of CBD (88.20–396.31 and 13.19–170.63 ng/mL) as well as of 7-OH-CBD (27.11–313.63 and 14.01–77.52 ng/mL) and 7-COOH-CBD (380.32–10,112.23 and 300.57–2851.82 ng/mL) were significantly higher (p < 0.05) in patients treated with GW pharma CBD compared to those of patients treated with galenic preparations. 6-α–OH–CBD and 6-β–OH–CBD were detected in the first group and were undetectable in the second group. 7-COOH-CBD was confirmed as the most abundant metabolite in serum (5–10 fold higher than CBD) followed by 7-OH-CBD. A significant correlation (p < 0.05) between the dose administrated and a higher bioavailability was confirmed in patients treated with a GW pharma CBD preparation

NKG2A expression identifies a subset of human V\u3b42 T\ua0cells exerting the highest antitumor effector functions

Human V delta 2 cells are innate-like gamma delta T effectors performing potent immune surveillance against tumors. The constitutive expression of NKG2A identifies a subset of V delta 2 T cells licensed with an intrinsic hyper-responsiveness against cancer. Indeed, the transcriptomic profiles of NKG2A(+) and NKG2A(-) cells characterize two distinct "intralineages'' of V delta 2 T lymphocytes that appear early during development, keep their phenotypes, and show self-renewal capabilities in adult life. The hyper-responsiveness of NKG2A(+) V delta 2 T cells is counterbalanced by the inhibitory signaling delivered by human leukocyte antigen E (HLA-E) expressed on malignant cells as a tumor-escape mechanism. However, either masking or knocking out NKG2A restores the capacity of V delta 2 T cells to exert the highest effector functions even against HLA-E+ tumors. This is highly relevant in the clinic, as the different degrees of engagement of the NKG2A-HLA-E checkpoint in hepatocellular carcinoma, glioblastoma, and non-small cell lung cancer directly impact patients' overall survival. These findings open avenues for developing combined cellular and immunologic anticancer therapies

Defective Fas function in the ALPS and DALD patients carrying the UNC13D variations.

<p>[A] Fas-induced cell death in T cells from the ALPS and DALD patients carrying the <i>UNC13D</i> variations. Activated T cells were treated with anti-Fas mAb and survival was assessed after 18 hours. The results are expressed as specific cell survival %. The dotted line indicates the upper limit of the normal range calculated as the 95^th percentile of data obtained from 200 healthy controls; two or more were run in each experiment as positive controls; each patient was evaluated at least twice with the same result. [B] Fas expression and caspase-8 activity in lysates of 293T cells transfected with the wild-type (WT) or mutated form of <i>FAS</i> (Pt.1: p.Gln273His, Pt.2: p.Glu261Lys); cells were lysed 24 hours after transfection. <i>Upper panels</i>: Western blot analysis of the transfected Fas performed using anti-FLAG and anti-β-actin antibodies<i>. Lower panels</i>: fluorimetric enzyme assay for caspase-8 activity. Data are relative to those displayed by mock-transfected cells and are expressed as the mean and SE of the results from 4 experiments performed in duplicate. *p<0.05; **p<0.01 vs. Fas^wt transfected cells.</p

<i>UNC13D</i> and <i>FAS</i> variations carried by ALPS/DALD patients.

<p>Graphical representation (not in scale) of the Munc13-4 [A] and Fas [B] proteins (upper schemes: numbers indicate the amino acid positions) and genes (lower scheme: boxes represent the exons; arrows indicate the mutations). C2: C2 domain; MHD: Munc13-homology domain. PLAD: preligand assembly domain; TM: transmembrane domain; DD: death domain.</p