A differential algebra based importance sampling method for impact probability computation on Earth resonant returns of Near Earth Objects

A differential algebra based importance sampling method for uncertainty propagation and impact probability computation on the first resonant returns of Near Earth Objects is presented in this paper. Starting from the results of an orbit determination process, we use a differential algebra based automatic domain pruning to estimate resonances and automatically propagate in time the regions of the initial uncertainty set that include the resonant return of interest. The result is a list of polynomial state vectors, each mapping specific regions of the uncertainty set from the observation epoch to the resonant return. Then, we employ a Monte Carlo importance sampling technique on the generated subsets for impact probability computation. We assess the performance of the proposed approach on the case of asteroid (99942) Apophis. A sensitivity analysis on the main parameters of the technique is carried out, providing guidelines for their selection. We finally compare the results of the proposed method to standard and advanced orbital sampling techniques

Impact probability computation of Near-Earth Objects using Monte Carlo Line Sampling and Subset Simulation

This work introduces two Monte Carlo (MC)-based sampling methods, known as line sampling and subset simulation, to improve the performance of standard MC analyses in the context of asteroid impact risk assessment. Both techniques sample the initial uncertainty region in different ways, with the result of either providing a more accurate estimate of the impact probability or reducing the number of required samples during the simulation with respect to standard MC techniques. The two methods are first described and then applied to some test cases, providing evidence of the increased accuracy or the reduced computational burden with respect to a standard MC simulation. Finally, a sensitivity analysis is carried out to show how parameter setting affects the accuracy of the results and the numerical efficiency of the two methods

Comparison of NGF and proNGF endosomal pathways

Le neurotrofine sono una famiglia di fattori di crescita coinvolta in una moltitudine di processi biologici quali: sviluppo, differenziamento e sopravvivenza dei neuroni, così come plasticità neuronale e percezione fisiopatologica del dolore. In particolare, queste proteine sono secrete in modeste quantità dalle cellule bersaglio, ovvero le cellule che devono stabilire un contatto con il neurone. Queste cellule possono essere a loro volta di tipo nervoso o di altro tipo. La famiglia delle neurotrofine comprende diversi membri tra i quali il Nerve Growth Factor (NGF). Il meccanismo generale di azione delle neurotrofine prevede il riconoscimento di queste da parte di recettori posti sulla membrana neuronale, l’endocitosi del complesso neurotrofina-recettore all’interno di endosomi speciallizzati, ed il trasporto di questi dal tip assonale verso il soma neuronale dove si espleta la loro funzione biologica. Per quanto riguarda il NGF, essa viene secreta dai tessuti target sottoforma di mix proteico costituito anche dalla sua forma immatura non processata (proNGF). E’ stato dimostrato che in condizioni patologiche, quali ad esempio malattie neurodegenerative come l’Alzheimer, vi è uno sbilanciamento tra le concentrazioni rispettive delle forme matura e non matura del NGF, con un aumento a favore di quest’ultima. Ulteriori indagini hanno mostrato che, sebbene molto simili strutturalmente, il NGF ed il proNGF possiedono ruoli contrapposti, promuovendo rispettivamente la sopravvivenza oppure la morte neuronale. La presente tesi si pone l’obiettivo di caratterizzare i determinanti molecolari alla base delle differenze nella funzione biologica del NGF e del proNGF. Per raggiungere questo obiettivo il laboratorio BioSNS del Prof. Cattaneo alla Scuola Normale Superiore ha ideato una strategia per inserire un peptidedi 11 amminoacidi al C-terminale di entrambe le neurotrofine. Questo costituisce un “tag chimico”, che può essere covalentemente funzionalizzato con stechiometria 1:1 a piccoli fluorofori organici con minimo impatto sulla struttura sia del NGF che del proNGF. Il mio lavoro di tesi è inserito in questa tematica di ricerca ed è stato articolato nei seguenti punti: i) Produzione di NGF e proNGF taggati in E.coli e loro purificazione tramite cromatografia a scambio ionico FPLC. ii) Marcatura delle neurotrofine taggate purificate con fluorofori organici, e successiva purificazione delle forme fluorescenti tramite un ulteriore step di purificazione in HPLC. iii) Validazione funzionale delle neurotrofine fluorescenti così ottenute tramite utilizzo di una piattaforma microarray; in particolare sono stati valutati i profili di espressione genica attivati dalla somministrazione delle neurotrofine fluorescenti a una coltura cellulare di feocromocitoma di ratto (PC12), tipicamente usata per lo studio delle neurotrofine. iv) Somministrazione delle neurotrofine fluorescenti validate in cellule PC12 seminate su vetrino e successiva immunocitochimica e microscopia confocale per valutare la loro evenutale colocalizzazione con alcuni partner proteici noti coinvolti nel signalling e nel trasporto delle neurotrofine all’interno dei neuroni, quali: TrkA, P75 e Sortilin. Questi partner possiedono diversa affinità per le due forme proteiche del NGF, inoltre sono caratterizzati da risposte cellulari opposte. Analisi di immagine quantitativa e qualitativa della colocalizzazione di NGF e proNGF con i vari partner proteici

An Optimized Procedure for the Site-Directed Labeling of NGF and proNGF for Imaging Purposes

Neurotrophins are growth factors of fundamental importance for the development, survival and maintenance of different neuronal and non-neuronal populations. Over the years, the use of labeled neurotrophins has helped in the study of their biological functions, leading to a better understanding of the processes that regulate their transport, traffic, and signaling. However, the diverse and heterogeneous neurotrophin labeling strategies adopted so far have often led to poorly reproducible protocols and sometimes conflicting conclusions. Here we present a robust, reliable, and fast method to obtain homogeneous preparations of fluorescent proNGF and NGF with 1:1 labeling stoichiometry. This strategy is well suited for several applications, ranging from advanced imaging techniques such as single particle tracking, to analyses that require large amounts of neurotrophins such as in vivo monitoring of protein biodistribution. As a proof of the quality of the labeled NGF and proNGF preparations, we provide a quantitative analysis of their colocalization with proteins involved in the signaling endosome function and sorting. This new analysis allowed demonstrating that proNGF localizes at a sub-population of endosomes not completely overlapped to the one hosting NGF

Cost-effectiveness analysis of initial HIV treatment under Italian guidelines

INTRODUCTION: Since the mid-1990s, highly active antiretroviral therapy (HAART) has modified the clinical course of human immunodeficiency virus (HIV) infection, reducing the rate of disease progression, the incidence of opportunistic infections, and mortality. The authors of this paper performed an economic analysis to estimate the cost-effectiveness of the HAART regimens in Italy for managing HIV-infected patients according to national guidelines. PATIENTS AND METHODS: The incremental cost-effectiveness analysis was carried out by means of a Markov model, which through a decision-analytic approach, made it possible to compare the studied antiretroviral regimens. The population considered in the model consisted of adult subjects with HIV who received antiretroviral HAART treatment for the first time. The population considered in the analysis reflects the patients' characteristics according to one of the regional surveillance systems HIV/AIDS infection report currently operating in Italy. The analysis was carried out from the point of view of the Italian health care system. The considered outcome measures were quality-adjusted life years (QALYs) and direct health costs calculated for the year 2010. Both the outcomes (QALYs) and the costs were discounted by 3.5%. The time horizon adopted in the model was 10 years. RESULTS: The model shows, in terms of cost per gained QALY, single tablet regimen (STR) appeared to be the most cost-effective therapeutic choice (22,017), followed by tenofovir (TDF) + lamivudine + efavirenz (EFV) (24,526), and TDF/emtricitabine (FTC) + nevirapine (26,416), and TDF + FTC + EFV (26,558); the remaining strategies have an incremental cost-effectiveness ratio (ICER) value varying from 28,000 to 41,000 per QALY. The sensitivity analysis on the main variables confirmed the validity of the base case scenario. CONCLUSION: STR is the most cost-effective treatment strategy, compared with the other therapeutic regimens recommended by the Italian guidelines. All the ICER values of the various regimens considered by the Italian guidelines were lower than the threshold value of 50,000 commonly accepted at the international level. The model developed represents a tool for policy makers and health care professionals to make short- and long-term cost projections and thus evaluate their impact on the available budgets for HIV patients

Booster: a Benchmark for Depth from Images of Specular and Transparent Surfaces

Estimating depth from images nowadays yields outstanding results, both in terms of in-domain accuracy and generalization. However, we identify two main challenges that remain open in this field: dealing with non-Lambertian materials and effectively processing high-resolution images. Purposely, we propose a novel dataset that includes accurate and dense ground-truth labels at high resolution, featuring scenes containing several specular and transparent surfaces. Our acquisition pipeline leverages a novel deep space-time stereo framework, enabling easy and accurate labeling with sub-pixel precision. The dataset is composed of 606 samples collected in 85 different scenes, each sample includes both a high-resolution pair (12 Mpx) as well as an unbalanced stereo pair (Left: 12 Mpx, Right: 1.1 Mpx), typical of modern mobile devices that mount sensors with different resolutions. Additionally, we provide manually annotated material segmentation masks and 15K unlabeled samples. The dataset is composed of a train set and two test sets, the latter devoted to the evaluation of stereo and monocular depth estimation networks. Our experiments highlight the open challenges and future research directions in this field.Comment: Extension of the paper "Open Challenges in Deep Stereo: the Booster Dataset" presented at CVPR 2022. Accepted at TPAM

Immune Checkpoint Inhibitors in Malignant Pleural Mesothelioma: A Systematic Review and Meta-Analysis

Many clinical trials have investigated the role of ICIs in PM, with contrasting results. We performed a systematic review and meta-analysis of clinical trials testing single-agent anti-Programmed Death -1 (PD-1)/Programmed Death-Ligand 1 (PD-L1), anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) or combined treatment in PM patients, analyzing response and survival rate as well as safety data. We selected 17 studies including 2328 patients. Both OS and PFS rates were significantly higher with combined ICI treatments than with single agent anti-PD-1/PD-L1 (p < 0.001 and p = 0.006, respectively) or anti CTLA-4 (p < 0.001) treatments. ORR and DCR for all ICI treatments were 20% (95% CI 13–27%) and 56% (95% CI 45–67%), respectively, and they did not significantly differ between combined and single agent treatments (p = 0.088 and p = 0.058, respectively). The 12-month OS and 6-month PFS rates did not differ significantly (p = 0.0545 and p = 0.1464, respectively) among pre-treated or untreated patients. Combined ICI treatments had a significantly higher rate of Adverse Events (AEs) (p = 0.01). PD-L1-positive patients had a higher probability of response and survival. In conclusion, combined ICI treatments have higher efficacy than single agents but are limited by higher toxicity. Efficacy was independent of treatment line, so a customized sequential strategy should still be speculated. PD-L1 expression could influence response to ICIs; however, reliable biomarkers are warranted

Cryopreservation protocol for human biliary tree stem/progenitors, hepatic and pancreatic precursors

Human biliary tree stem/progenitor cells (hBTSCs) are being used for cell therapies of patients with liver cirrhosis. A cryopreservation method was established to optimize sourcing of hBTSCs for these clinical programs and that comprises serum-free Kubota's Medium (KM) supplemented with 10% dimethyl sulfoxide (DMSO), 15% human serum albumin (HSA) and 0.1% hyaluronans. Cryopreserved versus freshly isolated hBTSCs were similar in vitro with respect to self-replication, stemness traits, and multipotency. They were able to differentiate to functional hepatocytes,cholangiocytes or pancreatic islets, yielding similar levels of secretion of albumin or of glucose-inducible levels of insulin. Cryopreserved versus freshly isolated hBTSCs were equally able to engraft into immunocompromised mice yielding cells with human-specific gene expression and human albumin levels in murine serum that were higher for cryopreserved than for freshly isolated hBTSCs. The successful cryopreservation of hBTSCs facilitates establishment of hBTSCs cell banking offering logistical advantages for clinical programs for treatment of liver diseases