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Evlp for lung transplant. Initial experience
Get PDFBackground
Il trapianto polmonare rappresenta l'unica soluzione percorribile per l'insufficienza respiratoria end-stage. La principale limitante ad un suo impiego è rappresentata dalla scarsità di polmoni idonei. In questo contesto si colloca il progetto di ricondizionamento ex-vivo. L'implementazione risulta possibile attraverso il ricondizionamento di organi cosiddetti “marginali” o giudicati inizialmente non idonei al trapianto e da donatori a cuore fermo (Donor after Cardiac Death – DCD).
Scopo
Lo scopo principale del progetto è quello di analizzare i risultati a breve e medio termine del trapianto polmonare effettuato impiegando polmoni sottoposti a procedura di ricondizionamento ex-vivo in due centri trapianti di polmone a basso volume.
Materiali e Metodi
I dati sono stati raccolti retrospettivamente (da Giugno 2013 per quanto riguarda l’ISMETT e dal 2014 quelli dell’ Ospedale S. Orsola-Malpighi) e in maniera prospettica dal 2019.
Risultati
Sommando i dati relativi ad entrambi i centri, dal 2013 sono stati eseguiti un totale di 26 procedure di riperfusione. Sei volte i polmoni sono stati giudicati idonei al trapianto al termine con 5 trapianti doppi e un trapianto singolo sinistro. I risultati in termine di sopravvivenza a medio termine sono risultati sovrapponibili a quelli disponibili in letteratura, tuttavia è stato registrato un alto tasso di PGD (Primary Graft Disfunction) di grado 3, da imputare alla patologia di base del ricevente (ipertensione polmonare), che per protocollo di istituto rimane con supporto cardio-respiratorio (ECMO) dopo il trapianto.
Conclusioni
L’EVLP si conferma in centri di piccolo e medio volume un metodo sicuro ed efficace per implementare in numero di polmoni idonei al trapianto.Background
Lung transplant is a life-saving treatment for patients with end stage lung disease. The shortage of suitable lung graft still a major limiting factor. Ex-vivo lung perfusion has emerged as a solution to increase transplantable graft.
Methods
We collected data about lung transplant in two different lung transplant center in Palermo and Bologna, retrospectively respectively since 2013 and 2014, and since 2019 in a prospective way.
Results
A total of 26 reperfusion procedures have been performed since 2013. Six times the lungs were judged suitable for transplant after 4 hours, leading to 5 double transplants and a single left transplant. The results in terms of medium-term survival were comparable to those available in the literature, however a high rate of grade 3 PGD (Primary Graft Disfunction) was recorded, attributable to the underlying disease of the recipient (pulmonary hypertension).
Conclusion
The EVLP is confirmed in small and medium volume centers as a safe and effective method to implement the number of lungs suitable for transplantation
Study of low grade temperature CCHP systems for the realization of zero power buildings
Get PDFCombined Cooling Heat and Power Generation (CCHP) or trigeneration has been considered worldwide as a suitable alternative to traditional energy systems in terms of significant energy saving and environmental conservation. The development and evaluation of a solar driven micro-CCHP system based on a ORC cogenerator and an Adsorption Chiller (AC) experimental prototypes has been the focus of this PhD research.
The specific objectives of the overall project are:
• To design, construct and evaluate an innovative Adsorption Chiller in order to improve the performances of the AC technology.
• To thermodynamically model the proposed micro-scale solar driven CHP system and to prove that the concept of trigeneration through solar energy combined with an organic Rankine turbine cycle (ORC) and an adsorption chiller (AC) is suitable for residential applications
Characterization and cloning of chemically-induced mutants in barley (Hordeum vulgare L.)
Get PDFInduced mutagenesis has been exploited for crop improvement and for investigating gene function and regulation. To unravel molecular mechanisms of stress resilience, we applied state-of-the-art genomics-based gene cloning methods to barley mutant lines showing altered root and shoot architecture and disease lesion mimic phenotypes.
With a novel method that we named complementation by sequencing, we cloned NEC3, the causal gene for an orange-spotted disease lesion mimic phenotype. NEC3 belongs to the CYP71P1 gene family and it is involved in serotonin biosynthesis. By comparative phylogenetic analysis we showed that CYP71P1 emerged early in angiosperm evolution but was lost in some lineages including Arabidopsis thaliana. By BSA-Seq, we cloned the gene whose mutation increased leaf width, and we showed that the gene corresponded to the previously cloned BROADLEAF1. By BSA coupled to WGS sequencing, we cloned EGT1 and EGT2, two genes that regulate root gravitropic set point angle. EGT1 encodes a Tubby-like F-box protein and EGT2 encodes a Sterile Alpha Motive protein; EGT2 is phylogenetically related to AtSAM5 in Arabidopsis and to WEEP in peach where it regulates branch angle. Both EGT1 and EGT2 are conserved in wheat. We hypothesized that both participate to an anti-gravitropic offset mechanism since their disruption causes mutant roots to grow along the gravity vector. By the MutMap+ method, we cloned the causal gene of a short and semi-rigid root mutant and found that it encodes for an endoglucanase and is the ortholog of OsGLU3 in rice whose mutant has the same phenotype, suggesting that the gene is conserved in barley and rice.
The mutants and the corresponding genes which were cloned in this work are involved in the response to stress and can potentially contribute to crop adaptation
Drive up electrochemical and electrochemiluminescence signal through biosensing mechanism optimization
Get PDFBiomarkers are biological indicators of human health conditions. Their ultra-sensitive quantification is of cardinal importance in clinical monitoring and early disease diagnosis. Biosensors are some worldwide simple and easy-to-use analytical devices as a matter of fact, biosensors using electrochemiluminescence (ECL) are one of the most promising biosensors that needs an ever-increasing sensitivity for improving its clinical effectiveness.
The principal aspiration of this project is the investigation of the ECL generation mechanisms for enhancing the ECL intensity and the development of an ultrasensitive sensor, the use of metal-oxide materials (Mox) and the substitution of metal-free dyes. Novel dyes such as BODIPY, TADF are used to improve the sensitivity of ECL techniques thanks to their advantageous and tunable properties, enhancing the signal and also the ECL efficiency. Additionally, the use of Mox could be beneficial for the investigation of two different ECL mechanisms, which occur simultaneously.
In this thesis, the investigation of size and distance effects on electrochemical (EC) mechanisms was carried out through the innovative combination of a standard detection system using different size of micromagnetic beads (MBs). That allowed the discovery of an unexpected and highly efficient mechanistic path for electrochemical generation at small distances from the electrode’s surface. The smallest MBs (0.1μm) demostrate an enhancement of electrochemical signal than the bigger one (2.8μm) until 4 times of magnitude.
Finally, a novel ultrasensitive sensor, based on the coreactant-luminophores mechanism, was developed for the determination of whole viral genome specific for cardiac HBV and COVID-19 virus.
In conclusion, the ECL and the use of EC techniques (such as amperometry), improved the understanding of mechanisms responsible for the ECL/EC signal led to a great enhancement in the signal
On the Wick product and Wong-Zakai approximations.
Get PDFThis thesis is a compilation of 6 papers that the author has written together with Alberto Lanconelli
(chapters 3, 5 and 8) and Hyun-Jung Kim (ch 7). The logic thread that link all these chapters together is the interest to analyze and approximate the solutions of certain stochastic differential equations using the so called Wick product as the basic tool. In the first chapter we present arguably the most important achievement of this thesis; namely the generalization to multiple dimensions of a Wick-Wong-Zakai approximation theorem proposed by Hu and Oksendal. By exploiting the relationship between the Wick product and the Malliavin derivative we propose an original reduction method which allows us to approximate semi-linear systems of stochastic differential equations of the Itô type. Furthermore in chapter 4 we present a non-trivial extension of the aforementioned results to the case in which the system of stochastic differential equations are driven by a multi-dimensional fraction Brownian motion with Hurst parameter bigger than 1/2.
In chapter 5 we employ our approach and present a “short time” approximation for the solution of the Zakai equation from non-linear filtering theory and provide an estimation of the speed of convergence. In chapters 6 and 7 we study some properties of the unique mild solution for the
Stochastic Heat Equation driven by spatial white noise of the Wick-Skorohod type.
In particular by means of our reduction method we obtain an alternative derivation of the Feynman-Kac representation for the solution, we find its optimal Hölder regularity in time and space and present a Feynman-Kac-type closed form for its spatial derivative.
Chapter 8 treats a somewhat different topic; in particular we investigate some probabilistic aspects of the unique global strong solution of a two dimensional system of semi-linear stochastic differential equations describing a predator-prey model perturbed by Gaussian noise
GENEOs, compactifications, and graphs
Get PDFOur objective in this thesis is to study the pseudo-metric and topological structure of the space of group equivariant non-expansive operators (GENEOs). We introduce the notions of compactification of a perception pair, collectionwise surjectivity, and compactification of a space of GENEOs. We obtain some compactification results for perception pairs and the space of GENEOs. We show that when the data spaces are totally bounded and endow the common domains with metric structures, the perception pairs and every collectionwise surjective space of GENEOs can be embedded isometrically into the compact ones through compatible embeddings. An important part of the study of topology of the space of GENEOs is to populate it in a rich manner. We introduce the notion of a generalized permutant and show that this concept too, like that of a permutant, is useful in defining new GENEOs. We define the analogues of some of the aforementioned concepts in a graph theoretic setting, enabling us to use the power of the theory of GENEOs for the study of graphs in an efficient way. We define the notions of a graph perception pair, graph permutant, and a graph GENEO. We develop two models for the theory of graph GENEOs. The first model addresses the case of graphs having weights assigned to their vertices, while the second one addresses weighted on the edges. We prove some new results in the proposed theory of graph GENEOs and exhibit the power of our models by describing their applications to the structural study of simple graphs. We introduce the concept of a graph permutant and show that this concept can be used to define new graph GENEOs between distinct graph perception pairs, thereby enabling us to populate the space of graph GENEOs in a rich manner and shed more light on its structure.Il nostro obiettivo in questa tesi è studiare la struttura pseudo-metrica e topologica dello spazio degli operatori di gruppo equivarianti non espansivi (GENEO). Introduciamo le nozioni di compattazione di una coppia di percezioni, suriettività collezionistica e compattazione di uno spazio di GENEO. Otteniamo alcuni risultati di compattazione per le coppie di percezione e lo spazio dei GENEO. Mostriamo che quando gli spazi di dati sono totalmente limitati e dotano i domini comuni di strutture metriche, le coppie di percezione e ogni spazio suriettivo di raccolta dei GENEO possono essere incorporati isometricamente in quelli compatti attraverso incorporamenti compatibili. Una parte importante dello studio della topologia dello spazio dei GENEO consiste nel popolarlo in modo ricco. Introduciamo la nozione di permutante generalizzato e dimostriamo che anche questo concetto, come quello di permutante, è utile per definire nuovi GENEO. Definiamo gli analoghi di alcuni dei suddetti concetti in un contesto di teoria dei grafi, consentendoci di utilizzare la potenza della teoria dei GENEO per lo studio dei grafi in modo efficiente. Definiamo le nozioni di coppia di percezione del grafo, permutante del grafo e GENEO del grafo. Sviluppiamo due modelli per la teoria dei grafi GENEO. Il primo modello si rivolge al caso di grafi aventi pesi assegnati ai vertici, mentre il secondo si rivolge a pesi sugli spigoli. Dimostriamo alcuni nuovi risultati nella proposta teoria dei grafi GENEO e mostriamo la potenza dei nostri modelli descrivendo le loro applicazioni allo studio strutturale di grafi semplici. Introduciamo il concetto di permutante del grafo e mostriamo che questo concetto può essere utilizzato per definire nuovi GENEO del grafo tra coppie distinte di percezione del grafo, consentendoci così di popolare lo spazio del grafo GENEO in modo ricco e fare più luce sulla sua struttura
Data assimilation for advanced cross-scale unstructured-grid ocean modeling.
Get PDFThe coastal ocean is a complex environment with extremely dynamic processes that require a high-resolution and cross-scale modeling approach in which all hydrodynamic fields and scales are considered integral parts of the overall system. In the last decade, unstructured-grid models have been used to advance in seamless modeling between scales. On the other hand, the data assimilation methodologies to improve the unstructured-grid models in the coastal seas have been developed only recently and need significant advancements. Here, we link the unstructured-grid ocean modeling to the variational data assimilation methods. In particular, we show results from the modeling system SANIFS based on SHYFEM fully-baroclinic unstructured-grid model interfaced with OceanVar, a state-of-art variational data assimilation scheme adopted for several systems based on a structured grid. OceanVar implements a 3DVar DA scheme. The combination of three linear operators models the background error covariance matrix. The vertical part is represented using multivariate EOFs for temperature, salinity, and sea level anomaly. The horizontal part is assumed to be Gaussian isotropic and is modeled using a first-order recursive filter algorithm designed for structured and regular grids. Here we introduced a novel recursive filter algorithm for unstructured grids. A local hydrostatic adjustment scheme models the rapidly evolving part of the background error covariance. We designed two data assimilation experiments using SANIFS implementation interfaced with OceanVar over the period 2017-2018, one with only temperature and salinity assimilation by Argo profiles and the second also including sea level anomaly. The results showed a successful implementation of the approach and the added value of the assimilation for the active tracer fields. While looking at the broad basin, no significant improvements are highlighted for the sea level, requiring future investigations. Furthermore, a Machine Learning methodology based on an LSTM network has been used to predict the model SST increments
Development of effect-based bio-chemiluminescent cell bioassays for nutraceutical and biomedical applications
Get PDFThe final goal of the bioassay developed during the first two years of my Ph.D. was its application for the screening of antioxidant activity of nutraceuticals and for monitoring the intracellular H2O2 production in peripheral blood mononuclear cells (PBMCs) from hypercholesterolemic subjects before and after two months treatment with Evolocumab, a new generation LDL-cholesterol lowering drug.
Moreover, a recombinant bioluminescent protein was developed during the last year using the Baculovirus expression system in insect cells. In particular, the protein combines the extracellular domain (ECD) of the Notch high affinity mutated form of one of the selective Notch ligands defined as Jagged 1 (Jag1) with a red emitting firefly luciferase since a pivotal role of “aberrant” Notch signaling activation in colorectal cancer (CRC) was reported. The probe was validated and characterized in terms of analytical performance and through imaging experiments, in order to understand if Jagged1-FLuc binding correlates with a Notch signaling overexpression and activation in CRC progression
Effects of sugars and lactic acid isomers on Chlamydia trachomatis infectivity, an in vitro study
Get PDFThe thesis investigates two different in vitro aspects of Chlamydia trachomatis (CT). The thesis analyzes the effect of different sugars on CT infectivity. which is investigated on HeLa cells after 2 hour-incubation of elementary bodies (EBs) with glucose, sucrose or mannitol. Sugars effect on EB membrane fluidity is investigated by fluorescence anisotropy measurement, whereas changes in lipopolysaccharide exposure are examined by cytofluorimetric analysis. By Western blot experiments, the phosphorylation state of Focal Adhesion Kinase in cells infected with EBs pre-incubated with sugars it’s explored. Sugar significantly increase infectivity, acting on the EB structure. Sugars induce an increase of EB membrane fluidity, leading to changes in LPS exposure. After incubation with sucrose and mannitol, EBs lead to higher FAK phosphorylation, enhancing activation of anti-apoptotic and proliferative signals in the host.
Secondly, the thesis explores the protective effect of different Lactobacilli against CT infection: Lactobacillus crispatus and Lactobacillus reuteri. CT infectivity is evaluated after host cells were treated for 1 hour with diluted supernatant cell-free fraction or with the bacterial cells. Assessed that L.crispatus is more protective than L.reuteri, lactic acid production is evaluated by HPLC. Subsequently Lactate dehydrogenases activity is evaluated by resazurin assay and by LC-MS. Then, D-lactate dehydrogenase specific activity has been investigated by measuring NADH formation. Afterwards, addition of D or L-lactic acid to L.reuteri supernatant has been performed and their effect in promoting protection in the host cells assessed. Then a metabolic analysis has been carried out by real-time measurement of mitochondrial respiration after treatment. Finally, histone acetylation and lactylation, and gene and protein expression of relevant targets, have been investigated. It is shown that the D isomer is more efficient in conferring protection, causing a shift in the host cell metabolic profile and a pattern of histone modifications that changes the expression of important targets
Targeting epigenetic mechanisms in gastric cancer
Get PDFGastric cancer (GC) is a hard challenge for medical oncology, with globally over one million of new diagnoses each year and low survival rates. Gastric carcinogenesis is guided by the interaction of several risk factors, exerting through sequential histopathologic steps, including chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia and cancer. GC is classified on the basis of anatomical, histological or molecular classification, reflecting the wide cancer heterogeneity, also highlighted by the inefficacy of the actual treatment schedules. Epigenetic mechanisms alterations affecting DNA methylation, histone methylation and acetylation, are a recognized hallmark of cancer and stand at the basis of gastric carcinogenesis and tumor development. The pharmacological targeting of these altered mechanisms is an attractive option for new cancer treatments.
Aim of this study was to test the therapeutic potential of the compound CM-272 for GC, a selective and strong dual inhibitor of DNMT1 and EHMT2, which reached important results in pre-clinical models of other gastrointestinal malignancies. Moreover, in a GC patients case series, the expression of the target of the compound was tested, to prove the rationale for inhibition of DNMT1, EHMT2 and their functional adaptor were over-expressed in the majority of GC patients tissues. Through in-vitro testing of CM-272 alone and in combination with the most used chemotherapeutic treatments for GC in a panel of GC cell lines, this study demonstrated that the compound has a strong ability in inhibiting GC cells growth. Even though not directly inducing apoptosis, CM-272 was able to induce a senescent phenotype in GC cells, and to epigenetically reprogram the transcription of genes involved in phosphorylation cascades and mitochondria metabolism, thus affecting the growth and energetic machinery of cancer cells. In conclusion, the pharmacological targeting of epigenetic mechanisms demonstrated good potential pre-clinical models of GC, and further investigations to test in-vivo efficacy are needed