Heteroatom containing polycyclic aromatic hydrocarbons with positive charge - synthesis and characterization

The synthesis and characterization of various heteroatom containing PAHs with positive charge were investigated in this work: 1. A series of 2-phenyl-benzo[8,9]quinolizino[4,5,6,7-fed]phenanthridinylium (PQP) salts with different alkyl chains and anions were synthesized. The synthesis of the extended derivates of PQP salts with two fused benzene rings, 2-phenyl-naphthacene[1,2]quinolizino[3,4,5,6-def]benzo[i]phenanthridinium (DBPQP) tetrafluoroborate was also developed. The self-assembly behavior of these amphiphilic PAHs was investigated in methanolic solution as well as in the bulk. Various aggregates with different morphologies such as fibers, tubes and vesicals were obtained from their solution. All of these morphology changes could be ascribed to the changes in intermolecular interactions which resulting from the difference in the molecular structures such as aromatic cores, alkyl chains and counterions. 2. The synthetic strategy of oxygen containing positively charged PAHs, benzo[5,6]naphthaceno[1,12,11,10-jklmna]xanthylium (BNAX) salts and its dibenzo derivates, DBNAX salts were developed. With a similar method, sulfur containing benzo[5,6]naphthaceno[1,12,11,10-jklmna]thioxanthylium (BNATX) salts were also synthesized. Various BNAX salts with different alkyl chains could be obtained and their supramolecular behavior were investigated. A discotic liquid crystalline behavior was observed for di- (3-25) and tridodecyl (3-27) substituted BNAX salts and both compounds exhibited large unit cell in their 2D-WAXS patterns which could be attributed to the formation of dimer structures. By drop casting their methanolic solution on silicon wafers, similar nanoscaled fibers from monododecyl substituted BNAX bromide 3-24 and DBNAX bromide 3-35 could be observed. 3. A novel synthetic method toward nitrogen containing 14-phenyl-dibenzo[jk,mn]naphtho[2,1,8-fgh]thebenidinium (DBNT) salts was also developed. In this method, the undehydrogenated precursor of DBNT, dibenzoacridinium salt could be produced directly from the reaction between dibenzoxanthenylium derivates and amine/aniline in reasonable yields. Various DBNT salts with different alkyl and alkylphenyl chains on their nitrogen atom were synthesized in this two-step method. The self-assembly behavior of two alkylated DBNT salts, 4-15a and 4-18b was also studied in this work. Compound 4-15a formed nanoscaled fibers and helical aggregates were obtained from 4-18b in their methanolic solutions. 4. Various ionic complexes were derived by complexing PQP and DBPQP cations with different sulfate/sulfonate group containing anionic surfactants. The ionic complexes resulting from the ionic self-assembly (ISA) method exhibited self-assembly behavior which was controllable by the species and shape of cations and anions. Various aggregates such as nanofibers and spherical aggregates could be produced from their methanolic solution in a defined manner conveniently.

Resonances in the two centers Coulomb system

In this work we investigate the existence of resonances for two-centers Coulomb systems with arbitrary charges in two and three dimensions, defining them in terms of generalized complex eigenvalues of a non-selfadjoint deformation of the two-center Schrödinger operator. After giving a description of the bifurcation of the classical system for positive energies, we construct the resolvent kernel of the operators and we prove that they can be extended analytically to the second Riemann sheet. The resonances are then defined and studied with numerical methods and perturbation theory.

Targeting the p53–MDM2 interaction by the small-molecule MDM2 antagonist Nutlin-3a: a new challenged target therapy in adult Philadelphia positive acute lymphoblastic leukemia patients

The human p53 tumor suppressor, known as the “guardian of the genome”, is one of the most important molecules in human cancers. One mechanism for suppressing p53 uses its negative regulator, MDM2, which modulates p53 by binding directly to and decreasing p53 stability. In testing novel therapeutic approaches activating p53, we investigated the preclinical activity of the MDM2 antagonist, Nutlin-3a, in Philadelphia positive (Ph+) and negative (Ph-) leukemic cell line models, and primary B-Acute lymphoblastic leukemia (ALL) patient samples. In this study we demonstrated that treatment with Nutlin-3a induced grow arrest and apoptosis mediated by p53 pathway in ALL cells with wild-type p53, in time and dose-dependent manner. Consequently, MDM2 inhibitor caused an increase of pro-apoptotic proteins and key regulators of cell cycle arrest. The dose-dependent reduction in cell viability was confirmed in primary blast cells from Ph+ ALL patients with the T315I Bcr-Abl kinase domain mutation. In order to better elucidate the implications of p53 activation and to identify biomarkers of clinical activity, gene expression profiling analysis in sensitive cell lines was performed. A total of 621 genes were differentially expressed (p < 0.05). We found a strong down-regulation of GAS41 (growth-arrest specific 1 gene) and BMI1 (a polycomb ring-finger oncogene) (fold-change -1.35 and -1.11, respectively; p-value 0.02 and 0.03, respectively) after in vitro treatment as compared to control cells. Both genes are repressors of INK4/ARF and p21. Given the importance of BMI in the control of apoptosis, we investigated its pattern in treated and untreated cells, confirming a marked decrease after exposure to MDM2 inhibitor in ALL cells. Noteworthy, the BMI-1 levels remained constant in resistant cells. Therefore, BMI-1 may be used as a biomarker of response. Our findings provide a strong rational for further clinical investigation of Nutlin-3a in Ph+ and Ph-ALL.

Ottimizzazione, guidata dall'applicazione, della scansione di canali WiFi in kernel Linux

La tesi ha visto la creazione di una applicazione in grado di inviare e ricevere messaggi verso un kernel Linux 3.6.8, che e' stato modificato nel modulo net/mac80211. Lo scopo e' stato permettere all'applicazione di attivare/disattivare comportamenti alternativi del metodo di scansione di canali Wi-Fi. Sono rese possibili le seguenti funzionalita': disattivare la scansione, rendere non interrompibile la scansione software, ricevere notifiche a completamento di una scansione software. Per la comunicazione sono stati usati i socket netlink.

Fast and accurate numerical solutions in some problems of particle and radiation transport: synthetic acceleration for the method of short characteristics, Doppler-broadened scattering kernel, remote sensing of the cryosphere

The aim of this work is to present various aspects of numerical simulation of particle and radiation transport for industrial and environmental protection applications, to enable the analysis of complex physical processes in a fast, reliable, and efficient way. In the first part we deal with speed-up of numerical simulation of neutron transport for nuclear reactor core analysis. The convergence properties of the source iteration scheme of the Method of Characteristics applied to be heterogeneous structured geometries has been enhanced by means of Boundary Projection Acceleration, enabling the study of 2D and 3D geometries with transport theory without spatial homogenization. The computational performances have been verified with the C5G7 2D and 3D benchmarks, showing a sensible reduction of iterations and CPU time. The second part is devoted to the study of temperature-dependent elastic scattering of neutrons for heavy isotopes near to the thermal zone. A numerical computation of the Doppler convolution of the elastic scattering kernel based on the gas model is presented, for a general energy dependent cross section and scattering law in the center of mass system. The range of integration has been optimized employing a numerical cutoff, allowing a faster numerical evaluation of the convolution integral. Legendre moments of the transfer kernel are subsequently obtained by direct quadrature and a numerical analysis of the convergence is presented. In the third part we focus our attention to remote sensing applications of radiative transfer employed to investigate the Earth's cryosphere. The photon transport equation is applied to simulate reflectivity of glaciers varying the age of the layer of snow or ice, its thickness, the presence or not other underlying layers, the degree of dust included in the snow, creating a framework able to decipher spectral signals collected by orbiting detectors.

Next-Generation Sequencing-Based Mutations Scanning Strategy of the BCR-ABL Kinase Domain in Patients with PhiladelPhia-Chromosome Positive Leukemias Treated with Tyrosine Kinase Inhibitors

In chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia patients resistant to tyrosine kinase inhibitors (TKIs), BCR-ABL kinase domain mutation status is an essential component of the therapeutic decision algorithm. The recent development of Ultra-Deep Sequencing approach (UDS) has opened the way to a more accurate characterization of the mutant clones surviving TKIs conjugating assay sensitivity and throughput. We decided to set-up and validated an UDS-based for BCR-ABL KD mutation screening in order to i) resolve qualitatively and quantitatively the complexity and the clonal structure of mutated populations surviving TKIs, ii) study the dynamic of expansion of mutated clones in relation to TKIs therapy, iii) assess whether UDS may allow more sensitive detection of emerging clones, harboring critical 2GTKIs-resistant mutations predicting for an impending relapse, earlier than SS. UDS was performed on a Roche GS Junior instrument, according to an amplicon sequencing design and protocol set up and validated in the framework of the IRON-II (Interlaboratory Robustness of Next-Generation Sequencing) International consortium.Samples from CML and Ph+ ALL patients who had developed resistance to one or multiple TKIs and collected at regular time-points during treatment were selected for this study. Our results indicate the technical feasibility, accuracy and robustness of our UDS-based BCR-ABL KD mutation screening approach. UDS was found to provide a more accurate picture of BCR-ABL KD mutation status, both in terms of presence/absence of mutations and in terms of clonal complexity and showed that BCR-ABL KD mutations detected by SS are only the “tip of iceberg”. In addition UDS may reliably pick 2GTKIs-resistant mutations earlier than SS in a significantly greater proportion of patients.The enhanced sensitivity as well as the possibility to identify low level mutations point the UDS-based approach as an ideal alternative to conventional sequencing for BCR-ABL KD mutation screening in TKIs-resistant Ph+ leukemia patients

Ergodicity and regularity of invariant measure for branching Markov processes with immigration

In this thesis we consider systems of finitely many particles moving on paths given by a strong Markov process and undergoing branching and reproduction at random times. The branching rate of a particle, its number of offspring and their spatial distribution are allowed to depend on the particle's position and possibly on the configuration of coexisting particles. In addition there is immigration of new particles, with the rate of immigration and the distribution of immigrants possibly depending on the configuration of pre-existing particles as well. In the first two chapters of this work, we concentrate on the case that the joint motion of particles is governed by a diffusion with interacting components. The resulting process of particle configurations was studied by E. Löcherbach (2002, 2004) and is known as a branching diffusion with immigration (BDI). Chapter 1 contains a detailed introduction of the basic model assumptions, in particular an assumption of ergodicity which guarantees that the BDI process is positive Harris recurrent with finite invariant measure on the configuration space. This object and a closely related quantity, namely the invariant occupation measure on the single-particle space, are investigated in Chapter 2 where we study the problem of the existence of Lebesgue-densities with nice regularity properties. For example, it turns out that the existence of a continuous density for the invariant measure depends on the mechanism by which newborn particles are distributed in space, namely whether branching particles reproduce at their death position or their offspring are distributed according to an absolutely continuous transition kernel. In Chapter 3, we assume that the quantities defining the model depend only on the spatial position but not on the configuration of coexisting particles. In this framework (which was considered by Höpfner and Löcherbach (2005) in the special case that branching particles reproduce at their death position), the particle motions are independent, and we can allow for more general Markov processes instead of diffusions. The resulting configuration process is a branching Markov process in the sense introduced by Ikeda, Nagasawa and Watanabe (1968), complemented by an immigration mechanism. Generalizing results obtained by Höpfner and Löcherbach (2005), we give sufficient conditions for ergodicity in the sense of positive recurrence of the configuration process and finiteness of the invariant occupation measure in the case of general particle motions and offspring distributions.

Improvement of photon transport model by including coupled photon-electron transport and kernel refinement

The first part of this work deals with the inverse problem solution in the X-ray spectroscopy field. An original strategy to solve the inverse problem by using the maximum entropy principle is illustrated. It is built the code UMESTRAT, to apply the described strategy in a semiautomatic way. The application of UMESTRAT is shown with a computational example. The second part of this work deals with the improvement of the X-ray Boltzmann model, by studying two radiative interactions neglected in the current photon models. Firstly it is studied the characteristic line emission due to Compton ionization. It is developed a strategy that allows the evaluation of this contribution for the shells K, L and M of all elements with Z from 11 to 92. It is evaluated the single shell Compton/photoelectric ratio as a function of the primary photon energy. It is derived the energy values at which the Compton interaction becomes the prevailing process to produce ionization for the considered shells. Finally it is introduced a new kernel for the XRF from Compton ionization. In a second place it is characterized the bremsstrahlung radiative contribution due the secondary electrons. The bremsstrahlung radiation is characterized in terms of space, angle and energy, for all elements whit Z=1-92 in the energy range 1–150 keV by using the Monte Carlo code PENELOPE. It is demonstrated that bremsstrahlung radiative contribution can be well approximated with an isotropic point photon source. It is created a data library comprising the energetic distributions of bremsstrahlung. It is developed a new bremsstrahlung kernel which allows the introduction of this contribution in the modified Boltzmann equation. An example of application to the simulation of a synchrotron experiment is shown.

Quantum Einstein gravity - advancements of heat kernel-based renormalization group studies

The asymptotic safety scenario allows to define a consistent theory of quantized gravity within the framework of quantum field theory. The central conjecture of this scenario is the existence of a non-Gaussian fixed point of the theory's renormalization group flow, that allows to formulate renormalization conditions that render the theory fully predictive. Investigations of this possibility use an exact functional renormalization group equation as a primary non-perturbative tool. This equation implements Wilsonian renormalization group transformations, and is demonstrated to represent a reformulation of the functional integral approach to quantum field theory.rnAs its main result, this thesis develops an algebraic algorithm which allows to systematically construct the renormalization group flow of gauge theories as well as gravity in arbitrary expansion schemes. In particular, it uses off-diagonal heat kernel techniques to efficiently handle the non-minimal differential operators which appear due to gauge symmetries. The central virtue of the algorithm is that no additional simplifications need to be employed, opening the possibility for more systematic investigations of the emergence of non-perturbative phenomena. As a by-product several novel results on the heat kernel expansion of the Laplace operator acting on general gauge bundles are obtained.rnThe constructed algorithm is used to re-derive the renormalization group flow of gravity in the Einstein-Hilbert truncation, showing the manifest background independence of the results. The well-studied Einstein-Hilbert case is further advanced by taking the effect of a running ghost field renormalization on the gravitational coupling constants into account. A detailed numerical analysis reveals a further stabilization of the found non-Gaussian fixed point.rnFinally, the proposed algorithm is applied to the case of higher derivative gravity including all curvature squared interactions. This establishes an improvement of existing computations, taking the independent running of the Euler topological term into account. Known perturbative results are reproduced in this case from the renormalization group equation, identifying however a unique non-Gaussian fixed point.rn

Folic acid derivatives for PET imaging and therapy addressing folate receptor positive tumors

Folic acid, also known as vitamin B9, is the oxidized form of 5,6,7,8-tetrahydrofolate, which serves as methyl- or methylene donor (C1-building blocks) during DNA synthesis. Under physiological conditions the required amount of 5,6,7,8-tetrahydrofolate for survival of the cell is accomplished through the reduced folate carrier (RFC). In contrast, the supply of 5,6,7,8-tetrahydrofolate is insufficient under pathophysiological conditions of tumors due to an increased proliferation rate. Consequently, many tumor cells exhibit an (over)expression of the folate receptor. This phenomenon has been applied to diagnostics (PET, SPECT, MR) to image FR-positive tumors and on the other hand to treat malignancies related to a FR (over)expression. Based on this concept, a new 18F-labeled folate for PET imaging has been developed and was evaluated in vivo using tumor-bearing mice. The incorporation of oligoethylene spacers into the molecular structure led to a significant enhancement of the pharmacokinetics in comparison to previously developed 18F-folates. The liver uptake could be reduced by one sixth by remaining a tumor uptake of 3%ID/g leading to better contrast ratios. Encouraged by these results, a clickable 18F-labeled serine-based prosthetic group has been synthesized, again with the idea to improve the metabolic and pharmacokinetic profile of hydrophilic radiotracers. Therefore, an alkyne-carrying azido-functionalized serine derivative for coupling to biomolecules was synthesized and a chlorine leaving group for 18F-labeling, which could be accomplished using a microwave-assisted synthesis, a [K⊂2.2.2]+/carbonate system in DMSO. Radiochemical yields of 77±6% could be achieved.rnThe promising results obtained from the FR-targeting concept in the diagnostic field have been transferred to the boron neutron capture therapy. Therefore, a folate derivative was coupled to different boron clusters and cell uptake studies were conducted. The synthesis of the folate-boron clusters was straightforward. At first, a linker molecule based on maleic acid was synthesized, which was coupled to the boron cluster via Michael Addition of a thiol and alkene and subsequently coupled to the targeting moiety using CuAAC. The new conjugates of folate and boron clusters led to a significant increase of boron concentration in the cell of about 5-times compared to currently used and approved boron pharmaceuticals. rnMoreover, azido-folate derivatives were coupled to macromolecular carrier systems (pHPMA), which showed an enhanced and specific accumulation at target sites (up to 2.5-times) during in vivo experiments. A specific blockade could be observed up to 30% indicating an efficient targeting effect. A new kind of nanoparticles consisting of a PDLLA core and p((HPMA)-b-LMA)) as surfactants were developed and successfully radiolabeled via 18F-click chemistry in good RCYs of 8±3%rnThe nanoparticles were obtained via the miniemulsion technique in combination with solvent evaporation. The 18F-labeled nanoparticles were applied to in vivo testing using a mouse model. PET imaging showed a “mixed” biodistribution of low molecular weight as well as high molecular weight systems, indicating a partial loss of the 18F-labeled surfactant.rnIn conclusion, the presented work successfully utilized the FR-targeting concept in both, the diagnostic field (PET imaging) and for therapeutic approaches (BNCT, drug delivery systems). As a result, the high potential of FR-targeting in oncological applications has been shown and was confirmed by small animal PET imaging.rn

Studio di fattibilità per l'applicazione dei "positive displacement motors" in ambienti HT-HP

Questo studio concerne uno studio di fattibilità per l'applicazione dei "positive displacement motors" in ambienti ambienti fortemente critici, soggetti ad alta pressione e alta temperatura. Tali motori sono utilizzati nell'industria Oil & Gas per la perforazione di pozzi petroliferi. L’analisi è stata portata a termine attraverso definizione dell’intervallo di temperatura per cui le performance degli strumenti in commercio presenta il maggior numero di failures, compreso tra i 175°C e i 225°C , e per il quale si vuole riuscire a limitare i rischi connessi e le criticità associate, garantendo così il raggiungimento dei target con un maggior grado di affidabilità e disponibilità del PDM utilizzato. Analizzando le sollecitazioni agenti sul motore durante le fasi di utilizzo, è stato possibile rilevare le principali cause di rottura e malfunzionamento che, nella maggior parte dei casi, possono essere attribuite al rigonfiamento e alla degradazione del materiale elastomerico che costituisce lo statore della power section. Investigando in merito alle differenze e alle proprietà di resistenza di numerosi materiali elastomerici a diversi range di temperatura, sono stati evidenziati dei margini di ottimizzazione in particolare relativi alla potenziale riduzione e totale sostituzione della superficie elastomerica con materiale metallico. Ciò ha fatto si che fosse necessario un approfondimento sulle caratteristiche degli acciai e delle leghe metalliche, in termini di resistenza a corrosione, costo del materiale, resistenza meccanica e della capacità di mantenere elevate proprietà meccaniche con l’aumento della temperatura, al fine di individuare i migliori “candidati” per sostituire interamente il materiale elastomerico dello statore in materiale metallico e risolvere così il problema dell’applicazione dei PDM in ambienti HT-HP.

Transmission Error Detector per Wi-Fi su kernel Linux 4.0

Il lavoro descrive la progettazione, l'implementazione e il test sperimentale di un meccanismo, integrato nel kernel Linux 4.0, dedicato al riconoscimento delle perdite dei frame Wi-Fi.

Population doublings and percentage of S100-positive cells as predictors of in vitro chondrogenicity of expanded human articular chondrocytes

The aim of this study was to investigate the interconnection between the processes of proliferation, dedifferentiation, and intrinsic redifferentiation (chondrogenic) capacities of human articular chondrocyte (HAC), and to identify markers linking HAC dedifferentiation status with their chondrogenic potential. Cumulative population doublings (PD) of HAC expanded in monolayer culture were determined, and a threshold range of 3.57-4.19 PD was identified as indicative of HAC loss of intrinsic chondrogenic capacity in pellets incubated without added chondrogenic factors. While several specific gene and surface markers defined early HAC dedifferentiation process, no clear correlation with the loss of intrinsic chondrogenic potential could be established. CD90 expression during HAC monolayer culture revealed two subpopulations, with sorted CD90-negative cells showing lower proliferative capacity and higher chondrogenic potential compared to CD90-positive cells. Although these data further validated PD as critical for in vitro chondrogenesis, due to the early shift in expression, CD90 could not be considered for predicting chondrogenic potential of HAC expanded for several weeks. In contrast, an excellent mathematically modeled correlation was established between PD and the decline of HAC expressing the intracellular marker S100, providing a direct link between the number of cell divisions and dedifferentiation/loss of intrinsic chondrogenic capacity. Based on the dynamics of S100-positive HAC during expansion, we propose asymmetric cell division as a potential mechanism of HAC dedifferentiation, and S100 as a marker to assess chondrogenicity of HAC during expansion, of potential value for cell-based cartilage repair treatments.

In vitro and in vivo characterization of novel 18F-labeled bombesin analogues for targeting GRPR-positive tumors

The gastrin-releasing peptide receptor (GRPR) is overexpressed on a number of human tumors and has been targeted with radiolabeled bombesin analogues for the diagnosis and therapy of these cancers. Seven bombesin analogues containing various linkers and peptide sequences were designed, synthesized, radiolabeled with (18)F, and characterized in vitro and in vivo as potential PET imaging agents. Binding studies displayed nanomolar binding affinities toward human GRPR for all synthesized bombesin analogues. Two high-affinity peptide candidates 6b (K(i) = 0.7 nM) and 7b (K(i) = 0.1 nM) were chosen for further in vivo evaluation. Both tracers revealed specific uptake in GRPR-expressing PC-3 tumors and the pancreas. Compared to [(18)F]6b, compound [(18)F]7b was characterized by superior tumor uptake, higher specificity of tracer uptake, and more favorable tumor-to-nontarget ratios. In vivo PET imaging allowed for the visualization of PC-3 tumor in nude mice suggesting that [(18)F]7b is a promising PET tracer candidate for the diagnosis of GRPR-positive tumors in humans.

Development of a potent DOTA-conjugated bombesin antagonist for targeting GRPr-positive tumours

Radiolabelled somatostatin-based antagonists show a higher uptake in tumour-bearing mouse models than agonists of similar or even distinctly higher receptor affinity. Very similar results were obtained with another family of G protein-coupled receptor ligands, the bombesin family. We describe a new conjugate, RM2, with the chelator DOTA coupled to D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH(2) via the cationic spacer 4-amino-1-carboxymethyl-piperidine for labelling with radiometals such as (111)In and (68)Ga.