Preclinical neuroblastoma models for a pharmacological study of a new MYCN oncogene inhibitor

Background. Neuroblastoma is the most deadly solid tumor of childhood. In the 25% of cases it is associated with MYCN amplification (MA), resulting in the disregulation of several genes involved in cancer progression, chemotherapy resistance and poor prognosis causing the disregulation of several genes involved in cancer progression and chemotherapy resistance and resulting in a poor prognosis. Moreover, in this contest, therapy-related p53 mutations are frequently found in relapsed cases conferring an even stronger aggressiveness. For this reason, the actual therapy requires new antitumor molecules. Therefore, rapid, accurate, and reproducible preclinical models are needed to evaluate the evolution of the different subtypes and the efficacy of new pharmacological strategies. Procedures. We report the real-time tumorigenesis of MA Neuroblastoma mouse models: transgenic TH-MYCN mice and orthotopic xenograft models with either p53wt or p53mut, by non-invasive micro PET and bioluminescent imaging, respectively. Characterization of MYCN amplification and expression was performed on every collected sample. We tested the efficacy of a new MYCN inhibitor in vitro and in vivo. Results. MicroPET in TH-MYCN mice permitted the identification of Neuroblastoma at an early stage and offered a sensitive method to follow metabolic progression of tumors. The MA orthotopic model harboring multitherapy-related p53 mutations showed a shorter latency and progression and a stronger aggressiveness respect to the p53wt model. The presence of MA and overexpression was confirmed in each model and we saw a better survival in the TH-MYCN homozigous mice treated with the inhibitor. Conclusions. The mouse models obtained show characteristics of non-invasiveness, rapidity and sensitivity that make them suitable for the in vivo preclinical study of MA-NB. In particular, our firstly reported p53mut BLI xenograft orthotopic mouse model offers the possibility to evaluate the role of multitherapy-related p53 mutations and to validate new p53 independent therapies for this highly aggressive Neuroblastoma subtype. Moreover, we have shown potential clinical suitability of an antigene strategy through its cellular and molecular activity, ability to specifically inhibit transcription and in vivo efficacy with no evidence of toxicity.

L'altro eccezionalismo: William Appleman Williams tra storia, storiografia e impegno civile

La storiografia statunitense, a partire dagli anni Cinquanta, vide l’affermarsi di una nuova interpretazione della politica estera americana. Archiviata la storia diplomatica come storia dei trattati o storia delle interazioni delle élites dominanti, abbandonata una visione incentrata sull’equilibrio di potenza, il dibattito storiografico si arricchì della cosiddetta interpretazione «revisionista», antitetica rispetto a quella che, fino a quel momento, aveva predominato. Soggetto di analisi storica restava sempre lo Stato ma l’enfasi maggiore era posta sui fattori economici che ne influenzavano l’azione: si metteva in rilievo l’interazione tra l’interesse privato e il soggetto statale. Capofila di questa nuova scuola fu William Appleman Williams. Questa ricerca si pone l’obiettivo di delineare il contesto storiografico dal quale emersero gli studi di Williams e di cui egli ne roviesciò alcuni assunti fondamentali. Si intende tracciare il suo percorso intellettuale – storiografico e pubblico – al fine di restituire la complessità di un personaggio che divenne un vero e proprio «intellettuale pubblico». I quesiti, a cui questa ricerca vuole dar risposta riguardano l’evoluzione del percorso intellettuale di Williams tanto in ambito storiografico quanto, più in generale, in quello pubblico; il contributo alla ridefinizione dell’identità statunitense e del suo ruolo internazionale; il lascito della sua riflessione nella storiografia. Prendendo le mosse dall’idea di frontiera proposta da Turner, Williams sostenne che la fine dell’espansione territoriale «interna» aveva obbligato gli Stati Uniti a cercare nuovi mercati per il proprio surplus. Era stata tale necessità a catalizzare la Open Door Diplomacy, guidata da ragioni economiche, che presto identificarono l’interesse nazionale per trasformarsi in una vera e propria ideologia nel XX secolo.L’esito di tale politica estera fu la creazione di un impero non più territoriale ma frutto dell’espansione economica. E proprio questa riflessione sull’impero influenzò, negli anni Sessanta, la protesta studentesca che chiese un ripensamento del ruolo internazionale degli Stati Uniti.

Valutazione dell'efficacia di iniezioni peritendinee di acido ialuronico nel tendine rotuleo di ratto disallenato

Introduzione L’attività fisica moderata seguita da improvvisa interruzione può influenzare le caratteristiche biologiche del tendine. Lo scopo del lavoro è stato quello di valutare l’attività cellulare, le caratteristiche istologiche, istomorfometriche e microstrutturali del tendine patellare e della sua entesi in condizioni di non allenamento (sedentarietà), allenamento ed improvviso arresto dell’attività fisica. E’ stato ipotizzato che un’iniezione peri-tendinea di acido ialuronico nelle settimane successive all’improvviso arresto dell’attività fisica potesse mantenere l’integrità strutturale e biologica del tendine patellare. Materiali e Metodi 24 ratti Sprague Dawley maschi di 8 settimane sono stati suddivisi in tre gruppi, allenati per 10 settimane, fino a 60-80% VO2max. I ratti sono stati suddivisi in tre gruppi: Non Allenati (6), Allenati (6), Disallenati (12). A 6 dei 12 ratti del gruppo Detrained, è stata praticata un’infiltrazione peri-tendinea a nel tendine patellare destro di 300 μl di acido ialuronico, mentre nei rimanenti 6, è stata praticata l’infiltrazione con soluzione fisiologica. I tendini rotulei espiantati sono stati valutati con coltura cellulare, valutazione biologica molecolare, valutazioni morfologiche microstrutturali, proliferazione, conta ed attività cellulare. Risultati I risultati in vitro hanno evidenziato vitalità e conta cellulare simili fra i Gruppi Trained e Detrained-HA con un incremento significativo del metabolismo cellulare rispetto agli altri Gruppi. La cellularità ha mostrato valori maggiori nei Gruppi Non Allenati e Detrained-NaCl ove si è osservata una biosintesi del collagene III superiore ai Gruppi Trained e Detrained-HA. Contrariamente, la produzione di collagene I e II presentava valori maggiori nei Gruppi Trained e Detrained-HA suggerendo una superiore efficienza tessutale e metabolica di questi ultimi. Conclusioni Questi risultati confermano che l’allenamento ed il suo improvviso arresto hanno effetti sulla struttura tendinea patellare di ratto e che l’iniezione peritendinea di acido ialuronico nel periodo di inattività ha effetti significativi su metabolismo cellulare e sul tendine rispetto al trattamento con soluzione fisiologica.

L'amministrazione Johnson e le origini della distensione. 1964-1968

La tesi analizza una parte della politica estera dell’amministrazione Johnson, e più specificamente l’avvio del dialogo con l’Urss in materia di non proliferazione e controllo degli armamenti e la revisione della China policy, inquadrando entrambe nell’adattamento della cold war strategy all’evoluzione sistema internazionale, argomentando che la distensione intesa come rilassamento delle tensioni e ricerca di terreno comune per il dialogo, fosse perlomeno uno degli strumenti politici che l’amministrazione scelse di usare. Il primo capitolo analizza i cambiamenti che interessarono il Blocco sovietico e il movimento comunista internazionale tra la fine degli anni Cinquanta e l’inizio degli anni Sessanta, soprattutto la rottura dell’alleanza sino-sovietica, e l’impatto che essi ebbero sul sistema bipolare su cui si basava la Guerra Fredda. Il capitolo secondo affronta più specificamente l’evoluzione delle relazioni tra Stati Uniti e Unione Sovietica, il perseguimento di una politica di distensione, dopo la crisi dei missili cubani, e in che relazione si trovasse ciò con lo status della leadership sovietica a seguito dei cambiamenti che avevano avuto luogo. Soffermandosi sulla questione del controllo degli armamenti e sul percorso che portò alla firma del Trattato di Non-proliferazione, si analizza come la nuova rotta intrapresa col dialogo sulle questioni strategiche sia stato anche un cambiamento di rotta in generale nella concezione della Guerra Fredda e l’introduzione della distensione come strumento politico. Il terzo capitolo affronta la questione della modifica della politica verso Pechino e il processo tortuoso e contorto attraverso cui l’amministrazione Johnson giunse a distaccarsi dalla China policy seguita sino ad allora.

Studio ed ottimizzazione di una via di sintesi di idrossitirosolo a ridotto impatto ambientale

In questo progetto di tesi abbiamo lavorato all’ottimizzazione di un nuovo processo di sintesi di idrossitirosolo eco-compatibile e di possibile applicazione industriale. Il processo, che risulta una via molto competitiva per ottenere idrossitirosolo, si compone di due step: una prima sintesi di un intermedio acetalico e la successiva riduzione di questo al prodotto di interesse. In particolare il lavoro di tesi ha riguardato lo studio di catalizzatori e delle condizioni per le due reazioni al fine di aumentare le selettività dei prodotti target, analizzando la formazione dei sottoprodotti. Si è cercato, inoltre, di intraprendere una strada alternativa, provando la sintesi di un intermedio acetalico ciclico (possibilmente più stabile dell’altro intermedio acetalico) e, quindi, la sua riduzione, ritenendo di poter così evitare la formazione dei sottoprodotti. In this project we worked on the optimization of a new and industrially applicable process for the synthesis of hydroxytyrosol. Furthermore, we devised a process according to the principles of green chemistry. The process, that is a competitive way to obtain hydroxytyrosol, consists of two steps: first the synthesis of an acetalic precursor and then its reduction. Particularly the work was focused on the study of the catalysts and the conditions for the two reactions in order to increase the selectivity of target products, also analyzing the formation of the by-products. At last, we tried to take an alternative route with the synthesis of another acetalic precursor: a cyclic one. This because we thought that a cyclic acetal should be more stable than not cyclic one and maybe the reduction on this second precursor could not pass by the formation of the by-products already saw.

Surface-acoustic-wave counterflow micropumps for on-chip liquid motion control in two-dimensional microchannel arrays

Fully controlled liquid injection and flow in hydrophobic polydimethylsiloxane (PDMS) two-dimensional microchannel arrays based on on-chip integrated, low-voltage-driven micropumps are demonstrated. Our architecture exploits the surface-acoustic-wave (SAW) induced counterflow mechanism and the effect of nebulization anisotropies at crossing areas owing to lateral propagating SAWs. We show that by selectively exciting single or multiple SAWs, fluids can be drawn from their reservoirs and moved towards selected positions of a microchannel grid. Splitting of the main liquid flow is also demonstrated by exploiting multiple SAW beams. As a demonstrator, we show simultaneous filling of two orthogonal microchannels. The present results show that SAW micropumps are good candidates for truly integrated on-chip fluidic networks allowing liquid control in arbitrarily shaped two-dimensional microchannel arrays.

Accidental infection of veterinary personnel with Mycobacterium tuberculosis at necropsy: a case study

Mycobacterium tuberculosis is the main cause of human tuberculosis. Infection in companion animals is mainly acquired from close contact to a diseased human patient and hence rarely diagnosed in countries with low tuberculosis incidence rates. Therefore the general awareness of the disease might be low. Here we report the potential risk of infection for veterinary personnel with M. tuberculosis during the clinical and pathological examination of a dog with unexpected disseminated tuberculosis. The dog had presented with symptoms of a central nervous system disease; rapid deterioration prevented a complete clinical workup, however. Post-mortem examination revealed systemic mycobacteriosis, and M. tuberculosis was identified by PCR amplification of DNA extracts from paraffin-embedded tissue sections and spoligotyping. Contact investigations among the owners and veterinary personnel using an IFN-? release assay indicated that the index dog did not infect humans during its lifetime. Serological and IFN-? release assay results of one of two cats in direct contact with the index dog, however, suggested that transmission of M. tuberculosis might have occurred. Importantly, all three pathologists performing the necropsy on the dog tested positive. Accidental infection was most likely due to inhalation of M. tuberculosis containing aerosols created by using an electric saw to open the brain cavity. As a consequence routine necropsy procedures have been adapted and a disease surveillance program, including tuberculosis, has been initiated. Our results highlight the importance of disease awareness and timely diagnosis of zoonotic infectious agents in optimizing work safety for veterinary personnel.

Combined use of pulsed arterial spin-labeling and susceptibility-weighted imaging in stroke at 3T

Background and Purpose: In acute stroke it is no longer sufficient to detect simply ischemia, but also to try to evaluate reperfusion/recanalization status and predict eventual hemorrhagic transformation. Arterial spin labeling (ASL) perfusion may have advantages over contrast-enhanced perfusion-weighted imaging (cePWI), and susceptibility weighted imaging (SWI) has an intrinsic sensitivity to paramagnetic effects in addition to its ability to detect small areas of bleeding and hemorrhage. We want to determine here if their combined use in acute stroke and stroke follow-up at 3T could bring new insight into the diagnosis and prognosis of stroke leading to eventual improved patient management. Methods: We prospectively examined 41 patients admitted for acute stroke (NIHSS >1). Early imaging was performed between 1 h and 2 weeks. The imaging protocol included ASL, cePWI, SWI, T2 and diffusion tensor imaging (DTI), in addition to standard stroke protocol. Results: We saw four kinds of imaging patterns based on ASL and SWI: patients with either hypoperfusion and hyperperfusion on ASL with or without changes on SWI. Hyperperfusion was observed on ASL in 12/41 cases, with hyperperfusion status that was not evident on conventional cePWI images. Signs of hemorrhage or blood-brain barrier breakdown were visible on SWI in 15/41 cases, not always resulting in poor outcome (2/15 were scored mRS = 0–6). Early SWI changes, together with hypoperfusion, were associated with the occurrence of hemorrhage. Hyperperfusion on ASL, even when associated with hemorrhage detected on SWI, resulted in good outcome. Hyperperfusion predicted a better outcome than hypoperfusion (p = 0.0148). Conclusions: ASL is able to detect acute-stage hyperperfusion corresponding to luxury perfusion previously reported by PET studies. The presence of hyperperfusion on ASL-type perfusion seems indicative of reperfusion/collateral flow that is protective of hemorrhagic transformation and a marker of favorable tissue outcome. The combination of hypoperfusion and changes on SWI seems on the other hand to predict hemorrhage and/or poor outcome.

We Did It Our Way: Motivations, Satisfactions, and Accomplishments of Senior Academic Women

In a survey of senior academic women whose careers began around 1970, over half of the 98 respondents cited the desire to serve or make a difference and sought personal fulfillment in their work. Most saw men’s motivations as dissimilar, typically as more self-interested and competitive. Despite generally high satisfaction, dissatisfaction with time pressure/workload and with support was common. Satisfactions and accomplishments overlapped. Frequently mentioned were teaching, scholarship, and their discipline, especially by faculty, and programmatic accomplishments, especially by administrators. Many respondents mentioned helping women; many mentioned a collaborative, nurturing style as integral to their success and as different from their typical male colleagues. Context is provided by the metaphor of immigration (Martin, 1997, 2000), the concept of ambivalent sexism (Krefting, 2003; Glick & Fiske, 1999), and recent work on women and leadership by Eagly and colleagues (e.g., Eagly, 2005; Eagly & Carli, 2007).

Effect of unilateral temporal-lobe excision on perception and imagery of songs

Auditory imagery for songs was studied in two groups of patients with left or right temporal-lobe excision for control of epilepsy, and a group of matched normal control subjects. Two tasks were used. In the perceptual task, subjects saw the text of a familiar song and simultaneously heard it sung. On each trial they judged if the second of two capitalized lyrics was higher or lower in pitch than the first. The imagery task was identical in all respects except that no song was presented, so that subjects had to generate an auditory image of the song. The results indicated that all subjects found the imagery task more difficult than the perceptual task, but patients with right temporal-lobe damage performed significantly worse on both tasks than either patients with left temporal-lobe lesions or normal control subjects. These results support the idea that imagery arises from activation of a neural substrate shared with perceptual mechanisms, and provides evidence for a right temporal- lobe specialization for this type of auditory imaginal processing.

Mental scanning in auditory imagery for songs

Four experiments examined how people operate on memory representations of familiar songs. The tasks were similar to those used in studies of visual imagery. In one task, subjects saw a one word lyric from a song and then saw a second lyric; then they had to say if the second lyric was from the same song as the first. In a second task, subjects mentally compared pitches of notes corresponding to song lyrics. In both tasks, reaction time increased as a function of the distance in beats between the two lyrics in the actual song, and in some conditions reaction time increased with the starting beat of the earlier lyric. Imagery instructions modified the main results somewhat in the first task, but not in the second, much harder task. The results suggest that song representations have temporal-like characteristics. (PsycINFO Database Record (c) 2012 APA, all rights reserved)

The Effect on Financial Reporting Quality of an Exemption From the SEC Reporting Requirements for Foreign Private Issuers

We test for differences in financial reporting quality between companies that are required to file periodically with the SEC and those that are exempted from filing reports with the SEC under Rule 12g3-2(b). We examine three earnings quality measures: conservatism, abnormal accruals, and the predictability of earnings. Our results, for all three measures, show different financial reporting quality for companies that file with the SEC than for companies exempt from filing requirements. This paper provides empirical evidence of a link between filing with the SEC and financial reporting quality for foreign firms.

Hearing in the mind's ear: A PET investigation of musical imagery and perception

Neuropsychological studies have suggested that imagery processes may be mediated by neuronal mechanisms similar to those used in perception. To test this hypothesis, and to explore the neural basis for song imagery, 12 normal subjects were scanned using the water bolus method to measure cerebral blood flow (CBF) during the performance of three tasks. In the control condition subjects saw pairs of words on each trial and judged which word was longer. In the perceptual condition subjects also viewed pairs of words, this time drawn from a familiar song; simultaneously they heard the corresponding song, and their task was to judge the change in pitch of the two cued words within the song. In the imagery condition, subjects performed precisely the same judgment as in the perceptual condition, but with no auditory input. Thus, to perform the imagery task correctly an internal auditory representation must be accessed. Paired-image subtraction of the resulting pattern of CBF, together with matched MRI for anatomical localization, revealed that both perceptual and imagery. tasks produced similar patterns of CBF changes, as compared to the control condition, in keeping with the hypothesis. More specifically, both perceiving and imagining songs are associated with bilateral neuronal activity in the secondary auditory cortices, suggesting that processes within these regions underlie the phenomenological impression of imagined sounds. Other CBF foci elicited in both tasks include areas in the left and right frontal lobes and in the left parietal lobe, as well as the supplementary motor area. This latter region implicates covert vocalization as one component of musical imagery. Direct comparison of imagery and perceptual tasks revealed CBF increases in the inferior frontal polar cortex and right thalamus. We speculate that this network of regions may be specifically associated with retrieval and/or generation of auditory information from memory.

An Ethical History of Photography in Combat and of Combat Photography in the United States during World War II

With the United States‘ entry into the Second World War, the word ?censorship? was seen largely as antithetical to, rather than a necessary counterpart to, victory among Americans. People did not want to be censored in their writing, photographs or speech,but it proved to be necessary even before the war began, in order to protect government secrets and the people on the home-front from scenes that were too disturbing. Even before the war had officially begun, there were problems with censorship among journalists and newspapers. The initial response of outrage in reference to censorship in the United States was common among journalists, newspapers, magazines, and radio news; nevertheless, there was a necessity for censorship among Americans, on the home frontand the front lines, and it would be tolerated throughout the war to ensure that enemies of America did not gain access to information that would assist in a defeat of the United States in the Second World War. The research I have conducted has dealt with the censorship of combat photography during World War II, in conjunction with the ethics that were in play at the time that affected the censors. Through exploring the work of three combat photographers — Tony Vaccaro, James R. Stephens and Charles E. Sumners — I wasable to effectively construct an explanatory ethical history of these three men. Research on the censorship and effects it had on the United States brought me to three distinctareas of censorship and ethics that would be explored: (1) the restrictions and limitations enforced by the Office of Censorship, (2) a general overview of war and photography as it influenced the soldiers and their families on the home-front, (3) and the combat photographers and personal and military censorship that influenced their work. Although their work was censored both by the military and the government, these men saw the war in a different light that remained with them long after the battles and war had ceased.Using the narratives of Tony Vaccaro, Charles E. Sumners and James R. Stephens as means for more in depth research, this thesis strives to create lenses through which to view the history and ethics of censorship that shaped combat photography during the Second World War and the images to which we refer as representative of that war today.

Chronicle of a death foretold: Plasmodium liver stage parasites decide on the fate of the host cell

Protozoan parasites of the genus Plasmodium are the causative agents of malaria. Despite more than 100 years of research, the complex life cycle of the parasite still bears many surprises and it is safe to say that understanding the biology of the pathogen will keep scientists busy for many years to come. Malaria research has mainly concentrated on the pathological blood stage of Plasmodium parasites, leaving us with many questions concerning parasite development within the mosquito and during the exo-erythrocytic stage in the vertebrate host. After the discovery of the Plasmodium liver stage in the middle of the last century, it remained understudied for many years but the realization that it represents a promising target for vaccination approaches has brought it back into focus. The last decade saw many new and exciting discoveries concerning the exo-erythrocytic stage and in this review we will discuss the highlights of the latest developments in the field.