Eosinophils may predict occult lymph node metastasis in early oral cancer

Objective The aim of this study was to investigate whether tumor-associated tissue eosinophilia (TATE) in early oral squamous cell carcinoma (OSCC) would aid in predicting occult lymph node metastasis. Patients and methods Seventy-one patients undergoing elective neck dissection for T1 and T2 OSCC were evaluated for clinical features, prognosis, and TATE. The degree of TATE in OSCC was statistically analyzed in relation to the clinicopathological features, tumor invasion, occult lymph node metastasis, and survival using chi (2) test and Kaplan-Meier method. Results Statistical analysis revealed that intense TATE was a significant feature (p = 0.004) to predict occult lymph node metastasis in patients with early OSCC. All regional recurrences of the OSCC occurred in patients showing intense TATE. Conclusions These results suggest that intense TATE can be clinically used as a predictive factor for occult lymph node metastasis. Clinical relevance The presence of intense TATE is an adjunctive histopathological marker to reinforce the indication of elective neck dissection of the patients with early OSCC.

Java Cryptographic Library for Smartphones

A JME-compliant cryptographic library for mobile application development is introduced in this paper. The library allows cryptographic protocols implementation over elliptic curves with different security levels and offers symmetric and asymmetric bilinear pairings operations, as Tate, Weil, and Ate pairings.

Percorsi di gender performance: fotografia tra arte e moda dagli anni Novanta ad oggi

My project explores and compares different forms of gender performance in contemporary art and visual culture according to a perspective centered on photography. Thanks to its attesting power this medium can work as a ready-made. In fact during the 20th century it played a key role in the cultural emancipation of the body which (using a Michel Foucault’s expression) has now become «the zero point of the world». Through performance the body proves to be a living material of expression and communication while photography ensures the recording of any ephemeral event that happens in time and space. My questioning approach considers the gender constructed imagery from the 1990s to the present in order to investigate how photography’s strong aura of realism promotes and allows fantasies of transformation. The contemporary fascination with gender (especially for art and fashion) represents a crucial issue in the global context of postmodernity and is manifested in a variety of visual media, from photography to video and film. Moreover the internet along with its digital transmission of images has deeply affected our world (from culture to everyday life) leading to a postmodern preference for performativity over the more traditional and linear forms of narrativity. As a consequence individual borders get redefined by the skin itself which (dissected through instant vision) turns into a ductile material of mutation and hybridation in the service of identity. My critical assumptions are taken from the most relevant changes occurred in philosophy during the last two decades as a result of the contributions by Jacques Lacan, Michel Foucault, Jacques Derrida, Gilles Deleuze who developed a cross-disciplinary and comparative approach to interpret the crisis of modernity. They have profoundly influenced feminist studies so that the category of gender has been reassessed in contrast with sex (as a biological connotation) and in relation to history, culture, society. The ideal starting point of my research is the year 1990. I chose it as the approximate historical moment when the intersection of race, class and gender were placed at the forefront of international artistic production concerned with identity, diversity and globalization. Such issues had been explored throughout the 1970s but it was only from the mid-1980s onward that they began to be articulated more consistently. Published in 1990, the book "Gender trouble: feminism and the subversion of identity" by Judith Butler marked an important breakthrough by linking gender to performance as well as investigating the intricate connections between theory and practice, embodiment and representation. It inspired subsequent research in a variety of disciplines, art history included. In the same year Teresa de Lauretis launched the definition of queer theory to challenge the academic perspective in gay and lesbian studies. In the meantime the rise of Third Wave Feminism in the US introduced a racially and sexually inclusive vision over the global situation in order to reflect on subjectivity, new technologies and popular culture in connection with gender representation. These conceptual tools have enabled prolific readings of contemporary cultural production whether fine arts or mass media. After discussing the appropriate framework of my project and taking into account the postmodern globalization of the visual, I have turned to photography to map gender representation both in art and in fashion. Therefore I have been creating an archive of images around specific topics. I decided to include fashion photography because in the 1990s this genre moved away from the paradigm of an idealized and classical beauty toward a new vernacular allied with lifestyles, art practices, pop and youth culture; as one might expect the dominant narrative modes in fashion photography are now mainly influenced by cinema and snapshot. These strategies originate story lines and interrupted narratives using models’ performance to convey a particular imagery where identity issues emerge as an essential part of fashion spectacle. Focusing on the intersections of gender identities with socially and culturally produced identities, my approach intends to underline how the fashion world has turned to current trends in art photography and in some case turned to the artists themselves. The growing fluidity of the categories that distinguish art from fashion photography represents a particularly fruitful moment of visual exchange. Varying over time the dialogue between these two fields has always been vital; nowadays it can be studied as a result of this close relationship between contemporary art world and consumer culture. Due to the saturation of postmodern imagery the feedback between art and fashion has become much more immediate and then increasingly significant for anyone who wants to investigate the construction of gender identity through performance. In addition to that a lot of magazines founded in the 1990s bridged the worlds of art and fashion because some of their designers and even editors were art-school graduates encouraging innovation. The inclusion of art within such magazines aimed at validating them as a form of art in themselves supporting a dynamic intersection for music, fashion, design and youth culture: an intersection that also contributed to create and spread different gender stereotypes. This general interest in fashion produced many exhibitions of and about fashion itself at major international venues such as the Victoria and Albert Museum in London, the Metropolitan Museum of Art and the Solomon R. Guggenheim Museum in New York. Since then this celebrated success of fashion has been regarded as a typical element of postmodern culture. Owing to that I have also based my analysis on some important exhibitions dealing with gender performance like "Féminin-Masculin" at the Centre Pompidou of Paris (1995), "Rrose is a Rrose is a Rrose. Gender performance in photography" at the Solomon R. Guggenheim Museum of New York (1997), "Global Feminisms" at the Brooklyn Museum (2007), "Female Trouble" at the Pinakothek der Moderne in München together with the workshops dedicated to "Performance: gender and identity" in June 2005 at the Tate Modern of London. Since 2003 in Italy we have had Gender Bender - an international festival held annually in Bologna - to explore the gender imagery stemming from contemporary culture. In few days this festival offers a series of events ranging from visual arts, performance, cinema, literature to conferences and music. Being aware that any method of research is neither race nor gender neutral I have traced these critical paths to question gender identity in a multicultural perspective taking account of the political implications too. In fact, if visibility may be equated with exposure, we can also read these images as points of intersection of visibility with social power. Since gender assignations rely so heavily on the visual, the postmodern dismantling of gender certainty through performance has wide-ranging effects that need to be analyzed. In some sense this practice can even contest the dominance of visual within postmodernism. My visual map in contemporary art and fashion photography includes artists like Nan Goldin, Cindy Sherman, Hellen van Meene, Rineke Dijkstra, Ed Templeton, Ryan McGinley, Anne Daems, Miwa Yanagi, Tracey Moffat, Catherine Opie, Tomoko Sawada, Vanessa Beecroft, Yasumasa Morimura, Collier Schorr among others.

A dictionary of modular threefolds

The thesis deals with the modularity conjecture for three-dimensional Calabi-Yau varieties. This is a generalization of the work of A. Wiles and others on modularity of elliptic curves. Modularity connects the number of points on varieties with coefficients of certain modular forms. In chapter 1 we collect the basics on arithmetic on Calabi-Yau manifolds, including general modularity results and strategies for modularity proofs. In chapters 2, 3, 4 and 5 we investigate examples of modular Calabi-Yau threefolds, including all examples occurring in the literature and many new ones. Double octics, i.e. Double coverings of projective 3-space branched along an octic surface, are studied in detail. In chapter 6 we deal with examples connected with the same modular forms. According to the Tate conjecture there should be correspondences between them. Many correspondences are constructed explicitly. We finish by formulating conjectures on the occurring newforms, especially their levels. In the appendices we compile tables of coefficients of weight 2 and weight 4 newforms and many examples of double octics.

Rigenerazione Riciclo. Riqualificazione dell'ex-cartiera Burgo a Lama di Reno

Negli ultimi cinquant’anni, in particolare dal 1956 al 2010, grazie a miglioramenti di tipo economico e sociale, il territorio urbanizzato italiano è aumentato di circa 600 mila ettari, cioè una superficie artificializzata pari quasi a quella dell’intera regione Friuli Venezia Giulia, con un aumento del 500% rispetto agli anni precedenti. Quando si parla di superfici “artificializzate” ci si riferisce a tutte quelle parti di suolo che perdono la propria caratteristica pedologica per essere asportate e divenire urbanizzate, cioè sostituite da edifici, spazi di pertinenza, parcheggi, aree di stoccaggio, strade e spazi accessori. La costruzione di intere periferie e nuclei industriali dagli anni ’50 in poi, è stata facilitata da un basso costo di mano d’opera e da una supposta presenza massiccia di risorse disponibili. Nonché tramite adeguati piani urbanistico-territoriali che hanno accompagnato ed assecondato questo orientamento. All’oggi, è evidente come questa crescita tumultuosa del tessuto urbanizzato non sia più sostenibile. Il consumo del suolo provoca infatti vari problemi, in particolare di natura ecologica e ambientale, ma anche sanitaria, economica e urbana. Nel dettaglio, secondo il dossier Terra Rubata1, lanciato all’inizio del 2012 dal FAI e WWF gli aspetti che vengono coinvolti direttamente ed indirettamente dalla conversione urbana dei suoli sono complessivamente i seguenti. Appartenenti alla sfera economico-energetica ritroviamo diseconomie dei trasporti, sperperi energetici, riduzione delle produzioni agricole. Per quanto riguarda la sfera idro-geo-pedologica vi è la possibilità di destabilizzazione geologica, irreversibilità d’uso dei suoli, alterazione degli assetti idraulici ipo ed epigei. Anche la sfera fisico-climatica non è immune a questi cambiamenti, ma può invece essere soggetta ad accentuazione della riflessione termica e dei cambiamenti 1 Dossier TERRA RUBATA Viaggio nell’Italia che scompare. Le analisi e le proposte di FAI e WWF sul consumo del suolo, 31 gennaio 2012 2 climatici, ad una riduzione della capacità di assorbimento delle emissioni, ad effetti sul sequestro del carbonio e sulla propagazione spaziale dei disturbi fisico-chimici. In ultimo, ma non per importanza, riguardo la sfera eco-biologica, ritroviamo problemi inerenti l’erosione fisica e la distruzione degli habitat, la frammentazione eco sistemica, la distrofia dei processi eco-biologici, la penalizzazione dei servizi ecosistemici dell’ambiente e la riduzione della «resilienza» ecologica complessiva. Nonostante ci sia ancora la speranza che questo orientamento possa “invertire la rotta”, non è però possibile attendere ancora. È necessario agire nell’immediato, anche adottando adeguati provvedimenti normativi e strumenti pianificatori ed operativi nell’azione delle pubbliche amministrazioni analogamente a quanto, come evidenziato nel dossier sopracitato2, hanno fatto altri paesi europei. In un recente documento della Commissione Europea3 viene posto l’anno 2050 come termine entro il quale “non edificare più su nuove aree”. Per fare ciò la Commissione indica che nel periodo 2000-2020 occorre che l’occupazione di nuove terre sia ridotta in media di 800 km2 totali. È indispensabile sottolineare però, che nonostante la stabilità demografica della situazione attuale, se non la sua leggera decrescenza, e la società attuale ha necessità di spazi di azione maggiori che non nel passato e possiede una capacità di spostamento a velocità infinitamente superiori. Ciò comporta una variazione enorme nel rapporto tra le superfici edificate (quelle cioè effettivamente coperte dal sedime degli edifici) e le superfici urbanizzate (le pertinenze pubbliche e private e la viabilità). Nell’insediamento storico, dove uno degli obiettivi progettuali era quello di minimizzare i tempi di accesso tra abitazioni e servizi urbani, questo rapporto varia tra il 70 e il 90%, mentre nell’insediamento urbano moderno è quasi sempre inferiore al 40-50% fino a valori anche inferiori al 20% in taluni agglomerati commerciali, 2 Dossier TERRA RUBATA Viaggio nell’Italia che scompare. Le analisi e le proposte di FAI e WWF sul consumo del suolo, 31 gennaio 2012 3 Tabella di marcia verso un’Europa efficiente nell’impiego delle risorse, settembre 2011 3 industriali o direzionali nei quali il movimento dei mezzi o le sistemazioni paesaggistiche di rappresentanza richiedono maggiori disponibilità di spazi. Come conciliare quindi la necessità di nuovi spazi e la necessità di non edificare più su nuove aree? Dai dati Istat il 3% del territorio Italiano risulta occupato da aree dismesse. Aree che presentano attualmente problemi di inquinamento e mancata manutenzione ma che potrebbero essere la giusta risorsa per rispondere alle necessità sopracitate. Enormi spazi, costruiti nella precedente epoca industriale, che possono essere restituiti al pubblico sotto forma di luoghi destinati alla fruizione collettiva come musei, biblioteche, centri per i giovani, i bambini, gli artisti. Allo stesso tempo questi spazi possono essere, completamente o in parte, rinaturalizzati e trasformati in parchi e giardini. La tematica, cosiddetta dell’archeologia industriale non si presenta come una novità, ma come una disciplina, definita per la sua prima volta in Inghilterra nel 1955, che vanta di esempi recuperati in tutta Europa. Dagli anni ’60 l’opinione pubblica cominciò ad opporsi alla demolizione di alcune strutture industriali, come ad esempio la Stazione Euston a Londra, riconoscendone l’importanza storica, culturale ed artistica. Questo paesaggio industriale, diviene oggi testimonianza storica di un’epoca e quindi per questo necessita rispetto e attenzione. Ciò non deve essere estremizzato fino alla esaltazione di questi immensi edifici come rovine intoccabili, ma deve invitare l’opinione pubblica e i progettisti a prendersene cura, a reintegrarli nel tessuto urbano donando loro nuove funzioni compatibili con la struttura esistente che andrà quindi lasciata il più possibile inalterata per mantenere una leggibilità storica del manufatto. L’Europa presenta vari casi di recupero industriale, alcuni dei quali presentano veri e propri esempi da seguire e che meritano quindi una citazione ed un approfondimento all’interno di questo saggio. Tra questi l’ex stabilimento FIAT del Lingotto a Torino, 4 la celebre Tate Modern di Londra, il Leipzig Baumwollspinnerei, il Matadero Madrid e la Cable Factory a Elsinky. Questi edifici abbandonati risultano all’oggi sparsi in maniera disomogenea anche in tutta Italia, con una maggiore concentrazione lungo le linee ferroviarie e nei pressi delle città storicamente industrializzate. Essi, prima di un eventuale recupero, risultano come rifiuti abbandonati. Ma come sopradetto questi rifiuti urbani possono essere recuperati, reinventati, riabilitati, ridotati di dignità, funzione, utilità. Se questi rifiuti urbani possono essere una nuova risorsa per le città italiane come per quelle Europee, perché non provare a trasformare in risorse anche i rifiuti di altra natura? Il problema dei rifiuti, più comunemente chiamati come tali, ha toccato direttamente l’opinione pubblica italiana nel 2008 con il caso drammatico della regione Campania e in particolare dalla condizione inumana della città di Napoli. Il rifiuto è un problema dovuto alla società cosiddetta dell’usa e getta, a quella popolazione che contrariamente al mondo rurale non recupera gli scarti impiegandoli in successive lavorazioni e produzioni, ma li getta, spesso in maniera indifferenziata senza preoccuparsi di ciò che ne sarà. Nel passato, fino agli anni ’60, il problema dello smaltimento dei rifiuti era molto limitato in quanto in genere gli scatti del processo industriale, lavorativo, costruttivo venivano reimpiegati come base per una nuova produzione; il materiale da riciclare veniva di solito recuperato. Il problema degli scarti è quindi un problema moderno e proprio della città, la quale deve quindi farsene carico e trasformarlo in un valore, in una risorsa. Se nell’equilibrio ecologico la stabilità è rappresentata dalla presenza di cicli chiusi è necessario trovare una chiusura anche al cerchio del consumo; esso non può terminare in un oggetto, il rifiuto, ma deve riuscire a reinterpretarlo, a trovare per 5 esso una nuova funzione che vada ad attivare un secondo ciclo di vita, che possa a sua volta generare un terzo ciclo, poi un quarto e cosi via. Una delle vie possibili, è quella di riciclare il più possibile i nostri scarti e quindi di disassemblarli per riportare alla luce le materie prime che stavano alla base della loro formazione. Uno degli ultimi nati, su cui è possibile agire percorrendo questa strada è il rifiuto RAEE4. Esso ha subito un incremento del 30,7% negli ultimi 5 anni arrivando ad un consumo di circa 19 kilogrammi di rifiuti all’anno per abitante di cui solo 4 kilogrammi sono attualmente smaltiti nelle aziende specializzate sul territorio. Dismeco s.r.l. è una delle aziende sopracitate specializzata nello smaltimento e trattamento di materiale elettrico ed elettronico, nata a Bologna nel 1977 come attività a gestione familiare e che si è poi sviluppata divenendo la prima in Italia nella gestione specifica dei RAEE, con un importante incremento dei rifiuti dismessi in seguito all'apertura del nuovo stabilimento ubicato nel Comune di Marzabotto, in particolare nel lotto ospitante l’ex-cartiera Rizzoli-Burgo. L’azienda si trova quindi ad operare in un contesto storicamente industriale, in particolare negli edifici in cui veniva stoccato il caolino e in cui veniva riciclata la carta stampata. Se la vocazione al riciclo è storica dell’area, grazie all’iniziativa dell’imprenditore Claudio Tedeschi, sembra ora possibile la creazione di un vero e proprio polo destinato alla cultura del riciclo, all’insegnamento e all’arte riguardanti tale tematica. L’intenzione che verrà ampliamente sviluppata in questo saggio e negli elaborati grafici ad esso allegati è quella di recuperare alcuni degli edifici della vecchia cartiera e donane loro nuove funzioni pubbliche al fine di rigenerare l’area. 4 RAEE: Rifiuti di Apparecchiature Elettriche ed Elettroniche, in lingua inglese: Waste of electric and electronic equipment (WEEE) o e-waste). Essi sono rifiuti di tipo particolare che consistono in qualunque apparecchiatura elettrica o elettronica di cui il possessore intenda disfarsi in quanto guasta, inutilizzata, o obsoleta e dunque destinata all'abbandono. 6 Il progetto, nello specifico, si occuperà di riqualificare energeticamente il vecchio laboratorio in cui veniva riciclata la carta stampata e di dotarlo di aree per esposizioni temporanee e permanenti, sale conferenze, aule didattiche, zone di ristoro e di ricerca. Per quanto riguarda invece l’area del lotto attualmente artificializzata, ma non edificata, vi è l’intenzione di riportarla a zona verde attraverso la creazione di un “Parco del Riciclo”. Questa zona verde restituirà al lotto un collegamento visivo con le immediate colline retrostanti, accoglierà i visitatori e li ospiterà nelle stagioni più calde per momenti di relax ma al tempo stesso di apprendimento. Questo perché come già detto i rifiuti sono risorse e quando non possono essere reimpiegati come tali vi è l’arte che se ne occupa. Artisti del calibro di Picasso, Marinetti, Rotella, Nevelson e molti altri, hanno sempre operato con i rifiuti e da essi sono scaturite opere d’arte. A scopo di denuncia di una società consumistica, semplicemente come oggetti del quotidiano, o come metafora della vita dell’uomo, questi oggetti, questi scarti sono divenuti materia sotto le mani esperte dell’artista. Se nel 1998 Lea Vergine dedicò proprio alla Trash Art una mostra a Rovereto5 significa che il rifiuto non è scarto invisibile, ma oggetto facente parte della nostra epoca, di una generazione di consumatori frugali, veloci, e indifferenti. La generazione dell’”usa e getta” che diviene invece ora, per necessita o per scelta generazione del recupero, del riciclo, della rigenerazione. L’ipotesi di progetto nella ex-cartiera Burgo a Lama di Reno è proprio questo, un esempio di come oggi il progettista possa guardare con occhi diversi queste strutture dismesse, questi rifiuti, gli scarti della passata società e non nasconderli, ma reinventarli, riutilizzarli, rigenerarli per soddisfare le necessità della nuova generazione. Della generazione riciclo.

Pseudodifferentialoperatoren mit nichtregulären banachraumwertigen Symbolen

Untersucht werden in der vorliegenden Arbeit Versionen des Satzes von Michlin f¨r Pseudodiffe- u rentialoperatoren mit nicht-regul¨ren banachraumwertigen Symbolen und deren Anwendungen a auf die Erzeugung analytischer Halbgruppen von solchen Operatoren auf vektorwertigen Sobo- levr¨umen Wp (Rn

Absence of somatostatin SST(2) receptor internalization in vivo after intravenous SOM230 application in the AR42J animal tumor model

Among clinically relevant somatostatin functions, agonist-induced somatostatin receptor subtype 2 (sst(2)) internalization is a potent mechanism for tumor targeting with sst(2) affine radioligands such as octreotide. Since, as opposed to octreotide, the second generation multi-somatostatin analog SOM230 (pasireotide) exhibits strong functional selectivity, it appeared of interest to evaluate its ability to affect sst(2) internalization in vivo. Rats bearing AR42J tumors endogenously expressing somatostatin sst(2) receptors were injected intravenously with SOM230 or with the [Tyr(3), Thr(8)]-octreotide (TATE) analog; they were euthanized at various time points; tumors and pancreas were analyzed by immunohistochemistry for the cellular localization of somatostatin sst(2) receptors. SOM230-induced sst(2) internalization was also evaluated in vitro by immunofluorescence microscopy in AR42J cells. At difference to the efficient in vivo sst(2) internalization triggered by intravenous [Tyr(3), Thr(8)]-octreotide, intravenous SOM230 did not elicit sst(2) internalization: immunohistochemically stained sst(2) in AR42J tumor cells and pancreatic cells were detectable at the cell surface at 2.5min, 10min, 1h, 6h, or 24h after SOM230 injection while sst(2) were found intracellularly after [Tyr(3), Thr(8)]-octreotide injection. The inability of stimulating sst(2) internalization by SOM230 was confirmed in vitro in AR42J cells by immunofluorescence microscopy. Furthermore, SOM230 was unable to antagonize agonist-induced sst(2) internalization, neither in vivo, nor in vitro. Therefore, SOM230 does not induce sst(2) internalization in vivo or in vitro in AR42J cells and pancreas, at difference to octreotide derivatives with comparable sst(2) binding affinities. These characteristics may point towards different tumor targeting but also to different desensitization properties of clinically applied SOM230.

Biodistribution of two octreotate analogs radiolabeled with indium and yttrium in rats

In this study, two octreotate derivatives N-[4-carboxy-4-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]butanoyl]-Tyr(3)-octreotate (DOTAGA-tate) and N-[[4,10-bis(carboxymethyl)-7-(1(1,3-dicarboxypropyl))-1,4,7,10-tetraaza-cyclododec-1-yl]acetyl]-Tyr(3)-octreotate (DOTA-t-GA-tate) were radio-labeled with (111)In or (88)Y and their biodistribution profiles together with their elimination characteristics in rats were compared.

Internalization of sst2, sst3, and sst5 receptors: effects of somatostatin agonists and antagonists

The uptake of radiolabeled somatostatin analogs by tumor cells through receptor-mediated internalization is a critical process for the in vivo targeting of tumoral somatostatin receptors. In the present study, the somatostatin receptor internalization induced by a variety of somatostatin analogs was measured with new immunocytochemical methods that allow characterization of trafficking of the somatostatin receptor subtype 2 (sst2), somatostatin receptor subtype 3 (sst3), and somatostatin receptor subtype 5 (sst5) in vitro at the protein level. METHODS: Human embryonic kidney 293 (HEK293) cells expressing the sst2, sst3, or the sst5 were used in a morphologic immunocytochemical internalization assay using specific sst2, sst3 and sst5 antibodies to qualitatively and quantitatively determine the capability of somatostatin agonists or antagonists to induce somatostatin receptor internalization. In addition, the internalization properties of a selection of these agonists have been compared and quantified in sst2-expressing CHO-K1 cells using an ELISA. RESULTS: Agonists with a high sst2-binding affinity were able to induce sst2 internalization in the HEK293 and CHO-K1 cell lines. New sst2 agonists, such as Y-DOTA-TATE, Y-DOTA-NOC, Lu-DOTA-BOC-ATE (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; TATE is [Tyr3, Thr8]-octreotide; NOC is [1-NaI3]-octreotide; and BOC-ATE is [BzThi3, Thr8]-octreotide), iodinated sugar-containing octreotide analogs, or BIM-23244 were considerably more potent in internalizing sst2 than was DTPA-octreotide (where DTPA is diethylenetriaminepentaacetic acid). Similarly, compounds with high sst3 affinity such as KE108 were able to induce sst3 internalization. In sst2- or sst3-expressing cell lines, agonist-induced receptor internalization was efficiently abolished by sst2- or sst3-selective antagonists, respectively. Antagonists alone had no effect on sst2 or sst3 internalization. We also showed that somatostatin-28 and somatostatin-14 can induce sst5 internalization. Unexpectedly, however, potent sst5 agonists such as KE108, BIM-23244, and L-817,818 were not able to induce sst5 internalization under the same conditions. CONCLUSION: Using sensitive and reproducible immunocytochemical methods, the ability of various somatostatin analogs to induce sst2, sst3, and sst5 internalization has been qualitatively and quantitatively determined. Whereas all agonists triggered sst2 and sst3 internalization, sst5 internalization was induced by natural somatostatin peptides but not by synthetic high-affinity sst5 agonists. Such assays will be of considerable help for the future characterization of ligands foreseen for nuclear medicine applications.

Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors

Targeting neuroendocrine tumors expressing somatostatin receptor subtypes (sst) with radiolabeled somatostatin agonists is an established diagnostic and therapeutic approach in oncology. While agonists readily internalize into tumor cells, permitting accumulation of radioactivity, radiolabeled antagonists do not, and they have not been considered for tumor targeting. The macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was coupled to two potent somatostatin receptor-selective peptide antagonists [NH(2)-CO-c(DCys-Phe-Tyr-DAgl(8)(Me,2-naphthoyl)-Lys-Thr-Phe-Cys)-OH (sst(3)-ODN-8) and a sst(2)-selective antagonist (sst(2)-ANT)], for labeling with (111/nat)In. (111/nat)In-DOTA-sst(3)-ODN-8 and (111/nat)In-DOTA-[4-NO(2)-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH(2)] ((111/nat)In-DOTA-sst(2)-ANT) showed high sst(3)- and sst(2)-binding affinity, respectively. They did not trigger sst(3) or sst(2) internalization but prevented agonist-stimulated internalization. (111)In-DOTA-sst(3)-ODN-8 and (111)In-DOTA-sst(2)-ANT were injected intravenously into mice bearing sst(3)- and sst(2)-expressing tumors, and their biodistribution was monitored. In the sst(3)-expressing tumors, strong accumulation of (111)In-DOTA-sst(3)-ODN-8 was observed, peaking at 1 h with 60% injected radioactivity per gram of tissue and remaining at a high level for >72 h. Excess of sst(3)-ODN-8 blocked uptake. As a control, the potent agonist (111)In-DOTA-[1-Nal(3)]-octreotide, with strong sst(3)-binding and internalization properties showed a much lower and shorter-lasting uptake in sst(3)-expressing tumors. Similarly, (111)In-DOTA-sst(2)-ANT was injected into mice bearing sst(2)-expressing tumors. Tumor uptake was considerably higher than with the highly potent sst(2)-selective agonist (111)In-diethylenetriaminepentaacetic acid-[Tyr(3),Thr(8)]-octreotide ((111)In-DTPA-TATE). Scatchard plots showed that antagonists labeled many more sites than agonists. Somatostatin antagonist radiotracers therefore are preferable over agonists for the in vivo targeting of sst(3)- or sst(2)-expressing tumors. Antagonist radioligands for other peptide receptors need to be evaluated in nuclear oncology as a result of this paradigm shift.

closo-borane conjugated regulatory peptides retain high biological affinity: synthesis of closo-borane conjugated Tyr(3)-octreotate derivatives for BNCT

Despite the improvements in cancer therapy during the past years, high-grade gliomas and many other types of cancer are still extremely resistant to current forms of therapy. Boron neutron capture therapy (BNCT) provides a promising way to destroy cancer cells without damaging healthy tissue. However, BNCT in practice is still limited due to the lack of boron-containing compounds that selectively deliver boron to cancer cells. Since many neuroendocrine tumors show an overexpression of the somatostatin receptor, it was our aim to synthesize compounds that contain a large number of boron atoms and still show high affinity toward this transmembrane receptor. The synthetic peptide Tyr (3)-octreotate (TATE) was chosen as a high-affinity and internalizing tumor targeting vector (TTV). Novel boron cluster compounds, containing 10 or 20 boron atoms, were coupled to the N-terminus of TATE. The obtained affinity data demonstrate that the use of a spacer between TATE and the closo-borane moiety is the option to avoid a loss of biological affinity of closo-borane conjugated TATE. For the first time, it was shown that closo-borane conjugated regulatory peptides retain high biological affinity and selectivity toward their transmembrane tumor receptors. The results obtained and the improvement of spacer and boron building block chemistry may stimulate new directions for BNCT.

Q & A

Question and answer session with presenters Daniel Schneider, Ryan Tate, and Brendan Pelto.

Flash in the Pan: Cross-Class Cooperation in 1916 Iron Range Strike

In the Iron Range Strike of 1916, working-class wives picketed alongside their husbands in a conflict-ridden and dangerous setting. Mine deputies abused immigrant women on the picket lines and in their homes, with several disquieting reports receiving statewide attention in Minnesota. Many middle-class reformers in the Twin Cities grew sympathetic to the plight of northern mining families and became controversially involved the labor struggle. Some middleclass women worked alongside working-class wives and radical organizers from the Industrial Workers of the World (IWW). At the center of this gendered analysis is the cross-class cooperation between an upper-middle class woman, Lenora Austin Hamlin, a radical reformer, Elizabeth Gurley Flynn, and the story of a working-class housewife, Mikla Masonovich. This study will ask how authentic, prevalent, and unproblematic their stories of cross-class cohesive action actually were. In answering this, it will address and identify those factors that impeded women’s potential for unity. “Flash in the Pan” argues that as a result of both real and perceived differences, these networks of women remained isolated, inhibiting each from gaining sufficient power to work cohesively, and marginalizing their influence. Drawing upon a variety of sources, including media representations in newspapers, and archives of social, labor and women’s organizations, this regional study lends state-level insight into the larger gender-labor historiography.

Highly efficient in vivo agonist-induced internalization of sst2 receptors in somatostatin target tissues

The successful peptide receptor imaging of tumors, as exemplified for somatostatin receptors, is based on the overexpression of peptide receptors in selected tumors and the high-affinity binding to these tumors of agonist radioligands that are subsequently internalized into the tumor cells in which they accumulate. Although in vitro studies have shown ample evidence that the ligand-receptor complex is internalized, in vivo evidence of agonist-induced internalization of peptide receptors, such as somatostatin receptors, is missing. METHODS: Rats subcutaneously transplanted with the somatostatin receptor subtype 2 (sst(2))-expressing AR42J tumor cells were treated with intravenous injections of various doses of the sst(2) agonist [Tyr(3), Thr(8)]-octreotide (TATE) or of the sst(2) antagonist 1,4,7,10-tetraazacyclododecane-N,N',N'',N''',-tetraacetic acid (DOTA)-Bass and were sacrificed at various times ranging from 2.5 min to 24 h after injection. The tumors and pancreas were then removed from each animal. All tissue samples were processed for sst(2) immunohistochemistry using sst(2)-specific antibodies. RESULTS: Compared with the sst(2) receptors in untreated animals, which localized at the plasma membrane in pancreatic and AR42J tumor cells, the sst(2) receptors in treated animals are detected intracellularly after an intravenous injection of the agonist TATE. Internalization is fast, as the receptors are already internalizing 2.5 min after TATE injection. The process is extremely efficient, as most of the cell surface receptors internalize into the cell and are found in endosomelike structures after TATE injection. The internalization is most likely reversible, because 24 h after injection the receptors are again found at the cell surface. The process is also agonist-dependent, because internalization is seen with high-affinity sst(2) agonists but not with high-affinity sst(2) antagonists. The same internalization properties are seen in pancreatic and AR42J tumor cells. They can further be confirmed in vitro in human embryonic kidney-sst(2) cells, with an immunofluorescence microscopy-based sst(2) internalization assay. CONCLUSION: These animal data strongly indicate that the process of in vivo sst(2) internalization after agonist stimulation is fast, extremely efficient, and fully functional under in vivo conditions in neoplastic and physiologic sst(2) target tissues. This molecular process is, therefore, likely to be responsible for the high and long-lasting uptake of sst(2) radioligands seen in vivo in sst(2)-expressing tumors.