Pretargeted radioimmunotherapy using genetically engineered antibody-streptavidin fusion proteins for treatment of non-hodgkin lymphoma.

Purpose: Pretargeted radioimmunotherapy (PRIT) using streptavidin (SAv)-biotin technology can deliver higher therapeutic doses of radioactivity to tumors than conventional RIT. However, "endogenous" biotin can interfere with the effectiveness of this approach by blocking binding of radiolabeled biotin to SAv. We engineered a series of SAv FPs that downmodulate the affinity of SAv for biotin, while retaining high avidity for divalent DOTA-bis-biotin to circumvent this problem.Experimental Design: The single-chain variable region gene of the murine 1F5 anti-CD20 antibody was fused to the wild-type (WT) SAv gene and to mutant SAv genes, Y43A-SAv and S45A-SAv. FPs were expressed, purified, and compared in studies using athymic mice bearing Ramos lymphoma xenografts.Results: Biodistribution studies showed delivery of more radioactivity to tumors of mice pretargeted with mutant SAv FPs followed by (111)In-DOTA-bis-biotin [6.2 +/- 1.7% of the injected dose per gram (%ID/gm) of tumor 24 hours after Y43A-SAv FP and 5.6 +/- 2.2%ID/g with S45A-SAv FP] than in mice on normal diets pretargeted with WT-SAv FP (2.5 +/- 1.6%ID/g; P = 0.01). These superior biodistributions translated into superior antitumor efficacy in mice treated with mutant FPs and (90)Y-DOTA-bis-biotin [tumor volumes after 11 days: 237 +/- 66 mm(3) with Y43A-SAv, 543 +/- 320 mm(3) with S45A-SAv, 1129 +/- 322 mm(3) with WT-SAv, and 1435 +/- 212 mm(3) with control FP (P < 0.0001)].Conclusions: Genetically engineered mutant-SAv FPs and bis-biotin reagents provide an attractive alternative to current SAv-biotin PRIT methods in settings where endogenous biotin levels are high. Clin Cancer Res; 17(23); 7373-82. (C)2011 AACR.

Unified formalism for non-autonomous mechanical systems

We present a unified geometric framework for describing both the Lagrangian and Hamiltonian formalisms of regular and non-regular time-dependent mechanical systems, which is based on the approach of Skinner and Rusk (1983). The dynamical equations of motion and their compatibility and consistency are carefully studied, making clear that all the characteristics of the Lagrangian and the Hamiltonian formalisms are recovered in this formulation. As an example, it is studied a semidiscretization of the nonlinear wave equation proving the applicability of the proposed formalism.

The increased but non-predominant expression of Th17- and Th1-specific cytokines in Hashimoto’s thyroiditis but not in Graves’ disease

Hashimoto’s thyroiditis (HT) is considered to be mediated mainly by Th1 cells, but it is not known whether Graves’ disease (GD) is associated with Th1 or Th2 predominance. Th17 cells, a novel subset of Th cells, play a crucial role in the pathogenesis of various autoimmune disorders. In the present study, the expression of IL-17A and IFN-γ was investigated in patients with HT or GD. mRNA expression of IL-17A and IFN-γ in peripheral blood mononuclear cells (PBMC) from 43 patients with autoimmune thyroid disease (AITD) and in thyroid tissues from 40 AITD patients were measured by real-time qRT-PCR. The protein expression of IL-17A and IL-23p19 was examined by immunohistochemistry in thyroid tissues from 28 AITD patients. The mRNA levels of IL-17A and IFN-γ were higher in both PBMC and thyroid tissues of HT patients than in controls (mRNA levels are reported as the cytokine/β-actin ratio: IL-17 = 13.58- and 2.88-fold change and IFN-γ = 16.54- and 2.74-fold change, respectively, P < 0.05). Also, the mRNA levels of IL-17A and IFN-γ did not differ significantly in GD patients (P > 0.05). The high protein expression of IL-17A (IOD = 15.17 ± 4.8) and IL-23p19 (IOD = 16.84 ± 7.87) in HT was confirmed by immunohistochemistry (P < 0.05). The similar high levels of IL-17A and IFN-γ suggest a mixed response of Th17 and Th1 in HT, where both cells may play important roles in the destruction procedure by cell-mediated cytotoxicity.

Prompt and non-prompt J/ψ production in pp collisions at √s =7 TeV

The production of J/ψ mesons is studied in pp collisions at √s = 7 TeV with the CMS experiment at the LHC. The measurement is based on a dimuon sample corresponding to an integrated luminosity of 314 nb-1. The J/ψ differential cross section is determined, as a function of the J/ψ transverse momentum, in three rapidity ranges. A fit to the decay length distribution is used to separate the prompt from the non-prompt (b hadron to J/ψ) component. Integrated over J/ψ transverse momentum from 6.5 to 30 GeV/c and over rapidity in the range {pipe}y{pipe} < 2.4, the measured cross sections, times the dimuon decay branching fraction, are 70.9 ± 2.1(stat.) ± 3.0(syst.) ± 7.8(luminosity) nb for prompt J/ψ mesons assuming unpolarized production and 26.0 ± 1.4(stat.) ± 1.6(syst.) ± 2.9(luminosity) nb for J/ψ mesons from b-hadron decays. © CERN for the benefit of the CMS collaboration 2011.

Search for a non-standard-model Higgs boson decaying to a pair of new light bosons in four-muon final states

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Una mappa per la porta del non ritorno: l'appartenenza nella letteratura nera canadese

La presente tesi dimostra che la letteratura nera canadese può costituire una critica al concetto di appartenenza, così come è stato sempre rappresentato nel Canada anglofono. Più specificatamente, prende in considerazione tre scrittori contemporanei – George Elliott Clarke, Austin Clarke e Dionne Brand – che mettono in evidenza, seppure non nei termini classici, ciò che Stuart Hall descrive come “quegli aspetti delle nostre identità che scaturiscono dal nostro ‘appartenere’ a distinte culture etniche, razziali, linguistiche, religiose e soprattutto nazionali” (Stuart Hall, Modernity 596). Ognuno di essi, infatti, pone in evidenza il senso di appartenenza culturale in modo incerto, ambivalente e perfino estremamente critico. L’analisi dei loro testi, inoltre, è imprescindibile, dallo studio di tre discorsi (termine da intendersi secondo la definizione proposta da Ian Angus): il nazionalismo, il multiculturalismo e la diaspora che sembrano condizionare e limitare i termini semantici, concettuali e politici dell’appartenenza culturale, specialmente nell’ambito degli studi canadesi e postcoloniali. In realtà, autori quali Austin Clarke e Dionne Brand, offrendo una prospettiva unica ed originale da cui avviare una critica a tali concetti, propongono dei ‘linguaggi di appartenenza’ diversi e, di conseguenza, modi alternativi di manifestare e concretizzare, non solo un attaccamento culturale, ma anche un impegno politico profondo. Il lavoro è composto dall’Introduzione, in cui vengono esplicitate le ragioni dell’argomento scelto; il Capitolo I, che funge da impianto metodologico alla ricerca, spiega il concetto di appartenenza; da tre Capitoli centrali, ciascuno dedicato ad un singolo autore, che esaminano una serie di opere, di ogni singolo autore, al fine di esaminare e giudicare i tre discorsi; e dalla Conclusione che contiene delle considerazioni sul ruolo della letteratura nera canadese all’interno degli studi canadesi contemporanei e postcoloniali.

TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition, strongly associated with the metabolic syndrome, that can lead to progressive hepatic fibrosis, cirrhosis and hepatic failure. Subtle inter-patient genetic variation and environmental factors combine to determine variation in disease progression. A common non-synonymous polymorphism in TM6SF2 (rs58542926 c.449 C>T, p.Glu167Lys) was recently associated with increased hepatic triglyceride content, but whether this variant promotes clinically relevant hepatic fibrosis is unknown. Here we confirm that TM6SF2 minor allele carriage is associated with NAFLD and is causally related to a previously reported chromosome 19 GWAS signal that was ascribed to the gene NCAN. Furthermore, using two histologically characterized cohorts encompassing steatosis, steatohepatitis, fibrosis and cirrhosis (combined n=1,074), we demonstrate a new association, independent of potential confounding factors (age, BMI, type 2 diabetes mellitus and PNPLA3 rs738409 genotype), with advanced hepatic fibrosis/cirrhosis. These findings establish new and important clinical relevance to TM6SF2 in NAFLD.

Oncogenic activation of c-Abl tyrosine kinase in non-small cell lung cancer: FUS1 tumor suppressor down-regulates c-Abl tyrosine kinase

The FUS1 tumor suppressor gene (TSG) has been found to be deficient in many human non-small cell lung cancer (NSCLC) tissue samples and cell lines (1,2,3). Studies have shown potent anti-tumor activity of FUS1 in animal models where FUS1 was delivered through a liposomal vector (4) and the use of FUS1 as a therapeutic agent is currently being studied in clinical human trials (5). Currently, the mechanisms of FUS1 activity are being investigated and my studies have shown that c-Abl tyrosine kinase is inhibited by the FUS1 TSG.^ Considering that many NSCLC cell lines are FUS1 deficient, my studies further identified that FUS1 deficient NSCLC cells have an activated c-Abl tyrosine kinase. C-Abl is a known proto-oncogene and while c-Abl kinase is tightly regulated in normal cells, constitutively active Abl kinase is known to contribute to the oncogenic phenotype in some types of hematopoietic cancers. My studies show that the active c-Abl kinase contributes to the oncogenicity of NSCLC cells, particularly in tumors that are deficient in FUS1, and that c-Abl may prove to be a viable target in NSCLC therapy.^ Current studies have shown that growth factor receptors play a role in NSCLC. Over-expression of the epidermal growth factor receptor (EGFR) plays a significant role in aggressiveness of NSCLC. Current late stage treatments include EFGR tyrosine kinase inhibitors or EGFR antibodies. Platelet-derived growth factor receptor (PDGFR) also has been shown to play a role in NSCLC. Of note, both growth factor receptors are known upstream activators of c-Abl kinase. My studies indicate that growth factor receptor simulation along deficiency in FUS1 expression contributes to the activation of c-Abl kinase in NSCLC cells. ^