R-Symmetry and the Topological Twist of N=2 Effective Supergravities of Heterotic Strings

We discuss R-symmetries in locally supersymmetric N=2 gauge theories coupled to hypermultiplets which can be thought of as effective theories of heterotic superstring models. In this type of supergravities a suitable R-symmetry exists and can be used to topologically twist the theory: the vector multiplet containing the dilaton-axion field has different R-charge assignments with respect to the other vector multiplets. Correspondingly a system of coupled instanton equations emerges, mixing gravitational and Yang--Mills instantons with triholomorphic hyperinstantons and axion-instantons. For the tree-level classical special manifolds $ST(n)=SU(1,1)/U(1)\times SO(2,n)/(SO(2)$ $\times SO(n))$ R-symmetry with the specified properties is a continuous symmetry, but for the quantum corrected manifolds ${\hat {ST}}(n)$ a discrete R--group of electric--magnetic duality rotations is sufficient and we argue that it exists.Comment: 40 pages, plain LaTeX. Final version to appear on IJMP

A Search for Non-Perturbative Dualities of Local N=2N=2 Yang--Mills Theories from Calabi--Yau Threefolds

The generalisation of the rigid special geometry of the vector multiplet quantum moduli space to the case of supergravity is discussed through the notion of a dynamical Calabi--Yau threefold. Duality symmetries of this manifold are connected with the analogous dualities associated with the dynamical Riemann surface of the rigid theory. N=2 rigid gauge theories are reviewed in a framework ready for comparison with the local case. As a byproduct we give in general the full duality group (quantum monodromy) for an arbitrary rigid $SU(r+1)$ gauge theory, extending previous explicit constructions for the $r=1,2$ cases. In the coupling to gravity, R--symmetry and monodromy groups of the dynamical Riemann surface, whose structure we discuss in detail, are embedded into the symplectic duality group $\Gamma_D$ associated with the moduli space of the dynamical Calabi--Yau threefold.Comment: Latex. Version of previous paper with enlarged and revised appendix 35 pages, plain LaTe

Radioterapia intraoperatoria nei tumori maligni avanzati estesi all’orecchio medio: valutazione da uno studio retrospettivo

Obiettivo dello studio è stato quello di valutare la sicurezza, l’efficacia e i risultati funzionali della radioterapia intraoperatoria (IORT) seguita dalla radioterapia a intensità modulata (IMRT) nel trattamento di tumori maligni avanzati estesi all’orecchio medio. Sono stati inclusi nello studio in modo retrospettivo 13 pazienti consecutive affetti da tumore dell’orecchio esterno esteso all’orecchio medio. Il follow-up è stato in media di 33 mesi (range 6-133). Cinque pazienti (38%) erano di stadio III e 8 pazienti (62%) erano di stadio IV secondo la classificazione dell’Università di Pittsburgh. Una petrosectomia laterale (LTBR) è stata eseguita in tutti i pazienti, la LTBR è stata associata a parotidectomia in 5 (38%) casi e a svuotamento latero-cervicale associato a parotidectomia in 6 (46%) casi. In tutti i casi si è effettuata asportazione della malattia macroscopicamente evidente. Il trattamento chirurgico è stato completato da IORT (12 Gy) e IMRT (50Gy). Chemioterapia adiuvante è stata eseguita in 4 (30%) casi. Test audiometrici pre- e post-operatori sono stati eseguiti per valutare la perdita uditiva. Il tasso di controllo di malattia locale (LC) a 5 anni, di metastasi a distanza (DM) a 5 anni, la sopravvivenza libera da malattia (DFS) e la sopravvivenza globale (OS) a 5 anni sono state calcolate con il metodo di Kaplan-Meyer. Variazioni significative nella conduzione per via ossea sono state osservate dopo trattamento. Una necrosi parziale del lembo di ricostruzione è stata l’unica complicanza precoce osservata in 3(23%) casi, mentre una fistola meningea è stata osservata in un solo caso (7,6%) come complicanza tardiva. Il tasso di LC è stato del 68%. Il tasso di DM è stato del 90%. Il tasso di DFS è stato del 61%. Il tasso di OS è stato del 69%. La IORT seguita dalla IMRT nel trattamento dei tumori maligni avanzati dell’orecchio esterno e medio sembra essere sicuro. Nel nostro studio non sono riportati morti. La IORT può ridurre la dose di radioterapia postoperatoria a livello del tessuto residuo ottenendo la medesima dose a livello della sede del tumore. Non abbiamo osservato alcuna complicanza a livello dell’orecchio esterno residuo, mentre si è notato un peggioramento dell’udito anche a livello neurosensoriale. Sono necessari studi prospettici al fine di confermare quanto da noi osservato

The human antibody fragment DIATHIS1 specific for CEACAM1 enhances natural killer cell cytotoxicity against melanoma cell lines in vitro

Several lines of evidence show that de novo expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is strongly associated with reduced disease-free survival of patients affected by metastatic melanoma. Previously published investigations report that homophilic interactions between CEACAM1 expressed on natural killer (NK) cells and tumors inhibit the NK cell-mediated killing independently of major histocompatibility complex class I recognition. This biological property can be physiologically relevant in metastatic melanoma because of the increased CEACAM1 expression observed on NK cells from some patients. Moreover, this inhibitory mechanism in many cases might hinder the efficacy of immunotherapeutic treatments of CEACAM1 malignancies because of tumor evasion by activated effector cells. In the present study, we designed an in vitro experimental model showing that the human single-chain variable fragment (scFv) DIATHIS1 specific for CEACAM1 is able to enhance the lytic machinery of NK cells against CEACAM1 melanoma cells. The coincubation of the scFv DIATHIS1 with CEACAM1 melanoma cells and NK-92 cell line significantly increases the cell-mediated cytotoxicity. Moreover, pretreatment of melanoma cells with scFv DIATHIS1 promotes the activation and the degranulation capacity of in vitro-expanded NK cells from healthy donors. It is interesting to note that the melanoma cell line MelC and the primary melanoma cells STA that respond better to DIATHIS1 treatment, express higher relative levels of CEACAM1-3L and CEACAM1-3S splice variants isoforms compared with Mel501 cells that are less responsive to DIATHIS1-induced NK cell-mediated cytotoxicity. Taken together, our results suggest that the fully human antibody fragment DIATHIS1 originated by biopanning approach from a phage antibody library may represent a relevant biotechnological platform to design and develop completely human antimelanoma therapeutics of biological origin

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81

1H, 13C and 15N assignment of the GNA1946 outer membrane lipoprotein from Neisseria meningitidis

GNA1946 (Genome-derived Neisseria Antigen 1946) is a highly conserved exposed outer membrane lipoprotein from Neisseria meningitidis bacteria of 287 amino acid length (31 kDa). Although the structure of NMB1946 has been solved recently by X-Ray crystallography, understanding the behaviour of GNA1946 in aqueuos solution is highly relevant for the discovery of the antigenic determinants of the protein that will possibly lead to a more efficient vaccine development against virulent serogroup B strain of N.meningitidis. Here we report almost complete 1H, 13C and 15N resonance assignments of GNA1946 (residues 10–287) in aqueous buffer solution

The Top-Implart Proton Linear Accelerator: Interim Characteristics of the 35 Mev Beam

In the framework of the Italian TOP-IMPLART project (Regione Lazio), ENEA-Frascati, ISS and IFO are developing and constructing the first proton linear accelerator based on an actively scanned beam for tumor radiotherapy with final energy of 150 MeV. An important feature of this accelerator is modularity: an exploitable beam can be delivered at any stage of its construction, which allows for immediate characterization and virtually continuous improvement of its performance. Currently, a sequence of 3 GHz accelerating modules combined with a commercial injector operating at 425 MHz delivers protons up to 35 MeV. Several dosimetry systems were used to obtain preliminary characteristics of the 35-MeV beam in terms of stability and homogeneity. Short-term stability and homogeneity better than 3% and 2.6%, respectively, were demonstrated; for stability an improvement with respect to the respective value obtained for the previous 27 MeV beam

Use of phosphorus fertilization and mycorrhization as strategies for reducingcopper toxicity in young grapevines.

Established vineyard soils may have high copper (Cu) contents due to the ongoing foliar applications of copper-based fungicides. In viticulture, the replacement of old vineyards with new vines is common practice, however,limited by Cu excess in soil and its toxicity to young grapevines. The application of phosphorus (P) and ar-buscular mycorrhizal fungi (AMF) inoculation are potential strategies to reduce Cu toxicity to young grapevines.This study aimed to assess the effects of phosphorus fertilization and AMF (Rhizophagus clarus) inoculation ongrowth and physiological parameters of young grapevines grown in soil with high Cu content. The experimentwas conducted in a greenhouse, where natural grassland soil was artificially contaminated by the addition of60 mg kg−1Cu. The soils were treated with and without AMF inoculation, combined with additions of 0, 40 and100 mg P kg−1. After 90 days of cultivation, grapevine plants were assessed for chlorophyllafluorescence,photosynthetic pigment contents, superoxide dismutase (SOD) activity, plant height, plant biomass, and con-centrations of Cu and P in roots and shoots. Phosphorus fertilization promoted increases in seedling growth(related to the increase of total P concentration in roots and shoots), soluble Pi concentration in leaves, and thequantum yield of the PSII (YII) (associated with a reduction in shoot Cu concentration). The AMF inoculationincreased the concentration of P in roots and shoots, soluble Pi in leaves and electron transport rate (ETR).Phosphorus fertilization and inoculation of grapevines with AMF are strategies capable of reducing Cu toxicity inyoung grapevines

Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors

New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC₅₀ = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes