Influence of UGT1A9 intronic I399C4T polymorphism on SN-38 glucuronidation in Asian cancer patients

Genetic polymorphisms in hepatically expressed UGT1A1 and UGT1A9 contribute to the interindividual variability i-n irinotecan disposition and toxicity. We screened UGT1A1 (UGT1A1*60, g.−3140G>A, UGT1A1*28 and UGT1A1*6) and UGT1A9 (g.−118(T)9>10 and I399C>T) genes for polymorphic variants in the promoter and coding regions, and the genotypic effect of UGT1A9 I399C>T polymorphism on irinotecan disposition in Asian cancer patients was investigated. Blood samples were collected from 45 patients after administration of irinotecan as a 90 min intravenous infusion of 375 mg/m2 once in every 3 weeks. Genotypic–phenotypic correlates showed that cancer patients heterozygous or homozygous for the I399C>T allele had approximately 2-fold lower systemic exposure to SN-38 (P<0.05) and a trend towards a higher relative extent of glucuronidation (REG) of SN-38 (P>0.05). UGT1A1–1A9 diplotype analysis showed that patients harbouring the H1/H2 (TG6GT10T/GG6GT9C) diplotype had 2.4-fold lower systemic exposure to SN-38 glucuronide (SN-38G) compared with patients harbouring the H1/H5 (TG6GT10T/GG6GT10C) diplotype (P=0.025). In conclusion, this in vivo study supports the in vitro findings of Girard et al. and suggests that the UGT1A9 I399C>T variant may be an important glucuronidating allele affecting the pharmacokinetics of SN-38 and SN-38G in Asian cancer patients receiving irinotecan chemotherapy.

The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38

Members of the human epidermal receptor (HER) family are frequently associated with aggressive disease and poor prognosis in multiple malignancies. Lapatinib is a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and HER-2. This study evaluated the therapeutic potential of lapatinib, alone and in combination with SN-38, the active metabolite of irinotecan (CPT-11), in colon and gastric cancer cell lines. Concentration-dependent antiproliferative effects of both lapatinib and SN-38 were observed in all colon and gastric cancer cell lines tested but varied significantly between individual cell lines (lapatinib range 0.08-11.7 muM; SN-38 range 3.6-256 nM). Lapatinib potently inhibited the growth of a HER-2 overexpressing gastric cancer cell line and demonstrated moderate activity in gastric and colon cancer cells with detectable HER-2 expression. The combination of lapatinib and SN-38 interacted synergistically to inhibit cell proliferation in all colon and gastric cancer cell lines tested. Cotreatment with lapatinib and SN-38 also resulted in enhanced cell cycle arrest and the induction of apoptosis with subsequent cellular pharmacokinetic analysis demonstrating that lapatinib promoted the increased intracellular accumulation and retention of SN-38 when compared to SN-38 treatment alone. Finally, the combination of lapatinib and CPT-11 demonstrated synergistic antitumor efficacy in the LoVo colon cancer mouse xenograft model with no apparent increase in toxicity compared to CPT-11 monotherapy. These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas.

Cellular FLICE-inhibitory protein regulates chemotherapy-induced apoptosis in breast cancer cells

Combination treatment regimens that include topoisomerase-II-targeted drugs, such as doxorubicin, are widely used in the treatment of breast cancer. Previously, we demonstrated that IFN-� and doxorubicin co-treatment synergistically induced apoptosis in MDA435 breast cancer cells in a STAT1-dependent manner. In this study, we found that this synergy was caspase 8-dependent. In addition, we found that IFN-γ down-regulated the expression of the caspase 8 inhibitor c-FLIP. Furthermore, IFN-� down-regulated c-FLIP in a manner that was dependent on the transcription factors STAT1 and IRF1. However, IFN-� had no effect on c-FLIP mRNA levels, indicating that c-FLIP was down-regulated at a post-transcriptional level following IFN-� treatment. Characterisation of the functional significance of c-FLIP modulation by siRNA gene silencing and stable over-expression studies, revealed it to be a key regulator of IFN-γ- and doxorubicin-induced apoptosis in MDA435 cells. Analysis of a panel of breast cancer cell lines indicated that c-FLIP was an important general determinant of doxorubicin- and IFN-�-induced apoptosis in breast cancer cells. Furthermore, c-FLIP gene silencing sensitised MDA435 cells to other chemotherapies, including etoposide, mitoxantrone and SN-38. These results suggest that c-FLIP plays a pivotal role in modulating drug-induced apoptosis in breast cancer cells.

DESIGN AND SYNTHESIS OF MULTIFUNCTIONAL POLYMERIC MICELLES FOR GENE-DIRECTED ENZYME PRODRUG THERAPY

Gene-directed enzyme prodrug therapy is a form of cancer therapy in which delivery of a gene that encodes an enzyme is able to convert a prodrug, a pharmacologically inactive molecule, into a potent cytotoxin. Currently delivery of gene and prodrug is a two-step process. Here, we propose a one-step method using polymer nanocarriers to deliver prodrug, gene and cytotoxic drug simultaneously to malignant cells. Prodrugs acyclovir, ganciclovir and 5-doxifluridine were used to directly to initiate ring-opening polymerization of epsilon-caprolactone, forming a hydrophobic prodrug-tagged poly(epsilon-caprolactone) which was further grafted with hydrophilic polymers (methoxy poly(ethylene glycol), chitosan or polyethylenemine) to form amphiphilic copolymers for micelle formation. Successful synthesis of copolymers and micelle formation was confirmed by standard analytical means. Conversion of prodrugs to their cytotoxic forms was analyzed by both two-step and one-step means i.e. by first delivering gene plasmid into cell line HT29 and then challenging the cells with the prodrug-tagged micelle carriers and secondly by complexing gene plasmid onto micelle nanocarriers and delivery gene and prodrug simultaneously to parental HT29 cells. Anticancer effectiveness of prodrug-tagged micelles was further enhanced by encapsulating chemotherapy drugs doxorubicin or SN-38. Viability of colon cancer cell line HT29 was significantly reduced. Furthermore, in an effort to develop a stealth and targeted carrier, CD47-streptavidin fusion protein was attached onto the micelle surface utilizing biotin-streptavidin affinity. CD47, a marker of self on the red blood cell surface, was used for its antiphagocytic efficacy, results showed that micelles bound with CD47 showed antiphagocytic efficacy when exposed to J774A.1 macrophages. Since CD47 is not only an antiphagocytic ligand but also an integrin associated protein, it was used to target integrin alpha(v)beta(3), which is overexpressed on tumor-activated neovascular endothelial cells. Results showed that CD47-tagged micelles had enhanced uptake when treated to PC3 cells which have high expression of alpha(v)beta(3). The synthesized multifunctional polymeric micelle carriers developed could offer a new platform for an innovative cancer therapy regime.

Interdiffusion and Growth of the Superconductor Nb3Sn in Nb/Cu(Sn) Diffusion Couples

The confusion over the growth rate of the Nb3Sn superconductor compound following the bronze technique is addressed. Furthermore, a possible explanation for the corrugated structure of the product phase in the multifilamentary structure is discussed. Kirkendall marker experiments are conducted to study the relative mobilities of the species, which also explains the reason for finding pores in the product phase layer. The movement of the markers after interdiffusion reflects that Sn is the faster diffusing species. Furthermore, different concentrations of Sn in the bronze alloy are considered to study the effect of Sn content on the growth rate. Based on the parabolic growth constant at different temperatures, the activation energy for the growth is determined.

Interacting supernovae and supernova impostors. SN 2007sv: the major eruption of a massive star in UGC 5979

We report the results of the photometric and spectroscopic monitoring campaign of the transient SN 2007sv. The observables are similar to those of Type IIn supernovae, a well-known class of objects whose ejecta interact with pre-existing circumstellar material (CSM). The spectra show a blue continuum at early phases and prominent Balmer lines in emission; however, the absolute magnitude at the discovery of SN 2007sv (M-R=-14.25 +/- 0.38) indicate it to be most likely a supernova impostor. This classification is also supported by the lack of evidence in the spectra of very high velocity material as expected in supernova ejecta. In addition, we find no unequivocal evidence of broad lines of alpha- and/or Fe-peak elements. The comparison with the absolute light curves of other interacting objects (including Type IIn supernovae) highlights the overall similarity with the prototypical impostor SN 1997bs. This supports our claim that SN 2007sv was not a genuine supernova, and was instead a supernova impostor, most likely similar to the major eruption of a luminous blue variable.

Reflexions sobre la realitat educativa de les Illes Balears : per què són tan difícils els pactes educatius?. 'Reflexiones sobre la realidad educativa de las Islas Baleares : ¿por qué son tan difíciles los pactos educativos?'.

Resumen tomado de la publicación

Nanoestruturas luminescentes de Ge e Sn em camadas de SiO/sub 2/ implantadas com íons

Neste trabalho estudam-se as propriedades de nanoestruturas de Ge e Sn formadas em amostras de SiO2/Si(100) através dos processos de implantação iônica e tratamento térmico. A formação de nanocristais de Ge foi investigada em função de tratamentos térmicos em ambiente de N2. Os resultados obtidos foram correlacionados com as propriedades de luminescência das amostras, sendo feita uma discussão sobre os mecanismos atômicos envolvidos no processo de crescimento dos nanocristais de Ge, bem como seus efeitos na criação de centros luminescentes no interior da camada de SiO2, que são responsáveis por intensas bandas de fotoluminescência (PL) nas regiões espectrais do azul-violeta (≈ 3,2 eV) e ultravioleta (≈ 4,2 eV). Além disso, experimentos de irradiação com diferentes íons (He+, Si+, Kr++, Au+) foram realizados antes da implantação do Ge com o objetivo de estudar o efeito de memória que os danos criados pela irradiação apresentam sobre as propriedades estruturais e luminescentes das amostras de SiO2/Si(100) No estudo das amostras de SiO2/Si(100) implantadas com Sn, a síntese de nanopartículas de Sn foi estudada em função da temperatura e do ambiente de tratamento térmico (N2 e vácuo). De maneira pioneira mostrou-se que através da manipulação desses parâmetros é possível formar desde grandes nanocristais bi-fásicos de Sn (≈ 12 a 25 nm) em estruturas concêntricas com núcleo de β-Sn e camada externa de SnOx, até pequenas nanopartículas de Sn com diâmetros de ≈ 2 nm e uniformemente distribuídas ao longo da camada de SiO2. Além disso, observou-se que a evolução estrutural do sistema de nanopartículas de Sn influencia diretamente as características das emissões de PL azul-violeta e UV. Por fim, um outro aspecto das nanoestruturas de Sn foi estudado: a formação de um denso arranjo de ilhas epitaxiais de β-Sn na região de interface SiO2/Si. Este sistema de nano-ilhas, que cresce epitaxialmente, é uniformemente distribuído sobre a superfície do Si, apresentando uma pequena dispersão em tamanho e tendência a se auto-organizar. A criação desse sistema de nano-ilhas epitaxiais através da utilização da implantação iônica é um processo inédito, sendo discutida aqui com base nas propriedades de equilíbrio do sistema Sn-Si.

Theater 38.3 : Censorship and Performance

Censorship and Performance, edited by Tom Sellar, examines the politics of censorship, and continuing contests over the ‘right’ to claim theatrical and cultural stages for controversial forms of social and self representation, at the start of the twenty-first century. In bringing this collection together, Sellar has taken a broad-based approach to the concept of censorship in theatrical performance—and, indeed, to the concept of theatrical performance itself. Sellar and his contributors clearly accept that surveillance, suppression and restriction of specific forms of representation is a complex, culturally specific phenomenon. In this sense, Censorship and Performance addresses direct political control over content, as well as thornier arguments about media controversy, moral panic, and the politics of self-censorship amongst artists and arts organisations.

Gate 38

Airports are a place of transition, empty halls of fleeting comings, goings and waitings. 'Gate 38' follows the experience of four groups of young people trapped at this point of departure. As contact with the outside world is cut off, the focus is placed squarely on what they’re doing, and where they’re going. A non-traditional musical set at the end of the world. Commissioned by MacGregor State High School's Centre of Artistic Development, script development included workshops with the CAD class of 2007. No musical score required.

The effect of metamictization on the Raman spectroscopy of the uranyl titanate mineral davidite (La,Ce)(Y,U,Fe2+)(Ti,Fe3+)20(O,OH)38

Raman spectra of the uranyl titanate mineral davidite-(La) (La,Ce)(Y,U,Fe2+)(Ti,Fe3+)20(O,OH)38 were analysed and related to the mineral structure. Observed bands are attributed to the TiO and (UO2)2+ stretching and bending vibrations, U-OH bending vibrations, H2O and (OH)- stretching, bending and libration modes. U-O bond lengths in uranyls and O-H…O bond lengths are calculated from the wavenumbers assigned to the stretching vibrations. Raman bands of davidite-(La) are in harmony with those of the uranyl oxyhydroxides. The mineral davidite-(La) is metamict as is evidenced by the intensity of the UO stretching and bending modes being of lower intensity than expected and with bands that are significantly broader.

Gate 38

Airports are a place of transition, empty halls of fleeting comings, goings and waitings. 'Gate 38' follows the experience of four groups of young people trapped at this point of departure. As contact with the outside world is cut off, the focus is placed squarely on what they’re doing, and where they’re going. A non-traditional musical set at the end of the world. Commissioned by MacGregor State High School's Centre of Artistic Development, script development included workshops with the CAD class of 2007. No musical score required.

Short utterance PLDA speaker verification using SN-WLDA and variance modelling techniques

This paper proposes a combination of source-normalized weighted linear discriminant analysis (SN-WLDA) and short utterance variance (SUV) PLDA modelling to improve the short utterance PLDA speaker verification. As short-length utterance i-vectors vary with the speaker, session variations and phonetic content of the utterance (utterance variation), a combined approach of SN-WLDA projection and SUV PLDA modelling is used to compensate the session and utterance variations. Experimental studies have found that a combination of SN-WLDA and SUV PLDA modelling approach shows an improvement over baseline system (WCCN[LDA]-projected Gaussian PLDA (GPLDA)) as this approach effectively compensates the session and utterance variations.

Growth and electron effective mass measurements of strained Si and Si0.94Ge0.06 on relaxed Si0.62Ge0.38 buffers grown by rapid thermal chemical vapor deposition

Abstract: We report the growth and the electron cyclotron resonance measurements of n-type Si/Si0.62Ge0.38 and Si0.94Ge0.06/Si0.62Ge0.38 modulation-doped heterostructures grown by rapid thermal chemical vapor deposition. The strained Si and Si0.94Ge0.06 channels were grown on relaxed Si0.62Ge0.38 buffer layers, which consist of 0.6 mu m uniform Si0.62Ge0.38 layers and 0.5 mu m compositionally graded relaxed SiGe layers from 0 to 38% Ge. The buffer layers were annealed at 800 degrees C for 1 h to obtain complete relaxation. A 75 Angstrom Si(SiGe) channel with a 100 Angstrom spacer and a 300 Angstrom 2 X 10(19) cm(-3) n-type supply layer was grown on the top of the buffer layers. The cross-sectional transmission electron microscope reveals that the dense dislocation network is confined to the buffer layer, and relatively few dislocations terminate on the surface. The plan-view image indicates the threading dislocation density is about 4 X 10(6) cm(-2). The far-infrared measurements of electron cyclotron resonance were performed at 4 K with the magnetic field of 4-8 T. The effective masses determined from the slope of the center frequency of the absorption peak versus applied magnetic field plot are 0.203m(0) and 0.193m(0) for the two dimensional electron gases in the Si and Si0.94Ge0.06 channels, respectively. The Si effective mass is very close to that of a two dimensional electron gas in an Si MOSFET (0.198m(0)). The electron effective mass of Si0.94Ge0.06 is reported for the first time and is about 5% lower than that of pure Si.