The Altered Metabolic Molecular Signatures Contribute to the RAD001 Resistance in Gastric Neuroendocrine Tumor

Although the inhibition of mTOR is a promising treatment for neuroendocrine tumors, several questions are still open for cell specificity and resistance. With the newly characterized gastric neuroendocrine tumor mouse model (CEA424-SV40 T antigen transgenic mice), the anti-tumor efficiency of RAD001 (Everolimus) was tested both in vitro and in vivo. Tumor samples were analyzed for the expression of RNA by cDNA microarrays and also signaling pathways to get more details on the local surviving or selected cells. RAD001 treatment dramatically slowed down tumor growth and prolonged the animals' survival. This inhibitory effect has a preference for tumor cells since gastrointestinal hormone and neuroendocrine tumor specific markers were more reduced than the epithelial ones. While phosphorylation of p70S6K was almost completely blocked both in vitro and in vivo, the phosphorylation of 4EBP1 was only partially inhibited in vitro and unaffected in vivo. RAD001 treatment induced feedback activation of metabolism related pathways like PI(3)K-Akt-mTOR and MEK/ERK signalings. An induction of senescence as well as differential expression of genes responsible for metabolism was also observed, which highlighted the contribution of metabolic molecular signatures to the escape of the tumor cells from the treatment. Together, our data revealed efficient anti-tumor ability of RAD001 in a new gastric neuroendocrine tumor mouse model system and offered new insights into the clinical aspects of the incomplete elimination of tumor cells in patients treated

Mehrwegeausbreitung bei Navigationssystemen - ein universeller Ansatz zur EMV-Analyse mit skalierten Messungen

Dieser Beitrag beschreibt einen universellen, messtechnisch verifizierten Ansatz, mit dem EMV-Analysen für oben genannte bzw. sogar beliebige Navigationssysteme in einer verkleinerten Messumgebung mit nahezu uneingeschränkter Flexibilität durchgeführt werden können. Die Skalierung beinhaltet dabei nicht nur das Verkleinern der Reflexionsobjekte selbst, sondern vielmehr die Nachbildung der betroffenen Navigationssysteme bei entsprechend höherer Frequenz; im hier beschriebenen Ansatz für das ILS und das Drehfunkfeuer bei 16 GHz. Die ingenieurtechnische Schwierigkeit besteht in der getreuen Nachbildung der Abstrahlcharakteristik und der eigentlichen Navigationsinformation des Originalsystems

Effect of non-abrupt doping and interfacial profiles on the carrier sheet density in one-side modulation-doped GaN/AlGaN quantum wells

The results of an accurate theoretical study on the effects of non-abrupt doping and interfacial profiles on the electron sheet density in one-side modulation-doped wurtzite GaN/AlGaN single quantum wells at low temperatures are presented. We solve coupled Schr¨odinger and Poisson equations self-consistently via the finite difference method. By employing a proper discretization on a nonuniform grid and taking into account the strong piezoelectric and spontaneous polarization fields exhibited by the wurtzite III-nitride heterostructures, a substantial increase in the 2DEG density is predicted with the increase of the donor diffusion length and the reduction of the spacer thickness

Expression of a Neuroendocrine Gene Signature in Gastric Tumor Cells from CEA 424-SV40 Large T Antigen-Transgenic Mice Depends on SV40 Large T Antigen

A large fraction of murine tumors induced by transgenic expression of SV40 large T antigen (SV40 TAg) exhibits a neuroendocrine phenotype. It is unclear whether SV40 TAg induces the neuroendocrine phenotype by preferential transformation of progenitor cells committed to the neuroendocrine lineage or by transcriptional activation of neuroendocrine genes. To address this question we analyzed CEA424-SV40 TAg-transgenic mice that develop spontaneous tumors in the antral stomach region. Immunohistology revealed expression of the neuroendocrine marker chromogranin A in tumor cells. By ELISA an 18-fold higher level of serotonin could be detected in the blood of tumor-bearing mice in comparison to nontransgenic littermates. Transcriptome analyses of antral tumors combined with gene set enrichment analysis showed significant enrichment of genes considered relevant for human neuroendocrine tumor biology. This neuroendocrine gene signature was also expressed in 424GC, a cell line derived from a CEA424-SV40 TAg tumor, indicating that the tumor cells exhibit a similar neuroendocrine phenotype also in vitro. Treatment of 424GC cells with SV40 TAg-specific siRNA downregulated expression of the neuroendocrine gene signature. SV40 TAg thus appears to directly induce a neuroendocrine gene signature in gastric carcinomas of CEA424-SV40 TAg-transgenic mice. This might explain the high incidence of neuroendocrine tumors in other murine SV40 TAg tumor models. Since the oncogenic effect of SV40 TAg is caused by inactivation of the tumor suppressor proteins p53 and RB1 and loss of function of these proteins is commonly observed in human neuroendocrine tumors, a similar mechanism might cause neuroendocrine phenotypes in human tumors

Platelet GPIIb supports initial pulmonary retention but inhibits subsequent proliferation of melanoma cells during hematogenic metastasis

Platelets modulate the process of cancer metastasis. However, current knowledge on the direct interaction of platelets and tumor cells is mostly based on findings obtained in vitro. We addressed the role of the platelet fibrinogen receptor glycoprotein IIb (integrin alpha IIb) for experimental melanoma metastasis in vivo. Highly metastatic B16-D5 melanoma cells were injected intravenously into GPIIb-deficient (GPIIb(-/-)) or wildtype (WT) mice. Acute accumulation of tumor cells in the pulmonary vasculature was assessed in real-time by confocal videofluorescence microscopy. Arrest of tumor cells was dramatically reduced in GPIIb(-/-) mice as compared to WT. Importantly, we found that mainly multicellular aggregates accumulated in the pulmonary circulation of WT, instead B16-D5 aggregates were significantly smaller in GPIIb(-/-) mice. While pulmonary arrest of melanoma was clearly dependent on GPIIb in this early phase of metastasis, we also addressed tumor progression 10 days after injection. Inversely, and unexpectedly, we found that melanoma metastasis was now increased in GPIIb(-/-) mice. In contrast, GPIIb did not regulate local melanoma proliferation in a subcutaneous tumor model. Our data suggest that the platelet fibrinogen receptor has a differential role in the modulation of hematogenic melanoma metastasis. While platelets clearly support early steps in pulmonary metastasis via GPIIb-dependent formation of platelet-tumor-aggregates, at a later stage its absence is associated with an accelerated development of melanoma metastases

Efeito de campos elétricos, dopagens não-abruptas e interfaces graduais na estrutura eletrônica de poços quânticos de GaAs/AlGaAs e GaN/AlGaN

Tese (doutorado)—Universidade de Brasília, Instituto de Física, 2007.Realizamos estudo sistemático da influência de dois campos de laser intenso linearmente polarizados, em configuração cruzada, nos níveis de energia do elétron e na densidade de estados em poços quânticos de GaAs/AlGaAs. Mostramos que tanto o padrão de confinamento dos portadores de carga quanto a densidade de estados são modificados pela aplicação dos campos. Para radiações intensas de laser polarizado na direção de crescimento da heteroestrutura semicondutora, apenas o perfil da banda de condução é modificado, induzindo fortes desvios para o azul nos níveis de energia que dependem monotonicamente da intensidade e da freqüência do laser, além disso, detectamos que tais desvios são mais pronunciados nos níveis de energia mais altos. Por outro lado, polarizações paralelas ao plano das heterointerfaces produzem alterações na densidade de estados, mudando seu perfil suavemente em função da intensidade e freqüência do laser aplicado, o que sugere um interessante mecanismo de regulagem do laser que pode ser utilizado na prática para ajustar as propriedades ópticas e de transporte de dispositivos semicondutores de baixa dimensionalidade sob ação de laser. Na ausência de campos, investigamos a influência do perfil não-abrupto de dopagem na densidade do gás de elétrons bidimensional em poços quânticos de GaAs/AlGaAs com interfaces graduais e dopagem modulada em uma das barreiras. Um método de discretização própria para malhas não-uniformes foi proposto a fim de resolver as equações acopladas de Schrödinger e Poisson de maneira autoconsistente. Observamos, para esse sistema, um aumento significante na densidade bidimensional dos portadores de carga em função do tamanho de difusão dos doadores, apontando assim a provável causa para os baixos valores encontrados em outros trabalhos nos quais um perfil gradual de dopagem não foi considerado. Verificamos ainda que o aumento da largura do espaçador, que separa os portadores de carga das impurezas residuais, diminui o efeito da dopagem gradual no processo de transferência de carga. Analisamos também o efeito dos campos elétricos internos e das interfaces graduais no perfil da banda de condução e nas energias de transição intersubbanda para poços quânticos de GaN/AlGaN com estrutura wurtzita. Identificamos, mais uma vez, a presença de desvios para azul induzidos pelos campos intensos de polarização bem como pelas interfaces graduais. Enquanto o efeito das polarizações piezoelétrica e espontânea é mais acentuado em poços quânticos mais largos, o efeito produzido pelas interfaces graduais é mais pronunciado para poços mais estreitos, indicando a grande importância desse último efeito em nanodispositivos semicondutores. Um aumento significativo na densidade bidimensional dos portadores de carga em função do tamanho de difusão dos doadores também foi encontrado para poços de GaN/AlGaN com dopagem modulada. ________________________________________________________________________________________ ABSTRACTA systematic study on the influence of two intense, linearly polarized, nonresonant laser fields, in a crossed configuration, on the electron energy levels and density of states in GaAs/AlGaAs quantum wells is performed. The carrier confinement pattern and the density of states are shown to be modified by the laser beams. For laser field polarizations parallel to the growth direction only the conduction band profile is changed, inducing strong blueshifts on energy levels which depend monotonically on both the laser intensity and frequency, besides, we detected that such blueshifts are larger for higher energy levels. On the other hand, for in-plane polarizations only the density of states is altered, changing its profile smoothly in function of the applied laser intensity and frequency, which suggests an interesting laser tuning mechanism that can be used to adjust the optical and transport properties of low-dimensional semiconductor devices under intense laser fields. In the absence of laser fields, we investigated the influence of non-abrupt doping profiles on the carrier sheet density in one-side modulation-doped GaAs/AlGaAs graded quantum wells. A proper discretization method for non-uniform meshes was proposed in order to solve the coupled Schrödinger and Poisson equations self-consistently. We noted, for this quantum system, a significant increase in the electron sheet density in function of the donors diffusion length, pointing, therefore, the probable cause for the underestimations in the two-dimensional electron gas density verified in previous works based upon the abrupt doping profile. We also found that the effect of the non-abruptness on the charge transfer is diminished by the increase of spacer layer thickness, which separates the carriers from the remote donors. The effects of internal electric fields and graded interfaces on the conduction band profile and on the energies of intersubband transitions for GaN/AlGaN quantum wells with wurtzite structure were also analyzed. Once more, the presence of blueshifts induced by intrinsic polarization electric fields and by graded interfaces was identified. While the effect of piezoelectric and spontaneous polarizations is more pronounced for larger quantum wells, the effect produced by the graded interfaces is more pronounced for narrow quantum wells, indicating the great importance of this latter effect on semiconductor nanodevices. A significant increase in the electron sheet density in function of the donors diffusion length was also found for modulation-doped GaN/AlGaN quantum wells