Fas ligand and soluble Fas -opposing molecules in melanoma lung metastasis

Deregulation of apoptotic cell death can result in aberrant accumulation of cells and increased tumor incidence. Fas (CD95) and Fas ligand (FasL) are a receptor-ligand pair whose activation induces apoptosis in many cell types. Previously, we demonstrated that low metastatic, Fas+ K1735-P murine melanoma cells spontaneously metastasize to the lung following orthotopic injection into FasL-deficient (gld) mice compared to wild-type (wt) controls. We further demonstrated that the expression of the Fas antagonist soluble Fas (sFas) directly correlates with disease stage in patients with melanoma, breast, and colon cancer. These findings document a role for host-derived FasL, in the control of metastatic disease and suggest a role for tumor-associated sFas in acquiring metastatic potential. To directly test whether FasL expressed on lymphocytes or on lung stromal cells restricts metastasis, bone marrow chimeras were generated between C3H wt and C3H gld mice. Chimeric animals were injected subcutaneously with 5 × 105 K1735-P and the incidence and number of spontaneous lung metastases scored. The data show that wt mice receiving gld marrow had a greater number of lung metastases (median 9.5, range 2–31) than gld mice reconstituted with wt marrow (median 1, range 0–31; p < 0.016). Interestingly, both groups had fewer metastases compared to gld controls (median 18.5, range 0–46) but more than wt controls (median 2, range 0–7). These observations provide the first evidence that both hematopoietic- and nonhematopoietic-host derived FasL, are important in the control of melanoma metastasis to the lung. To directly test whether tumor-associated sFas expression can enhance metastasis, K1735-P cells were transfected with three isoforms of sFas (Exo4Del, Exo6Del, and Exo3, 4, 6Del). RT-PCR and ELISA analysis confirmed the expression of sFas RNA and protein respectively. Following intravenous injection of 5 × 104 cells, sFas transfected cells formed significantly more experimental lung metastases [Exo6Del clone 3 (median 22, range 0–36), Exo6Del clone 7 (median 31, range 4–50), Exo3, 4, 6Del (median 22.5, range 13–48)] compared to vector control cells (median 6.5, range 3–29). Together, these data provide the first evidence that sFas is sufficient to enhance the metastatic potential of Fas+ melanoma cells. ^

Relaciones de similitud y valor discriminativo de los indicadores bibliométricos: el caso de los indicadores de Scimago Journal and Country Rank aplicados a las revistas generalistas de paleontología

Los objetivos de este trabajo son: (1) analizar las relaciones de similitud de los indicadores bibliométricos; y (2) estudiar el valor de estos para discriminar/agrupar revistas científicas. Como unidades de estudio se utilizaron los 15 indicadores brindados por SCImago Journal Rank (SCImagoJR), aplicados a las 11 revistas paleontológicas generalistas listadas en dicha fuente durante el lapso 1999-2013. Las relaciones de similitud entre los indicadores se estimaron mediante un fenograma, mientras que el valor de los indicadores para agrupar/discriminar revistas se estimó mediante un análisis de componentes principales. Los resultados permiten concluir que, al menos para las revistas consideradas en este estudio, los 15 indicadores utilizados por SCImagoJR muestran redundancia por grupos, debido a las correlaciones existentes entre indicadores de producción, por una parte, y de citación, por otra. Sin embargo, esto es válido solo a los efectos de agrupar las revistas, ya que al considerar cada indicador por separado se aprecian variaciones entre los mismos, que permiten establecer una caracterización más específica de cada revista e, incluso, colaboran a explicar los resultados del análisis multivariado. Por otra parte, los resultados coinciden con los obtenidos por otros autores al reunir en un mismo grupo al SJR y al número de citas/documento en un período de dos años y en otro al índice h y al indicador número total de citas en un lapso de tres años.

Relaciones de similitud y valor discriminativo de los indicadores bibliométricos: el caso de los indicadores de Scimago Journal and Country Rank aplicados a las revistas generalistas de paleontología

Los objetivos de este trabajo son: (1) analizar las relaciones de similitud de los indicadores bibliométricos; y (2) estudiar el valor de estos para discriminar/agrupar revistas científicas. Como unidades de estudio se utilizaron los 15 indicadores brindados por SCImago Journal Rank (SCImagoJR), aplicados a las 11 revistas paleontológicas generalistas listadas en dicha fuente durante el lapso 1999-2013. Las relaciones de similitud entre los indicadores se estimaron mediante un fenograma, mientras que el valor de los indicadores para agrupar/discriminar revistas se estimó mediante un análisis de componentes principales. Los resultados permiten concluir que, al menos para las revistas consideradas en este estudio, los 15 indicadores utilizados por SCImagoJR muestran redundancia por grupos, debido a las correlaciones existentes entre indicadores de producción, por una parte, y de citación, por otra. Sin embargo, esto es válido solo a los efectos de agrupar las revistas, ya que al considerar cada indicador por separado se aprecian variaciones entre los mismos, que permiten establecer una caracterización más específica de cada revista e, incluso, colaboran a explicar los resultados del análisis multivariado. Por otra parte, los resultados coinciden con los obtenidos por otros autores al reunir en un mismo grupo al SJR y al número de citas/documento en un período de dos años y en otro al índice h y al indicador número total de citas en un lapso de tres años.

Relaciones de similitud y valor discriminativo de los indicadores bibliométricos: el caso de los indicadores de Scimago Journal and Country Rank aplicados a las revistas generalistas de paleontología

Los objetivos de este trabajo son: (1) analizar las relaciones de similitud de los indicadores bibliométricos; y (2) estudiar el valor de estos para discriminar/agrupar revistas científicas. Como unidades de estudio se utilizaron los 15 indicadores brindados por SCImago Journal Rank (SCImagoJR), aplicados a las 11 revistas paleontológicas generalistas listadas en dicha fuente durante el lapso 1999-2013. Las relaciones de similitud entre los indicadores se estimaron mediante un fenograma, mientras que el valor de los indicadores para agrupar/discriminar revistas se estimó mediante un análisis de componentes principales. Los resultados permiten concluir que, al menos para las revistas consideradas en este estudio, los 15 indicadores utilizados por SCImagoJR muestran redundancia por grupos, debido a las correlaciones existentes entre indicadores de producción, por una parte, y de citación, por otra. Sin embargo, esto es válido solo a los efectos de agrupar las revistas, ya que al considerar cada indicador por separado se aprecian variaciones entre los mismos, que permiten establecer una caracterización más específica de cada revista e, incluso, colaboran a explicar los resultados del análisis multivariado. Por otra parte, los resultados coinciden con los obtenidos por otros autores al reunir en un mismo grupo al SJR y al número de citas/documento en un período de dos años y en otro al índice h y al indicador número total de citas en un lapso de tres años.

Dissolved and dissolvable iron concentrations and ligand characteristics in samples taken during POLARSTERN expedition ARK-XXII/2 to the Arctic Ocean

The speciation of iron was investigated in three shelf seas and three deep basins of the Arctic Ocean in 2007. The dissolved fraction (<0.2 µm) and a fraction < 1000 kDa were considered here. In addition, unfiltered samples were analyzed. Between 74 and 83% of dissolved iron was present in the fraction < 1000 kDa at all stations and depth, except at the chlorophyll maximum (42-64%). Distinct trends in iron concentrations and ligand characteristics were observed from the shelf seas toward the central deep basins, with a decrease of total dissolvable iron ([TDFe] > 3 nM on the shelves and [TDFe] < 2 nM in the Makarov Basin). A relative enrichment of particulate Fe toward the bottom was revealed at all stations, indicating Fe export toward the deep ocean. In deep waters, dissolved ligands became less saturated with Fe (increase of [Excess L]/[Fe]) from the Nansen Basin via the Amundsen Basin toward the Makarov Basin. This trend was explained by the reactivity of the ligands, higher (log alpha > 13.5) in the Nansen and Amundsen basins than in the Makarov Basin (log alpha <13) where the sources of Fe and ligands were limited. The ligands became nearly saturated with depth in the Amundsen and Nansen Basins, favoring Fe removal in the deep ocean, whereas in the deep Makarov Basin, they became unsaturated with depth. Still here scavenging occurred. Although scavenging of Fe was attenuated by the presence of unsaturated organic ligands, their low reactivity in combination with a lack of sources of Fe in the Makarov Basin might be the reason of a net export of Fe to the sediment.

Average fluorescence and dissolved iron and Fe-binding ligand characteristics during POLARSTERN expedition ANT-XXIV/3 in 2008

Organic complexation of dissolved iron (dFe) was investigated in the Atlantic sector of the Southern Ocean in order to understand the distribution of Fe over the whole water column. The total concentration of dissolved organic ligands ([Lt]) measured by voltammetry ranged between 0.54 and 1.84 nEq of M Fe whereas the conditional binding strength (K') ranged between 10**21.4 and 10**22.8. For the first time, trends in Fe-organic complexation were observed in an ocean basin by examining the ratio ([Lt]/[dFe]), defined as the organic ligand concentration divided by the dissolved Fe concentration. The [Lt]/[dFe] ratio indicates the saturation state of the natural ligands with Fe; a ratio near 1 means saturation of the ligands leading to precipitation of Fe. Reversely, high ratios mean Fe depletion and show a high potential for Fe solubilisation. In surface waters where phytoplankton is present low dissolved Fe and high variable ligand concentrations were found. Here the [Lt]/[dFe] ratio was on average 4.4. It was especially high (5.6-26.7) in the HNLC (High Nutrient, Low Chlorophyll) regions, where Fe was depleted. The [Lt]/[dFe] ratio decreased with depth due to increasing dissolved Fe concentrations and became constant below 450 m, indicating a steady state between ligand and Fe. Relatively low [Lt]/[dFe] ratios (between 1.1 and 2.7) existed in deep water north of the Southern Boundary, facilitating Fe precipitation. The [Lt]/[dFe] ratio increased southwards from the Southern Boundary on the Zero Meridian and from east to west in the Weddell Gyre due to changes both in ligand characteristics and in dissolved iron concentration. High [Lt]/[dFe] ratio expresses Fe depletion versus ligand production in the surface. The decrease with depth reflects the increase of [dFe] which favours scavenging and (co-) precipitation, whereas a horizontal increase in the deep waters results from an increasing distance from Fe sources. This increase in the [Lt]/[dFe] ratio at depth shows the very resistant nature of the dissolved organic ligands.

Oxygen Reduction Reaction on Pt Overlayers Deposited onto a Gold Film: Ligand, Strain, and Ensemble Effect

We study the oxygen reduction reaction (ORR), the catalytic process occurring at the cathode in fuel cells, on Pt layers prepared by electrodeposition onto an Au substrate. Using a nominal Pt layer by layer deposition method previously proposed, imperfect layers of Pt on Au are obtained. The ORR on deposited Pt layers decreases with increasing Pt thickness. In the submonolayer region, however, the ORR activity is superior to that of bulk Pt. Using density functional theory (DFT) calculations, we correlate the observed activity trend to strain, ligand, and ensemble effects. At submonolayer coverage certain atom configurations weaken the binding energies of reaction intermediates due to a ligand and ensemble effect, thus effectively increasing the ORR activity. At higher Pt coverage the activity is governed by a strain effect, which lowers the activity by decreasing the oxidation potential of water. This study is a nice example of how the influence of strain, ligand, and ensemble effects on the ORR can be deconvoluted.

Computational study of ligand binding in lipid transfer proteins: Structures, interfaces, and free energies of protein-lipid complexes

Plant nonspecific lipid transfer proteins (nsLTPs) bind a wide variety of lipids, which allows them to perform disparate functions. Recent reports on their multifunctionality in plant growth processes have posed new questions on the versatile binding abilities of these proteins. The lack of binding specificity has been customarily explained in qualitative terms on the basis of a supposed structural flexibility and nonspecificity of hydrophobic protein-ligand interactions. We present here a computational study of protein-ligand complexes formed between five nsLTPs and seven lipids bound in two different ways in every receptor protein. After optimizing geometries inmolecular dynamics calculations, we computed Poisson- Boltzmann electrostatic potentials, solvation energies, properties of the protein-ligand interfaces, and estimates of binding free energies of the resulting complexes. Our results provide the first quantitative information on the ligand abilities of nsLTPs, shed new light into protein-lipid interactions, and reveal new features which supplement commonly held assumptions on their lack of binding specificity.

Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-γ ligand troglitazone in patients with liposarcoma

Agonist ligands for the nuclear receptor peroxisome proliferator-activated receptor-γ have been shown to induce terminal differentiation of normal preadipocytes and human liposarcoma cells in vitro. Because the differentiation status of liposarcoma is predictive of clinical outcomes, modulation of the differentiation status of a tumor may favorably impact clinical behavior. We have conducted a clinical trial for treatment of patients with advanced liposarcoma by using the peroxisome proliferator-activated receptor-γ ligand troglitazone, in which extensive correlative laboratory studies of tumor differentiation were performed. We report here the results of three patients with intermediate to high-grade liposarcomas in whom troglitazone administration induced histologic and biochemical differentiation in vivo. Biopsies of tumors from each of these patients while on troglitazone demonstrated histologic evidence of extensive lipid accumulation by tumor cells and substantial increases in NMR-detectable tumor triglycerides compared with pretreatment biopsies. In addition, expression of several mRNA transcripts characteristic of differentiation in the adipocyte lineage was induced. There was also a marked reduction in immunohistochemical expression of Ki-67, a marker of cell proliferation. Together, these data indicate that terminal adipocytic differentiation was induced in these malignant tumors by troglitazone. These results indicate that lineage-appropriate differentiation can be induced pharmacologically in a human solid tumor.