Multimodal Treatment Eliminates Cancer Stem Cells and Leads to Long-Term Survival in Primary Human Pancreatic Cancer Tissue Xenografts.

Copyright: 2013 Hermann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.PURPOSE: In spite of intense research efforts, pancreatic ductal adenocarcinoma remains one of the most deadly malignancies in the world. We and others have previously identified a subpopulation of pancreatic cancer stem cells within the tumor as a critical therapeutic target and additionally shown that the tumor stroma represents not only a restrictive barrier for successful drug delivery, but also serves as a paracrine niche for cancer stem cells. Therefore, we embarked on a large-scale investigation on the effects of combining chemotherapy, hedgehog pathway inhibition, and mTOR inhibition in a preclinical mouse model of pancreatic cancer. EXPERIMENTAL DESIGN: Prospective and randomized testing in a set of almost 200 subcutaneous and orthotopic implanted whole-tissue primary human tumor xenografts. RESULTS: The combined targeting of highly chemoresistant cancer stem cells as well as their more differentiated progenies, together with abrogation of the tumor microenvironment by targeting the stroma and enhancing tissue penetration of the chemotherapeutic agent translated into significantly prolonged survival in preclinical models of human pancreatic cancer. Most pronounced therapeutic effects were observed in gemcitabine-resistant patient-derived tumors. Intriguingly, the proposed triple therapy approach could be further enhanced by using a PEGylated formulation of gemcitabine, which significantly increased its bioavailability and tissue penetration, resulting in a further improved overall outcome. CONCLUSIONS: This multimodal therapeutic strategy should be further explored in the clinical setting as its success may eventually improve the poor prognosis of patients with pancreatic ductal adenocarcinoma

Hemidesmus indicus induces apoptosis via proteasome inhibition and generation of reactive oxygen species.

Proteasome inhibition represents an important anticancer strategy. Here, we studied the mechanisms at the basis of the pro-apoptotic activity of the standardized decoction of Hemidesmus indicus, a plant evoking a complex anticancer activity, and explored its inhibition of proteasome activity in human leukemia cells. Additionally, we preliminary tested the cytotoxicity of some H. indicus's phytochemicals on leukemia cells and their intestinal absorption on a human intestinal epithelium model consisting of a monolayer of differentiated Caco2 cells. We observed a potent antileukemic effect for H. indicus, imputable to the modulation of different critical targets at protein and mRNA levels and the reduction of the 26S proteasome expression. We found that some phytomarkers of H. indicus decoction passed through the enterocyte monolayer. Overall, our study supports the pharmacological potential of H. indicus, which can represent an interesting botanical drug in the oncological area

Direct constraint on the distance of y2 Velorum from AMBER/VLTI observations

In this work, we present the first AMBER observations, of the Wolf-Rayet and O (WR+O) star binary system y2 Velorum. The AMBER instrument was used with the telescopes UT2, UT3, and UT4 on baselines ranging from 46m to 85m. It delivered spectrally dispersed visibilities, as well as differential and closure phases, with a resolution R = 1500 in the spectral band 1.95-2.17 micron. We interpret these data in the context of a binary system with unresolved components, neglecting in a first approximation the wind-wind collision zone flux contribution. We show that the AMBER observables result primarily from the contribution of the individual components of the WR+O binary system. We discuss several interpretations of the residuals, and speculate on the detection of an additional continuum component, originating from the free-free emission associated with the wind-wind collision zone (WWCZ), and contributing at most to the observed K-band flux at the 5% level. The expected absolute separation and position angle at the time of observations were 5.1±0.9mas and 66±15° respectively. However, we infer a separation of 3.62+0.11-0.30 mas and a position angle of 73+9-11°. Our analysis thus implies that the binary system lies at a distance of 368+38-13 pc, in agreement with recent spectrophotometric estimates, but significantly larger than the Hipparcos value of 258+41-31 pc

Near-Infrared interferometry of Eta Carinae with high spatial and spectral resolution using the VLTI and the AMBER instrument

We present the first NIR spectro-interferometry of the LBV Eta Carinae. The K band observations were performed with the AMBER instrument of the ESO Very Large Telescope Interferometer using three 8.2m Unit Telescopes with baselines from 42 to 89m. The aim of this work is to study the wavelength dependence of Eta Car's optically thick wind region with a high spatial resolution of 5 mas (11 AU) and high spectral resolution. The medium spectral resolution observations (R=1,500) were performed in the wavelength range around both the HeI 2.059 micron and the Br gamma 2.166 micron emission lines, the high spectral resolution observations (R=12,000) only in the Br gamma line region. In the K-band continuum, a diameter of 4.0 +/-0.2 mas (Gaussian FWHM, fit range 28-89m) was measured for Eta Car's optically thick wind region. If we fit Hillier et al. (2001) model visibilities to the observed AMBER visibilities, we obtain 50 % encircled-energy diameters of 4.2, 6.5 and 9.6mas in the 2.17 micron continuum, the HeI, and the Br gamma emission lines, respectively. In the continuum near the Br gamma line, an elongation along a position angle of 120+/-15 degrees was found, consistent with previous VLTI/VINCI measurements by van Boekel et al. (2003). We compare the measured visibilities with predictions of the radiative transfer model of Hillier et al. (2001), finding good agreement. Furthermore, we discuss the detectability of the hypothetical hot binary companion. For the interpretation of the non-zero differential and closure phases measured within the Br gamma line, we present a simple geometric model of an inclined, latitude-dependent wind zone. Our observations support theoretical models of anisotropic winds from fast-rotating, luminous hot stars with enhanced high-velocity mass loss near the polar regions.Comment: 22 pages, 14 figures, 2 tables; A&A in pres