High-grade ovarian serous carcinoma patients exhibit profound alterations in lipid metabolism

Ovarian cancer is a very severe type of disease with poor prognosis. Treatment of ovarian cancer is challenging because of the lack of tests for early detection and effective therapeutic targets. Thus, new biomarkers are needed for both diagnostics and better understanding of the cellular processes of the disease. Small molecules, consisting of metabolites or lipids, have shown emerging potential for ovarian cancer diagnostics. Here we performed comprehensive lipidomic profiling of serum and tumor tissue samples from high-grade serous ovarian cancer patients to find lipids that were altered due to cancer and also associated with progression of the disease. Ovarian cancer patients exhibited an overall reduction of most lipid classes in their serum as compared to a control group. Despite the overall reduction, there were also specific lipids showing elevation, and especially alterations in ceramide and triacylglycerol lipid species were dependent on their fatty acyl side chain composition. Several lipids showed progressive alterations in patients with more advanced disease and poorer overall survival, and outperformed CA-125 as prognostic markers. The abundance of many serum lipids correlated with their abundance in tumor tissue samples. Furthermore, we found a negative correlation of serum lipids with 3-hydroxybutyric acid, suggesting an association between decreased lipid levels and fatty acid oxidation. In conclusion, here we present a comprehensive analysis of lipid metabolism alterations in ovarian cancer patients, with clinical implications.Peer reviewe

The HARPS search for southern extra-solar planets XXXV. Super-Earths around the M-dwarf neighbors Gl433 and Gl667C

M dwarfs have been found to often have super-Earth planets with short orbital periods. Such stars are thus preferential targets in searches for rocky or ocean planets in the solar neighbourhood. In a recent paper (Bonfils et al. 2011), we announced the discovery of respectively 1 and 2 low mass planets around the M1.5V stars Gl433 and Gl667C. We found those planets with the HARPS spectrograph on the ESO~3.6-m telescope at La Silla Observatory, from observations obtained during the Guaranteed Time Observing program of that instrument. We have obtained additional HARPS observations of those two stars, for a total of respectively 67 and 179 Radial Velocity measurements for Gl433 and Gl667C, and present here an orbital analysis of those extended data sets and our main conclusion about both planetary systems. One of the three planets, Gl667Cc, has a mass of only M2.sin(i)~4.25 M_earth and orbits in the central habitable zone of its host star. It receives just 10% less stellar energy from Gl667C than the Earth receives from the Sun. However planet evolution in habitable zone can be very different if the host star is a M dwarf or a solar-like star, without necessarily questioning the presence of water. The two other planets, Gl433b and Gl667Cb, both have M2.sin(i) of ~5.5 M_earth and periods of ~7 days. The Radial Velocity measurements of both stars contain longer time scale signals, which we fit as longer period Keplerians. For Gl433 that signal probably originates in a Magnetic Cycle, while a longer time span will be needed to conclude for Gl667C. The metallicity of Gl433 is close to solar, while Gl667C is metal poor with [Fe/H] ~ -0.6. This reinforces the recent conclusion that the occurence of Super-Earth planets does not strongly correlate with stellar metallicity.Comment: 14 pages, 8 figures, submitted to A&

Classification of Molecular Subtypes of High-Grade Serous Ovarian Cancer by MALDI-Imaging.

Despite the correlation of clinical outcome and molecular subtypes of high-grade serous ovarian cancer (HGSOC), contemporary gene expression signatures have not been implemented in clinical practice to stratify patients for targeted therapy. Hence, we aimed to examine the potential of unsupervised matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) to stratify patients who might benefit from targeted therapeutic strategies. Molecular subtyping of paraffin-embedded tissue samples from 279 HGSOC patients was performed by NanoString analysis (ground truth labeling). Next, we applied MALDI-IMS paired with machine-learning algorithms to identify distinct mass profiles on the same paraffin-embedded tissue sections and distinguish HGSOC subtypes by proteomic signature. Finally, we devised a novel approach to annotate spectra of stromal origin. We elucidated a MALDI-derived proteomic signature (135 peptides) able to classify HGSOC subtypes. Random forest classifiers achieved an area under the curve (AUC) of 0.983. Furthermore, we demonstrated that the exclusion of stroma-associated spectra provides tangible improvements to classification quality (AUC = 0.988). Moreover, novel MALDI-based stroma annotation achieved near-perfect classifications (AUC = 0.999). Here, we present a concept integrating MALDI-IMS with machine-learning algorithms to classify patients according to distinct molecular subtypes of HGSOC. This has great potential to assign patients for personalized treatment

Immunotherapeutic targeting of membrane Hsp70-expressing tumors using recombinant human granzyme B

Background: We have previously reported that human recombinant granzyme B (grB) mediates apoptosis in membrane heat shock protein 70 (Hsp70)-positive tumor cells in a perforin-independent manner

Tumor Growth Rate Estimates Are Independently Predictive of Therapy Response and Survival in Recurrent High-Grade Serous Ovarian Cancer Patients

This study aimed to assess the predictive value of tumor growth rate estimates based on serial cancer antigen-125 (CA-125) levels on therapy response and survival of patients with recurrent high-grade serous ovarian cancer (HGSOC). In total, 301 consecutive patients with advanced HGSOC (exploratory cohort: n = 155, treated at the Medical University of Vienna; external validation cohort: n = 146, from the Ovarian Cancer Therapy–Innovative Models Prolong Survival (OCTIPS) consortium) were enrolled. Tumor growth estimates were obtained using a validated two-phase equation model involving serial CA-125 levels, and their predictive value with respect to treatment response to the next chemotherapy and the prognostic value with respect to disease-specific survival and overall survival were assessed. Tumor growth estimates were an independent predictor for response to second-line chemotherapy and an independent prognostic factor for second-line chemotherapy use in both univariate and multivariable analyses, outperforming both the predictive (second line: p = 0.003, HR 5.19 [1.73–15.58] vs. p = 0.453, HR 1.95 [0.34–11.17]) and prognostic values (second line: p = 0.042, HR 1.53 [1.02–2.31] vs. p = 0.331, HR 1.39 [0.71–2.27]) of a therapy-free interval (TFI) < 6 months. Tumor growth estimates were a predictive factor for response to third- and fourth-line chemotherapy and a prognostic factor for third- and fourth-line chemotherapy use in the univariate analysis. The CA-125-derived tumor growth rate estimate may be a quantifiable and easily assessable surrogate to TFI in treatment decision making for patients with recurrent HGSOC

Improvement of islet transplantation by the fusion of islet cells with functional blood vessels

Pancreatic islet transplantation still represents a promising therapeutic strategy for curative treatment of type 1 diabetes mellitus. However, a limited number of organ donors and insufficient vascularization with islet engraftment failure restrict the successful transfer of this approach into clinical practice. To overcome these problems, we herein introduce a novel strategy for the generation of prevascularized islet organoids by the fusion of pancreatic islet cells with functional native microvessels. These insulin-secreting organoids exhibit a significantly higher angiogenic activity compared to freshly isolated islets, cultured islets, and non-prevascularized islet organoids. This is caused by paracrine signaling between the β-cells and the microvessels, mediated by insulin binding to its corresponding receptor on endothelial cells. In vivo, the prevascularized islet organoids are rapidly blood-perfused after transplantation by the interconnection of their autochthonous microvasculature with surrounding blood vessels. As a consequence, a lower number of islet grafts are required to restore normoglycemia in diabetic mice. Thus, prevascularized islet organoids may be used to improve the success rates of clinical islet transplantation

Internal capsule size associated with outcome in first-episode schizophrenia

Subtle structural brain abnormalities are an established finding in first-episode psychosis. Nevertheless their relationship to the clinical course of schizophrenia is controversially discussed. In a multicentre study 45 first-episode schizophrenia patients (FE-SZ) underwent standardized MRI scanning and were followed up to 1 year. In 32 FE-SZ volumetric measurement of three regions of interests (ROIs) potentially associated with disease course, hippocampus, lateral ventricle and the anterior limb of the internal capsule (ALIC) could be performed. The subgroups of FE-SZ with good (12 patients) and poor outcome (11 patients), defined by a clinically relevant change of the PANSS score, were compared with regard to these volumetric measures. Multivariate analysis of covariance revealed a significant reduced maximal cross sectional area of the left ALIC in FE-SZ with clinically relevant deterioration compared to those with stable psychopathology. There were no differences in the other selected ROIs between the two subgroups. In conclusion, reduced maximal area of ALIC, which can be interpreted as a disturbance of fronto-thalamic connectivity, is associated with poor outcome during the 1 year course of first-episode schizophrenia

Reaction rates and transport in neutron stars

Understanding signals from neutron stars requires knowledge about the transport inside the star. We review the transport properties and the underlying reaction rates of dense hadronic and quark matter in the crust and the core of neutron stars and point out open problems and future directions.Comment: 74 pages; commissioned for the book "Physics and Astrophysics of Neutron Stars", NewCompStar COST Action MP1304; version 3: minor changes, references updated, overview graphic added in the introduction, improvements in Sec IV.A.