Metronomic antiangiogenic therapy with capecitabine and celecoxib in advanced tumor patients--results of a phase II study

Combined therapy of continuous low dose capecitabine and high dose celecoxib targeting angiogenesis was used in a phase II trial to treat advanced cancer patients. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to monitor antiangiogenic effects.; 37 Patients (21 men, 16 women), mean age 60 years, with advanced and progressive cancer of various tumor types were included. Therapy consisted of 2 x 500 mg oral capecitabine/ day and 2 x 400 mg oral celecoxib/day continuously until progression of disease. To monitor antiangiogenic effects, DCE-MRI measurements were performed at baseline, after 1 month, and after 3 months of therapy. Tumor assessment was performed according to RECIST criteria, toxicity was evaluated according to the CTC version 2.0 catalogue.; Therapy was well tolerated without grade 3 and 4 toxicities. The mean number of treatment cycles was 4 (range: 1-15+). Disease stabilization after 3 cycles was seen in 11 patients. 6 patients were stable over long periods. The mean number of treatment cycles in this group was 10 (range: 7-15+). DCE-MRI demonstrated a reduction of tumor vessel permeability and blood flow in patients who reached stable disease or some minor regression.; Continuous dosing of the combination of capecitabine and celecoxib was well tolerated, produced antiangiogenic effects, and has antitumor activity. Patients with rapid progression did not benefit

Beiträge zur Geschichte des Landkreises Regensburg 36

Lehrer der Realschule Neutraubling erzählen aus ihrer Schulzei

The Spitzer High Redshift Radio Galaxy Survey

We present results from a comprehensive imaging survey of 70 radio galaxies at redshifts 1<z<5.2 using all three cameras onboard the Spitzer Space Telescope. The resulting spectral energy distributions unambiguously show a stellar population in 46 sources and hot dust emission associated with the active nucleus in 59. Using a new restframe S_3um/S_1.6um versus S_um/S_3um criterion, we identify 42 sources where the restframe 1.6um emission from the stellar population can be measured. For these radio galaxies, the median stellar mass is high, 2x10^11 M_sun, and remarkably constant within the range 13, there is tentative evidence for a factor of two decrease in stellar mass. This suggests that radio galaxies have assembled the bulk of their stellar mass by z~3, but confirmation by more detailed decomposition of stellar and AGN emission is needed. The restframe 500 MHz radio luminosities are only marginally correlated with stellar mass but are strongly correlated with the restframe 5um hot dust luminosity. This suggests that the radio galaxies have a large range of Eddington ratios. We also present new Very Large Array 4.86 and 8.46 GHz imaging of 14 radio galaxies and find that radio core dominance --- an indicator of jet orientation --- is strongly correlated with hot dust luminosity. While all of our targets were selected as narrow-lined, type 2 AGNs, this result can be understood in the context of orientation-dependent models if there is a continuous distribution of orientations from obscured type 2 to unobscured type 1 AGNs rather than a clear dichotomy. Finally, four radio galaxies have nearby (<6") companions whose mid-IR colors are suggestive of their being AGNs. This may indicate an association between radio galaxy activity and major mergers.Comment: 31 pages, 125 figures. Accepted for publication in the Astrophysical Journa

Insulin Sensitivity Is Reflected by Characteristic Metabolic Fingerprints - A Fourier Transform Mass Spectrometric Non-Targeted Metabolomics Approach

BACKGROUND: A decline in body insulin sensitivity in apparently healthy individuals indicates a high risk to develop type 2 diabetes. Investigating the metabolic fingerprints of individuals with different whole body insulin sensitivity according to the formula of Matsuda, et al. (ISI(Matsuda)) by a non-targeted metabolomics approach we aimed a) to figure out an unsuspicious and altered metabolic pattern, b) to estimate a threshold related to these changes based on the ISI, and c) to identify the metabolic pathways responsible for the discrimination of the two patterns. METHODOLOGY AND PRINCIPAL FINDINGS: By applying infusion ion cyclotron resonance Fourier transform mass spectrometry, we analyzed plasma of 46 non-diabetic subjects exhibiting high to low insulin sensitivities. The orthogonal partial least square model revealed a cluster of 28 individuals with alterations in their metabolic fingerprints associated with a decline in insulin sensitivity. This group could be separated from 18 subjects with an unsuspicious metabolite pattern. The orthogonal signal correction score scatter plot suggests a threshold of an ISI(Matsuda) of 15 for the discrimination of these two groups. Of note, a potential subgroup represented by eight individuals (ISI(Matsuda) value between 8.5 and 15) was identified in different models. This subgroup may indicate a metabolic transition state, since it is already located within the cluster of individuals with declined insulin sensitivity but the metabolic fingerprints still show some similarities with unaffected individuals (ISI >15). Moreover, the highest number of metabolite intensity differences between unsuspicious and altered metabolic fingerprints was detected in lipid metabolic pathways (arachidonic acid metabolism, metabolism of essential fatty acids and biosynthesis of unsaturated fatty acids), steroid hormone biosyntheses and bile acid metabolism, based on data evaluation using the metabolic annotation interface MassTRIX. CONCLUSIONS: Our results suggest that altered metabolite patterns that reflect changes in insulin sensitivity respectively the ISI(Matsuda) are dominated by lipid-related pathways. Furthermore, a metabolic transition state reflected by heterogeneous metabolite fingerprints may precede severe alterations of metabolism. Our findings offer future prospects for novel insights in the pathogenesis of the pre-diabetic phase

Phase I and pharmacokinetic study of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin

The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that shows superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats, and dogs compared with doxorubicin. The purpose of the phase I study was to characterize the toxicity profile of DOXO-EMCH, establish a recommended dose for phase II studies, and assess potential anticancer activity.; A starting dose of 20 mg/m2 doxorubicin equivalents was chosen. Forty-one patients with advanced cancer disease were treated with an i.v. infusion of DOXO-EMCH once every 3 weeks at a dose level of 20 to 340 mg/m2 doxorubicin equivalents.; Treatment with DOXO-EMCH was well tolerated up to 200 mg/m2 without manifestation of drug-related side effects. Myelosuppression (grade 1-2) and mucositis (grade 1-2) were the predominant adverse effects at dose levels of 260 mg/m2 and myelosuppression (grade 1-3) as well as mucositis (grade 1-3) were dose limiting at 340 mg/m2. No cardiac toxicity was observed. Of 30 of 41 evaluable patients, 12 patients (40%) had progressive disease, 15 patients (57%) had stable disease, and 3 patients (10%) had a partial remission.; DOXO-EMCH showed a good safety profile and was able to induce tumor regressions in tumor types known to be anthracycline-sensitive tumors, such as breast cancer, small cell lung cancer, and sarcoma. The recommended doxorubicin equivalent dose for phase II studies is 260 mg/m2

Inhibition of Phosphatidylinositol 3-Kinase by Pictilisib Blocks Influenza Virus Propagation in Cells and in Lungs of Infected Mice

Influenza virus (IV) infections are considered to cause severe diseases of the respiratory tract. Beyond mild symptoms, the infection can lead to respiratory distress syndrome and multiple organ failure. Occurrence of resistant seasonal and pandemic strains against the currently licensed antiviral medications points to the urgent need for new and amply available anti-influenza drugs. Interestingly, the virus-supportive function of the cellular phosphatidylinositol 3-kinase (PI3K) suggests that this signaling module may be a potential target for antiviral intervention. In the sense of repurposing existing drugs for new indications, we used Pictilisib, a known PI3K inhibitor to investigate its effect on IV infection, in mono-cell-culture studies as well as in a human chip model. Our results indicate that Pictilisib is a potent inhibitor of IV propagation already at early stages of infection. In a murine model of IV pneumonia, the in vitro key findings were verified, showing reduced viral titers as well as inflammatory response in the lung after delivery of Pictilisib. Our data identified Pictilisib as a promising drug candidate for anti-IV therapies that warrant further studying. These results further led to the conclusion that the repurposing of previously approved substances represents a cost-effective and efficient way for development of novel antiviral strategies

Heat map of plasma metabolites from linoleic acid (LA), α-linolenic acid (ALA), arachidonic acid (AA) pathways and biosynthesis of unsaturated fatty acid (BUFA).

<p>The heat map represents the signal intensities of 18 subjects with normal insulin sensitivity (ISI_Matsuda >15), eight individuals who are in the metabolic transition state and 20 individuals with declined insulin sensitivity (ISI_Matsuda <15). Individual ISI_Matsuda levels in increasing order are given in the column at the bottom. Cells are coloured based on the signal intensity measured in plasma. Shades of red to green represent high to low signal intensities of the metabolite ions in plasma (see color scale on the right side of the heat map). A yellow line is drawn at an ISI_Matsuda value of 15 to mark the potential ISI_Matsuda threshold separating individuals with altered and normal insulin sensitivity revealed in our NT-metabolomics approach. A dash dotted white line drawn at an ISI_Matsuda value of 8.5 marks the suggested threshold between individuals with distinct insulin resistant metabolic alterations and subjects who are in the metabolic transition state.</p

Investigation of individual metabolite fingerprints reflecting the metabolic conversion from normal to reduced insulin sensitivity.

<p>(<b>A</b>) Individual ISI_Matsuda values (to the right of each dot) assigned to the metabolite fingerprints in an OSC-PLS score scatter plot t<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013317#pone.0013317-DeFronzo1" target="_blank">[1]</a>u<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013317#pone.0013317-DeFronzo1" target="_blank">[1]</a> achieving R²(Y) = 0.94 and Q²(cum) = 0.90. (<b>B</b>) Score scatter plot of the first component tPS<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013317#pone.0013317-DeFronzo1" target="_blank">[1]</a> against ISI_Matsuda values using the transition group as external dataset. From this visualization it was inferred that the transition group revealed properties closer to the class of subjects with reduced ISI values. (<b>C</b>) A threshold of ISI_Matsuda  = 15 was set to generate an OPLS model showing a clustering into two groups of subjects, i.e. with normal and declined insulin sensitivity. Using CrossValidation-ANOVA the model showed a high significance (p = 4,76199×10⁻¹⁹). Furthermore, the model achieved the following parameters: R²(Y) = 0.96 and Q²(cum) = 0.93. Definition of labels: (▴) ISI_Matsuda level < 8.5, (*) ISI_Matsuda from >8.5 and <15, and (•) ISI_Matsuda >15.</p

Comparison of the signal intensities of diacylglycerol and sphingomyelin in plasma of individuals with reduced and normal insulin sensitivity.

<p>A non parametric Wilcoxon rank sum test was applied on the signal intensities of the ions with the elemental composition of (<b>A</b>) C₃₇H₆₆O₅ (possible assignment: Diacylglycerol) and (<b>B</b>) C₄₁H₈₃N₂O₆P (possible assignment: Sphingomyelin) to evaluate statistical significances between the two groups (ISI <15 (n =  28) <i>vs</i>. ISI_Matsuda >15 (n =  18)). On the right side the corresponding individual ICR-FT/MS spectra of the nominal masses are given; green  =  ISI >15 and red  =  ISI < 15. Mean peak areas ± standard error are shown, statistical significance (*) was set at p<0.05.</p