Adapting tumor interstitial fluid pressure for intraperitoneal chemotherapy

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Pretreatment with VEGF(R)-inhibitors reduces interstitial fluid pressure, increases intraperitoneal chemotherapy drug penetration, and impedes tumor growth in a mouse colorectal carcinomatosis model

Cytoreductive surgery combined with intraperitoneal chemotherapy (IPC) is currently the standard treatment for selected patients with peritoneal carcinomatosis of colorectal cancer. However, especially after incomplete cytoreduction, disease progression is common and this is likely due to limited tissue penetration and efficacy of intraperitoneal cytotoxic drugs. Tumor microenvironment-targeting drugs, such as VEGF(R) and PDGFR inhibitors, can lower the heightened interstitial fluid pressure in tumors, a barrier to drug delivery. Here, we investigated whether tumor microenvironment-targeting drugs enhance the effectiveness of intraperitoneal chemotherapy. A mouse xenograft model with two large peritoneal implants of colorectal cancer cells was developed to study drug distribution and tumor physiology during intraperitoneal Oxaliplatin perfusion. Mice were treated for six days with either Placebo, Imatinib (anti-PDGFR, daily), Bevacizumab (anti-VEGF, twice) or Pazopanib (anti-PDGFR, -VEGFR; daily) followed by intraperitoneal oxaliplatin chemotherapy. Bevacizumab and Pazopanib significantly lowered interstitial fluid pressure, increased Oxaliplatin penetration (assessed by laser ablation inductively coupled plasma mass spectrometry) and delayed tumor growth of peritoneal implants (assessed by MRI). Our findings suggest that VEGF(R)-inhibition may improve the efficacy of IPC, particularly for patients for whom a complete cytoreduction might not be feasible

SR 2D micro-XRF imaging on entire rat thin sections in view of a pharmacokinetic study of a new bromine containing drug agains tuberculosis

Tuberculosis (TB) is a common and often deadly infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis in humans. Because of population growth, the absolute number of new cases is still increasing. Multi-drug-resistant tuberculosis (MDR-TB) is defined as resistance to the two most effective first-line TB drugs and is a public health issue in many developing countries, as treatment is longer and requires more expensive drugs. Recently, a new experimental diarylquinoline anti-tuberculosis drug was discovered at Janssen Pharmaceutica, referred to as TMC207 and shown in Fig. 1. Before TMC207 can be made commercially available, one of the necessary investigations is a thorough pharmacokinetic study to investigate its absorption, distribution, metabolism and excretion (ADME)

Elemental bio-imaging of uranium and plutonium in tissues from occupationally exposed former nuclear workers

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Tectonic history of the Kyrgyz South Tien Shan (Atbashi-Inylchek) suture zone : the role of inherited structures during deformation-propagation

Multimethod chronology was applied on intrusives bordering the Kyrgyz South Tien Shan suture (STSs) to decipher the timing of (1) formation and amalgamation of the suturing units and (2) intracontinental deformation that built the bordering mountain ranges. Zircon U/Pb data indicate similarities between the Tien Shan and Tarim Precambrian crust. Caledonian (similar to 440-410 Ma) and Hercynian (similar to 310-280 Ma) zircon U/Pb ages were found at the edge of the STSs, related to subduction and closure of the Turkestan Ocean and the formation of the suture itself. Permian-Triassic (similar to 280-210 Ma) titanite fission track and zircon (U-Th)/He data record the first signs of exhumation when the STSs evolved into a shear zone and the adjacent Tarim basin started to subside. Low-temperature thermochronological (apatite fission track, zircon and apatite (U-Th)/He) analyses reveal three distinct cooling phases, becoming younger toward the STSs center: (1) Jurassic-Cretaceous cooling ages provide evidence that a Mesozoic South Tien Shan orogen formed as a response to the Cimmerian orogeny; (2) Early Paleogene (similar to 60-45 Ma) data indicate a renewed pulse of STSs reactivation during the Early Cenozoic; (3) Neogene ages constrain the onset of the modern Tien Shan mountain building to the Late Oligocene (similar to 30-25 Ma), which intensified during the Miocene (similar to 10-8 Ma) and Pliocene (similar to 3-2 Ma). The Cenozoic signals may reflect renewed responses to collisions at the southern Eurasian border (i.e., the Kohistan-Dras and India-Eurasia collisions). This progressive rejuvenation of the STSs demonstrates that deformation has not migrated steadily into the forelands, but was focused on pre-existing basement structures

Method development using ICP-MS and LA-ICP-MS and their application in environmental and material science

Within this PhD thesis several methods were developed and validated which can find applicationare suitable for environmental sample and material science and should be applicable for monitoring of particular radionuclides and the analysis of the chemical composition of construction materials in the frame of ESS project. The study demonstrated that ICP-MS is a powerful analytical technique for ultrasensitive determination of 129I, 90Sr and lanthanides in both artificial and environmental samples such as water and soil. In particular ICP-MS with collision cell allows measuring extremely low isotope ratios of iodine. It was demonstrated that isotope ratios of 129I/127I as low as 10-7 can be measured with an accuracy and precision suitable for distinguishing sample origins. ICP-MS with collision cell, in particular in combination with cool plasma conditions, reduces the influence of isobaric interferences on m/z = 90 and is therefore well-suited for 90Sr analysis in water samples. However, the applied ICP-CC-QMS in this work is limited for the measurement of 90Sr due to the tailing of 88Sr+ and in particular Daly detector noise. Hyphenation of capillary electrophoresis with ICP-MS was shown to resolve atomic ions of all lanthanides and polyatomic interferences. The elimination of polyatomic and isobaric ICP-MS interferences was accomplished without compromising the sensitivity by the use of a high resolution mode as available on ICP-SFMS. nCombination of laser ablation with ICP-MS allowed direct micro and local uranium isotope ratio measurements at the ultratrace concentrations on the surface of biological samples. In particular, the application of a cooled laser ablation chamber improves the precision and accuracy of uranium isotopic ratios measurements in comparison to the non-cooled laser ablation chamber by up to one order of magnitude. In order to reduce the quantification problem, a mono gas on-line solution-based calibration was built based on the insertion of a microflow nebulizer DS-5 directly into the laser ablation chamber. A micro local method to determine the lateral element distribution on NiCrAlY-based alloy and coating after oxidation in air was tested and validated. Calibration procedures involving external calibration, quantification by relative sensitivity coefficients (RSCs) and solution-based calibration were investigated. The analytical method was validated by comparison of the LA-ICP-MS results with data acquired by EDX