No abstract

A wavelength modulated, distributed feedback diode laser based photoacoustic water vapor mixing ratio measuring system for atmospheric research applications is presented. Laser modulation parameters were optimized either at 180 or 500 mbar total pressure to enhance the system's sensitivity for low or high pressures (upper troposphere/lower stratosphere or biosphere exchange layer), respectively. A wavelength locking method was developed that ensured sub-picometer absolute (5 x 10(-7) relative) wavelength stability of the laser while consuming minimum additional measurement time. At the calibration of the system, correction factors for the pressure- and temperature-dependence of the photoacoustic signal were determined, which were in turn applied to the calculation of the water vapor mixing ratio from the measured signal during the test operation of the system. The introduced features resulted in reliable, sub-ppm-level water vapor detection even under abrupt gas pressure or temperature variations typical in open atmospheric applications.

Targeted tumour therapy is in the focus of recent cancer research. GnRH analogues are able to deliver anticancer agents selectively into tumour cells which highly express GnRH receptors. However, the effectiveness of different analogues as targeting moiety in drug delivery systems is rarely compared and the investigated types of cancers are also limited. Therefore, we prepared selectively labelled, fluorescent derivatives of GnRH-I, -II, and -III analogues which successfully used for drug targeting. In this manuscript we investigated these analogues solubility, stability, passive membrane permeability and compared their cellular uptake by various cancer cells.We found that these labelled GnRH conjugates provide great detectability, without undesired In summary, our presented results detail that the introduced conjugates could be innovative tools for the examination of the GnRH based drug delivery systems on various cells and offer novel information about these peptides.

Pancreatic cancer is an increasing cause of cancer related death worldwide. KRAS is the dominant oncogene in this cancer type and molecular rationale would indicate, that inhibitors of the downstream target MEK could be appropriate targeted agents, but clinical trials have failed so far to achieve statistically significant benefit in unselected patients. We aimed to identify predictive molecular biomarkers that can help to define subgroups where MEK inhibitors might be beneficial alone or in combination. Next-generation sequencing data of 50 genes in three pancreatic cancer cell lines (MiaPaCa2, BxPC3 and Panc1) were analyzed and compared to the molecular profile of 138 clinical pancreatic cancer samples to identify the molecular subtypes of pancreatic cancer these cell lines represent. Luminescent cell viability assay was used to determine the sensitivity of cell lines to kinase inhibitors. Western blot was used to analyze the pathway activity of the examined cell lines. According to our cell viability and pathway activity data on these model cell lines only cells harboring the rare G12C KRAS mutation and low EGFR expression are sensitive to single MEK inhibitor (trametinib) treatment. The common G12D KRAS mutation leads to elevated baseline Akt activity, thus treatment with single MEK inhibitors fails. However, combination of MEK and Akt inhibitors are synergistic in this case. In case of wild-type KRAS and high EGFR expression MEK inhibitor induced Akt phosphorylation leads to trametinib resistance which necessitates for MEK and EGFR or Akt inhibitor combination treatment. In all we provide strong preclinical rational and possible molecular mechanism to revisit MEK inhibitor therapy in pancreatic cancer in both monotherapy and combination, based on molecular profile analysis of pancreatic cancer samples and cell lines. According to our most remarkable finding, a small subgroup of patients with G12C KRAS mutation may still benefit from MEK inhibitor monotherapy.