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Wie in anderen Alpenregionen auch, erfolgt die Trinkwasserversorgung in den Zillertaler Alpen vorwiegend privat oder in Genossenschaften aus nahe gelegenen Quellen, typischerweise mit kleinen Einzugsgebieten. Durch eine Veranderung der osterreichischen Trinkwasserverordnung wurde der Arsengrenzwert von 50 µg/l auf 10 µg/l herabgesetzt, wodurch Quellwasser vielerorts nicht mehr den Anforderungen genugen. Es sind Masnahmen zur Einhaltung des Grenzwertes herbeizufuhren. In dieser Studie werden Ergebnisse der Stichtagsbeprobung des Zemmbacheinzugsgebietes auf einer Gesamtflache von 225 km2 vorgestellt. Binnen elf Tagen wurden 135 Quellen und Oberflachengewasser beprobt. Die Untersuchungen dienten der Auswahl alternativer Quellen anhand trinkwasserrechtlich relevanter Kennwerte mit Fokus auf Arsen und Uran. In einigen Teilen des Untersuchungsgebietes variiert die Grundwasserbeschaffenheit aufgrund diverser Wechsel petrographischer Einheiten kleinraumig. Das angewendete Konzept einer Stichtagsbeprobung ist gut dazu geeignet, einen weitraumigen Uberblick der Grundwasserbeschaffenheit zu erhalten und Quellen zur Erganzung oder Ersetzung der lokalen Wasserversorgung zu identifizieren. Diese Quellen sind intensiver zu beobachten, um letztlich mittels Zeitreihen Entscheidungen zu treffen.

In the unlined Tuxbach water transfer tunnel, running between Hintertux (1,500 m asl) and the Schlegeis Reservoir (Austria), a local geothermal anomaly with temperatures up to 14.6 °C exists. These temperatures are around 3 °C higher than expected, considering the tunnel’s shallow depth, together with its surrounding alpine environment and regional heat flow. This is especially noticeable because the temperatures have remained stable since the tunnel’s construction in 1969, although the tunnel is generally cooling the surrounding rock massive. The objective of this investigation is to explain the origin of the anomaly with hydrogeological methods and to evaluate the hydrogeological properties of the gneisses exposed in the tunnel. The anomaly is caused by the high hydraulic conductivity (~2.5∙10−5 m s−1) within a narrow shear-zone core, part of the Tux Shear Zones in the Ahorn Gneiss Core. The zone triggers fast groundwater transport over 1.5 km from both sides towards the tunnel. One reason is that the morphology provides thicker overburden with growing distance from the tunnel and therefore higher temperatures on the same horizontal level in the directions of the fault plane. The second explanation is that the narrowness of the shear zone permits effective heat transfer similar to a heat exchanger. No hydrothermal water share is recognizable; instead, mainly cold glacial melt water and snow contribute to the section of the anomaly and all other runouts of the tunnel. Factually based results show the disproportionately high contribution of snow and glaciers to the groundwater recharge in this alpine hard-rock aquifer.

The human luteinizing hormone receptor (hLH-R) is a member of the glycoprotein hormone family of G-protein-coupled receptors (GPCRs), activated by luteinizing hormone (hLH) and essentially involved in the regulation of sex hormone production. Thus, hLH-R represents a valid target for the treatment of sex hormone-dependent cancers and diseases (polycystic ovary syndrome, uterine fibroids, endometriosis) as well as contraception. Screening of the Bayer compound library led to the discovery of tetrahydrothienopyridine derivatives as novel, small-molecule (SMOL) hLH-R inhibitors and to the development of BAY-298, the first nanomolar hLH-R antagonist reducing sex hormone levels in vivo. Further optimization of physicochemical, pharmacokinetic, and safety parameters led to the identification of BAY-899 with an improved in vitro profile and proven efficacy in vivo. BAY-298 and BAY-899 serve as valuable tool compounds to study hLH-R signaling in vitro and to interfere with the production of sex hormones in vivo.

The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients are primarily driven by hormone-dependent and inflammatory processes-the latter being frequently associated with severe, acute, and chronic pelvic pain. The EP4 subtype of prostaglandin E2 (PGE2) receptors (EP4-R) is a particularly promising anti-inflammatory and antinociceptive target as both this receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Careful structure-activity relationship investigation guided by rational design identified a methyl substitution adjacent to the carboxylic acid as an appropriate means to accomplish favorable pharmacokinetic properties by reduction of glucuronidation. Further optimization led to the identification of benzimidazolecarboxylic acid BAY 1316957, a highly potent, specific, and selective hEP4-R antagonist with excellent drug metabolism and pharmacokinetics properties. Notably, treatment with BAY 1316957 can be expected to lead to prominent and rapid pain relief and significant improvement of the patient's quality of life.

Erdwarmesonden-Speicher konnen okonomisch zur Deckung des Warme-/Kaltebedarfs von grosen Gebauden genutzt werden. Deren Errichtung in Karstaquiferen ist hinsichtlich des Grundwasserschutzes und der korrekten Dimensionierung eine anspruchsvolle Planungsaufgabe. Die Erschliesung des Hochstegenmarmors im Tuxertal (Zillertal, Osterreich) war durch eine zweistufige Planungsphase gekennzeichnet, um die gewunschten Entzugs- und Speicherfunktionen sicherzustellen.

Karstaquifere konnen sich durch ihre erhohten Permeabilitaten vorteilhaft auf die Leistung geothermischer Systeme auswirken. Andererseits bedingen ihre hohen Grundwasserabstandsgeschwindigkeiten auch verringerte Nutzungsmoglichkeiten als Warmespeicher. In Finkenberg im Tuxertal (Zillertal, Tirol, Osterreich) wurde erstmalig der Marmorkarstaquifer der Hochstegen-Formation wissenschaftlich-technisch als mitteltiefes Erdwarmesondenfeld mit Speicherfunktion erkundet und ausgebaut.

A borehole heat exchanger array was installed in an Alpine karst aquifer for the first time in Europe. It is composed of nine 400 m deep boreholes in the dolomitic marble of the Hochstegen Formation. New approaches were developed for this unprecedented application and potential risks were checked throughout the sinking of the initial exploratory wellbore. As Finkenberg is located in a tourist area, drilling operations had to be executed within only a few weeks. Several springs downstream from the drilling site are sources of drinking water and tap water supply. Given that the degree and distribution of the Hochstegen Formation karstification was unknown, a spring monitoring program was mandatory in order to obtain drilling permission from public authorities. A practicable and affordable spring monitoring program including several physical and chemical parameters was developed and implemented to document the potential impact of the drilling activities on the spring water. A temporary and locally limited impact of the drilling works on groundwater quality was detected by turbidity measurements. This paper reports the implementation of geothermal drilling in a karst aquifer with a focus on karstification as well as planning, implementation and the results of the spring monitoring program. Such a program can be recommended for comparable projects or questions, adapting the characteristic parameters to be collected and the measurement intervals in consultation with the relevant authorities. It might also increase the chances of gaining approval for geothermal projects in karst and could enhance public acceptance. Key words: Pneumatic down hole hammer drilling, Borehole heat exchanger, Groundwater monitoring, Turbidity, Hochstegen Formation. Geotermalno vrtanje v alpskem kraskem vodonosniku in njegov vpliv na dolvodne izvire - studija primera Finkenberg, Tirolska, Avstrija V alpskem kraskem vodonosniku je bilo prvic v Evropi vzpostavljeno polje geosond. Vkljucuje devet 400 m globokih vrtin, izvrtanih v dolomitnem marmorju Hochstegenove formacije. Razvili smo nove pristope za to aplikacijo brez primere in potrdili morebitna tveganja v casu potopitve prvotne raziskovalne vrtine. Ker je studijsko obmocje Finkenberg na turisticnem obmocju, je bilo treba opraviti vrtanje v samo nekaj tednih. Vec izvirov od mesta vrtanja so viri oskrbe s pitno vodo. Glede na to, da stopnja in porazdelitev zakraselosti Hochstegenove formacije nista bili znani, je bilo treba za pridobitev dovoljenja za vrtanje nujno opazovati izvire. Da bi dokumentirali vpliv vrtanja na izvirsko vodo, je bilo pri spremljanju izvirov treba upostevati vec fizikalnih in kemijskih parametrov. Zaznali smo obcasen in lokalno omejen vpliv vrtanja na kakovost podzemne vode. V prispevku smo predstavili izvajanje geotermalnega vrtanja v kraskem vodonosniku s poudarkom na identifikaciji zakraselosti ter nacrtovanju ter na izvedbi in spremljanju kakovosti voda na izviru. Tak program se lahko uporabi pri primerljivih projektih ali iskanju odgovorov na podobna vprasanja s prilagojenim programom opazovanih parametrov in intervalov merjenja. Prav tako bi lahko povecal možnosti za pridobitev soglasja za geotermalne projekte na krasu in povecal ozavescenost javnosti. Kljucne besede: vrtanje s pnevmatskim kladivom, geosonda, spremljanje podzemne vode, motnost, Hochstegenova formacija. A borehole heat exchanger array was installed in an Alpinekarst aquifer for the first time in Europe. It is composed of nine400 m deep boreholes in the dolomitic marble of the HochstegenFormation. New approaches were developed for thisunprecedented application and potential risks were checkedthroughout the sinking of the initial exploratory wellbore. AsFinkenberg is located in a tourist area, drilling operations hadto be executed within only a few weeks. Several springs downstreamfrom the drilling site are sources of drinking water andtap water supply. Given that the degree and distribution of theHochstegen Formation karstification was unknown, a springmonitoring program was mandatory in order to obtain drillingpermission from public authorities. A practicable and affordablespring monitoring program including several physical andchemical parameters was developed and implemented to documentthe potential impact of the drilling activities on the springwater. A temporary and locally limited impact of the drillingworks on groundwater quality was detected by turbidity measurements.This paper reports the implementation of geothermaldrilling in a karst aquifer with a focus on karstification aswell as planning, implementation and the results of the springmonitoring program. Such a program can be recommended forcomparable projects or questions, adapting the characteristic

Targeting the vascular endothelial growth factor signaling axis in glioblastoma inevitably leads to tumor recurrence and a more aggressive phenotype. Therefore, other angiogenic pathways, like the angiopoietin/tunica interna endothelial cell kinase (TIE) signaling axis, have become additional targets for therapeutic intervention. Here, we explored whether targeting the receptor tyrosine kinase TIE-2 using a novel, highly potent, orally available small molecule TIE-2 inhibitor (BAY-826) improves tumor control in syngeneic mouse glioma models. BAY-826 inhibits TIE-2 phosphorylation in vitro and in vivo as demonstrated by suppression of Angiopoietin-1- or Na3 VO4 -induced TIE-2 phosphorylation in glioma cells or extracts of lungs from BAY-826-treated mice. There was a trend toward prolonged survival upon single-agent treatment in two of four models (SMA-497 and SMA-540) and there was a significant survival benefit in one model (SMA-560). Co-treatment with BAY-826 and irradiation was ineffective in one model (SMA-497), but provided synergistic prolongation of survival in another (SMA-560). Decreased vessel densities and increased leukocyte infiltration were observed, but might be independent processes as the effect was also observed in single treatment modalities. These data demonstrate that TIE-2 inhibition may improve tumor response to treatment in highly vascularized tumors such as glioblastoma.

New types of chiral phosphorus/nitrogen ligands, capable of forming six-membered-ring metal chelates have been prepared from α,α,α′,α′-tetraaryl-1,2-dioxolane-4,5-dimethanols (TADDOLs), PCl3, and dihydrooxazole alcohols (from amino acids) (7 in Scheme 1). The X-ray crystal structure of a Rh complex of one of these ligands, 8b, has been determined (Scheme 2 and Fig.). Enantioselective hydrosilylations of dialkyl and aryl alkyl ketones with Ph2SiH2/0.01 equiv. RhI⋅7 have been studied and found to provide secondary alcohols in enantiomer ratios of up to 97 : 3 (Scheme 3 and Table). The ligand prepared from (R,R)-TADDOL and the (R)-valine-derived (R)-α,α-dimethyl-4-isopropyl-4,5-dihydrooxazole-2-methanol gives better results than the (R,R,S)-isomer (7dvs.7c in Scheme 3), and an i-Pr group on the 4,5-dihydrooxazole ring gives rise to a slightly better selectivity than a Ph group. With the (R,R,R)-ligands the hydrogen transfer occurs from the Re face of the oxo groups (Scheme 4).

RATIONALE AND OBJECTIVES A new ultrasound contrast agent (SH U 563 A), consisting of hollow biodegradable polymeric microparticles, and a new imaging technique (stimulated acoustic emission) were used for delineation of experimental liver tumors. After intravenous injection, these microparticles are phagocytosed by cells of the reticuloendothelial system (RES) and create a color-coded signal using color Doppler. Because of the different distribution of phagocytic cells in healthy liver tissue and tumors, the delineation of focal lesions was to be tested. METHODS Sixteen rabbits with VX2 liver tumors received doses of 0.15-mL SH U 563 A per kilogram of body weight intravenously. Liver investigations (UM9, HD1, L10.5, ATL, Bothell, USA) were performed in vivo before and after SH U 563 A application in B and color Doppler modes. Additionally, the liver and spleen of these rabbits were examined ex vivo in color Doppler. The sonographic diagnosis was confirmed by pathology. RESULTS After application of SH U 563 A, the healthy liver tissue of all rabbits was characterized by a typical mosaic color pattern in vivo and ex vivo, using color Doppler. Entire VX2 liver tumors were detectable exclusively in color Doppler after SH U 563 A application. This was possible in 14 of 16 rabbits in vivo and in all 16 livers ex vivo. Furthermore, all ex vivo investigated spleens were color enhanced homogeneously. Sonographic diagnoses were in accordance with pathologic findings. CONCLUSIONS SH U 563 A, combined with stimulated acoustic emission, provides potential for delineation of small isoechogenic liver lesions by sonography.

New types of chiral phosphorus/nitrogen ligands, capable of forming six-membered-ring metal chelates have been prepared from α,α,α′,α′-tetraaryl-1,2-dioxolane-4,5-dimethanols (TADDOLs), PCl3, and dihydrooxazole alcohols (from amino acids) (7 in Scheme 1). The X-ray crystal structure of a Rh complex of one of these ligands, 8b, has been determined (Scheme 2 and Fig.). Enantioselective hydrosilylations of dialkyl and aryl alkyl ketones with Ph2SiH2/0.01 equiv. RhI⋅7 have been studied and found to provide secondary alcohols in enantiomer ratios of up to 97 : 3 (Scheme 3 and Table). The ligand prepared from (R,R)-TADDOL and the (R)-valine-derived (R)-α,α-dimethyl-4-isopropyl-4,5-dihydrooxazole-2-methanol gives better results than the (R,R,S)-isomer (7dvs.7c in Scheme 3), and an i-Pr group on the 4,5-dihydrooxazole ring gives rise to a slightly better selectivity than a Ph group. With the (R,R,R)-ligands the hydrogen transfer occurs from the Re face of the oxo groups (Scheme 4).

The receptor tyrosine kinase Tie2 is predominantly expressed in the endothelium but has also been identified on primitive hematopoietic stem cells, monocyte and macrophage subclasses, as well as on glioma or hematological tumor cells. Based on its expression in many patient-derived leukemic blasts inhibition of the Tie2 pathway may provide an attractive opportunity for therapeutic intervention in leukemias. In this study we report the pharmacological profile of a novel, highly potent and orally available Tie2 inhibitor (BAY-Tie2). The discovery and design process leading to BAY-Tie2 was performed with the goal of sparing other angiogenic RTKs, such as VEGFRs, FGFRs or PDGFRs. BAY-Tie2 is based on a novel imidazopyrazole core, combined with a SF5-substituted phenyl ring that fills the deep DFG-out pocket. BAY-Tie2 binds to Tie2 with a Kd value of 1.6 nM and is selective against VEGFR2 (Kd of 1600 nM), FGFR1 ( In subcutaneous xenograft models of highly angiogenic tumors, BAY-Tie2 reduced tumor growth and showed evidence for potential combination benefit with anti-VEGF therapy. In order to explore the potential of a Tie2 inhibitor beyond affecting angiogenesis, we established disseminated leukemia models, using Tie2-expressing cell lines, such as the CML cell lines MEG-01 and EM-2. Both cell lines engrafted predominantly in bone marrow and spleen. Treatment started 3 days after i.v. cell implantation with either BAY-Tie2 or cytarabine and was well tolerated. Efficacy was monitored by a) inhibition of disease progression, b) weekly fluorescence-based in vivo imaging (IVI) using an Alexa750-labeled anti-human CD33 antibody, and c) q-RT-PCR specific for BCR-ABL and hCD45 in murine peripheral blood. BAY-Tie2 inhibited disease progression comparable to cytarabine. Tumor load measured by IVI was reduced in BAY-Tie2 treated groups by 45% in the MEG-01 and by 65% in the EM-2 model compared with the untreated control, very similar to the cytotoxic treatment with cytarabine. Quantitative RT-PCR on peripheral blood revealed that BAY-Tie2 and cytarabine delayed the appearance of circulating tumor cells in both CML models. These data demonstrate that BAY-Tie2 is an orally active Tie2 inhibitor that may have therapeutic benefit not only in angiogenic tumors but also in hematological, Tie2-expressing malignancies. Citation Format: Sylvia Gruenewald, Julia Schueler, Michael Haerter, Frank Suessmeier, Kerstin Klingner, Ulf Boemer, Stefan Kaulfuss, Alexander Walter, Mario Lobell, Ingo V. Hartung, Bernd Buchmann, Dieter Heldmann, Holger Hess-Stumpp, Karl Ziegelbauer. Novel Tie2 inhibitor with in vivo efficacy in disseminated hematological tumor models in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1026. doi:10.1158/1538-7445.AM2014-1026