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Purpose Tumour blood flow (TBF) is a crucial determinant of cancer growth. Recently, we validated Rubidium-82 (82Rb) positron emission tomography (PET) for TBF measurement in prostate cancer (PCa) and found TBF and cancer aggressiveness positively correlated. The aims of the present study were to determine the ability of TBF for separating significant from insignificant PCa and to examine the relation to underlying Na+/K+-ATPase density, which is relevant as 82Rb is transported intracellularly via the Na+/K+-ATPase. Methods One hundred and two patients were included for pelvic 82Rb PET scan prior to magnetic resonance imaging (MRI)-guided prostate biopsy. Findings constituted 100 PCa lesions (86 patients) and 25 benign lesions (16 patients). Tumours were defined on MRI and transferred to 82Rb PET for TBF measurement. Immunohistochemical Na+/K+-ATPase staining was subsequently performed on biopsies. Results TBF was the superior predictor (rho = 0.68, p p = 0.01), independent of ADC value and tumour volume (p +/K+-ATPase density per PCa cell profile was 38% lower compared with that of the benign prostate cell profiles. Neither cell density nor Na+/K+-ATPase density determined tumour 82Rb uptake. Conclusion TBF is an independent predictor of PCa aggressiveness and deserves more attention, as it may be valuable in separating clinically significant from insignificant PCa.

Ocean acidification (OA), caused by the oceanic uptake of anthropogenic CO2, is predicted to negatively affect marine mussels and oysters. In addition, the rapid rate at which OA occurs may outpace species’ ability to genetically adapt, leaving pre-existing genetic variation as a potential key to species resilience under OA. Against this backdrop, this thesis investigated the physiological mechanisms underlying intra-specific variation of OA sensitivity of Kiel Fjord blue mussels (Mytilus edulis) and Sydney rock oysters (Saccostrea glomerata). A long-term CO2 acclimation experiment with different family lines of blue mussel revealed that families whose offspring successfully settled at all experimental PCO2 levels (control, intermediate and high PCO2 level) were characterised by an inherently higher metabolic capacity at the whole animal and the cellular level compared to more sensitive family lines, whose offspring failed to survive at the highest experimental PCO2. This increased metabolic scope of tolerant family lines seems to cover elevated metabolic costs at the intermediate PCO2, however; at the highest PCO2, filtration rates and gill aerobic capacity declined, indicating an unfavourable shift in energy demand and supply. A second comparative CO2 acclimation study between a wild population of Sydney rock oysters and a more CO2 tolerant aquaculture line (selected for faster growth) showed that, in contrast to wild oysters, selected oysters were able to avoid a CO2-induced drop of extracellular pH, likely facilitated by an increased capacity for systemic CO2 release due to higher and more energetically efficient filtration rates. In conclusion, the observed pre-existing intra-specific variation in both species suggests potential adaptive capacities. However, as the physiology of marine bivalves is tightly linked with their functions within ecosystems, observed negative OA effects could have far reaching consequences at an ecosystem scale.

Ongoing climate change and the related ocean warming as well as ocean acidification represent a major challenge for marine organisms. Marine fish are very efficient osmotic regulators, however, the details of the underlying compensation mechanisms remain to be explored, such as the interaction with elevated temperature. In the present study, effects on marine fish from ocean acidification and warming were investigated in long-term incubation experiments on Atlantic cod (Gadus morhua). Isolated perfused gill experiments were conducted to examine in vivo costs of the branchial energy budget and acid-base relevant ion transport under hypercapnia at optimum temperature (10 degree celsius) and in the warmth (18 degree celsius). In addition, potential effects on whole animal level as well as maximum enzyme capacities of central metabolic pathways in liver and muscle tissue were investigated. In conclusion, Gadus morhua possesses a wide range of compensational mechanisms on different systemic levels to cope with the challenge of ocean acidification, whereas high temperature has been confirmed as limiting factor.

Nitrite secures essential nitric oxide (NO) bioavailability in hypoxia at low endogenous concentrations, whereas it becomes toxic at high concentrations. We exposed brown trout to normoxic and hypoxic water in the absence and presence of added ambient nitrite to decipher the cellular metabolism and effects of nitrite at basal and elevated concentrations under different oxygen regimes. We also tested hypotheses concerning the influence of nitrite on branchial nitric oxide synthase (NOS), Na+/K+-ATPase (nka) and heat shock protein (hsp70) mRNA expression. Basal plasma and erythrocyte nitrite levels were higher in hypoxia than normoxia, suggesting increased NOS activity. Nitrite exposure strongly elevated nitrite concentrations in plasma, erythrocytes, heart tissue and white muscle, which was associated with an extensive metabolism of nitrite to nitrate and to iron-nitrosylated and S-nitrosated compounds. Nitrite uptake was slightly higher in hypoxia than normoxia, and high internal nitrite levels extensively converted blood hemoglobin to methemoglobin and nitrosylhemoglobin. Hypoxia increased inducible NOS (iNOS) mRNA levels in the gills, which was overruled by a strong inhibition of iNOS expression by nitrite in both normoxia and hypoxia, suggesting negative-feedback regulation of iNOS gene expression by nitrite. A similar inhibition was absent for neuronal NOS. Branchial NKA activity stayed unchanged, but mRNA levels of the nkaα1a subunit increased with hypoxia and nitrite, which may have countered an initial NKA inhibition. Nitrite also increased hsp70 gene expression, probably contributing to the cytoprotective effects of nitrite at low concentrations. Nitrite displays a concentration-dependent switch between positive and negative effects similar to other signaling molecules. Nitrite secures essential nitric oxide (NO) bioavailability in hypoxia at low endogenous concentrations, whereas it becomes toxic at high concentrations. We exposed brown trout to normoxic and hypoxic water in the absence and presence of added ambient nitrite to decipher the cellular metabolism and effects of nitrite at basal and elevated concentrations under different oxygen regimes. We also tested hypotheses concerning the influence of nitrite on branchial nitric oxide synthase (NOS), Na+/K+-ATPase (nka) and heat shock protein (hsp70) mRNA expression. Basal plasma and erythrocyte nitrite levels were higher in hypoxia than normoxia, suggesting increased NOS activity. Nitrite exposure strongly elevated nitrite concentrations in plasma, erythrocytes, heart tissue and white muscle, which was associated with an extensive metabolism of nitrite to nitrate and to iron-nitrosylated and S-nitrosated compounds. Nitrite uptake was slightly higher in hypoxia than normoxia, and high internal nitrite levels extensively converted blood hemoglobin to methemoglobin and nitrosylhemoglobin. Hypoxia increased inducible NOS (iNOS) mRNA levels in the gills, which was overruled by a strong inhibition of iNOS expression by nitrite in both normoxia and hypoxia, suggesting negative-feedback regulation of iNOS gene expression by nitrite. A similar inhibition was absent for neuronal NOS. Branchial NKA activity stayed unchanged, but mRNA levels of the nkaα1a subunit increased with hypoxia and nitrite, which may have countered an initial NKA inhibition. Nitrite also increased hsp70 gene expression, probably contributing to the cytoprotective effects of nitrite at low concentrations. Nitrite displays a concentration-dependent switch between positive and negative effects similar to other signaling molecules.