Two Independent Value Orientations: Ideal and Counter-Ideal Leader Values and Their Impact on Followers' Respect for and Identification with Their Leaders

__Abstract__ Traditionally, conceptualizations of human values are based on the assumption that individuals possess a single integrated value system comprising those values that people are attracted by and strive for. Recently, however, van Quaquebeke et al. (in J Bus Ethics 93:293-305, 2010) proposed that a value system might consist of two largely independent value orientations-an orientation of ideal values and an orientation of counter-ideal values (values that individuals are repelled by), and that both orientations exhibit antithetic effects on people's responses to the social world. Following a call for further research on this distinction, we conducted two studies to assess the independent effects of ideal and counter-ideal values in leadership settings. Study 1 (N = 131) finds both value orientations to explain unique variance in followers' vertical respect for their leaders. Study 2 (N = 136) confirms these results and additionally shows an analogous effect for followers' identification with their leaders. Most importantly, we find that both value orientations exhibit their effects only independently when the content of the two orientations pertain to different value types in Schwartz's (in J Soc Issues 50:19-46, 1994) circumplex model. Implications for theory and practice are discussed

DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy

Key biologic effects of the alpha-particle emitter Actinium-225 in comparison to beta-particle emitter Lutetium-177 labeled somatostatin analogue DOTATOC in vitro and in vivo were studied to evaluate the significance of H2AX-foci formation and its downstream effects. To determine relative biological effectiveness (RBE) between the two isotopes somatostatin expressing AR42J cells were incubated with Ac-225-DOTATOC and Lu-177-DOTATOC up to 48 h and viability was analyzed using the MTT assay. DNA double strand breaks were quantified after immunofluorescence staining of H2AX. Cell cycle was analyzed by flow cytometry. In vivo, uptake of both radiolabeled somatostatin-analogues into subcutaneous AR42J tumors and number of cells displaying H2AX-foci were measured. Therapeutic efficacy was assayed by monitoring tumor growth after treatment with activities translated from in vitro cytotoxicity. Ac-225-DOTATOC was synthesized with specific activities between 0.2-0.4 MBq/µg and radiochemical purity of > 90%. ED50 values were 30 kBq/ml after 24 h and 14 kBq/ml after 48 h. Lu-177-DOTATOC displayed radiochemical purity of >95% and ED50 values of 10 MBq/ml after 48 h. Number of DNA double strand breaks increased with increasing concentration of Ac 225 DOTATOC and Lu-177-DOTATOC similarly, if a factor of approximately 700 of Lu-177 activities over Ac-225 activities was applied. Already 24 h after incubation with 2.5, 5, and 10 kBq/ml Ac 225 DOTATOC cell cycle studies showed an increment of the percentage of tumor cells in G2/M phase up to 60%. After 72 h an apoptotic subG1 peak was also detectable. Tumor uptake for both radio peptides at 48 h was identical with 7.5 %ID/g, though overall number of cells with H2AX-foci was higher for tumors treated with 48 kBq Actinium-225-DOTATOC than tumors treated with 30 MBq Lutetium-177-DOTATOC (35% vs. 21%). Tumors with a mean volume of 0.34 ml reached exponential tumor growth after 25 days (44 kBq Ac-225-DOTATOC), after 21 days (34 MBq Lu-177-DOTATOC) and after 5 days (control). Thus H2AX-foci displayed the key parameter after irradiation with similar downstream effects for beta and alpha irradiation.JRC.E.5-Nuclear chemistr

In vitro evaluation of alpha-particle emitter Ac-225 for somatostatin receptor radiotherapy

Ziel/ Aim Alpha-particle emitters display high linear energy transfer combined with short range and are promising for treatment of tumor micrometastases. Indeed, efficiency and high specificity of tumor-specific antibodies labeled with alpha emitting nuclides were described in vitro and in vivo. Radiolabeled somatostatin analogues with high affinity to somatostatin receptor overexpressing tumors are an attractive option for peptide-receptor radionuclide therapy of metastasized neuroendocrine tumors. In this study, we investigated cellular effects of alpha-particle emitter Ac-225 labeled somatostatin analogue DOTATOC in vitro. Cellular studies were performed in p53 dependent and somatostatin receptor expressing rat pancreatic acinar carcinoma AR42J cells. Methodik/ Methods Ac-225-DOTATOC was synthesized with a specific activity of 0,4 MBq/µg and radiochemical purity of > 90% as assessed via ITLC. For investigation of alpha radiation induced cytotoxicity AR42J cells were incubated with Ac-225-DOTATOC (0.005 to 250 kBq/ml) for 24 and 48 h, respectively. Viability of cells was analyzed using the MTT colorimetric assay. DNA double strand breaks were quantified by microscopy after immunofluorescence staining of H2AX. Furthermore, cell cycle studies and induction of apoptosis was analyzed after incubation with Ac-225-DOTATOC by flow cytometry. Ergebnisse/ Results Cellular studies showed a reduced viability of AR42J cells after incubation with Ac-225-DOTATOC. ED50 values were calculated to 30 kBq/ml after 24 h and respectively 10 kBq/ml after 48 h. The number of DNA double strand breaks, localized by H2AX staining, increased with increasing concentration of Ac 225 DOTATOC after 24 and 48 h. Already 24 h after incubation with 2.5, 5, and 10 kBq/ml Ac 225 DOTATOC cell cycle studies showed an increment of the percentage of tumor cells in G2/M phase up to 60%. Further, increasing amount of polyploid cells could be detected after 48 and 72 h. After 72 h also subG1 peak was detectable. Preliminary data indicated induction of apoptosis after 72 h by Annexin-V staining. Schlussfolgerungen/ Conclusions Our data demonstrate a G2/M cell cycle arrest and induction of apoptosis in AR42J tumor cells due to efficient induction of DNA double strand breaks after Ac-225 alpha-particle radiation. The results are a promising prerequisite for further evaluation of Ac-225-DOTATOC in vitro and in vivo for peptide-receptor radionuclide therapy.JRC.E.5-Nuclear chemistr

DNA double strand break assessment by yH2AX-foci quantification after alpha-particle emitter Ac-225 and electron emitter Lu-177 somatostatin receptor targeted radiotherapy correlates with cell death and apoptosis in vitro

Alpha-particle emitters display high linear energy transfer combined with short range and are promising for treatment of metastasized tumors. Indeed, efficiency and high specificity of tumor-specific antibodies labelled with alpha emitting nuclides were described in vitro and in vivo. Radiolabeled somatostatin analogues with high affinity to somatostatin receptor overexpressing tumors are an attractive option for peptide-receptor radionuclide therapy of metastasized neuroendocrine tumors and great clinical success has been demonstrated with Lutetium-177 as therapeutic isotope. In this study, we investigated cellular effects of the alpha-particle emitter Actinium-225 in comparison to the beta-particle emitter Lutetium-177 labelled DOTATOC in vitro. Cellular studies were performed in p53 dependent and somatostatin receptor expressing rat pancreatic acinar carcinoma cells (AR42J).JRC.E.5-Nuclear chemistr