Evaluation of Dutch election programs: The impact of parameter uncertainty

Shortly before the national elections in the Netherlands, the Netherlands Bureau for Economic Policy Analysis (CPB) evaluates the economic effects of the policy proposals in election programs. This paper investigates the sensitivity of this analysis to the uncertainty of parameter estimates in the economic models that are used. For this purpose, a Monte Carlo analysis of five election programs is performed, using a core version of one of the CPB models. We find that the range of projected outcomes is surprisingly small. Nonetheless, caution remains needed, especially when the estimated effects of different parties are roughly similar.Model simulation; policy evaluation; parameter uncertainty; CGE models

DLBCL cells with acquired resistance to venetoclax are not sensitized to BIRD-2 but can be resensitized to venetoclax through Bcl-XL inhibition

Anti-apoptotic Bcl-2-family members are frequently dysregulated in both blood and solid cancers, contributing to their survival despite ongoing oncogenic stress. Yet, such cancer cells often are highly dependent on Bcl-2 for their survival, a feature that is exploited by so-called BH3-mimetic drugs. Venetoclax (ABT-199) is a selective BH3-mimetic Bcl-2 antagonist that is currently used in the clinic for treatment of chronic lymphocytic leukemia patients. Unfortunately, venetoclax resistance has already emerged in patients, limiting the therapeutic success. Here, we examined strategies to overcome venetoclax resistance. Therefore, we used two diffuse large B-cell lymphoma (DLBCL) cell lines, Riva WT and venetoclax-resistant Riva (VR). The latter was obtained by prolonged culturing in the presence of venetoclax. We report that Riva VR cells did not become more sensitive to BIRD-2, a peptide targeting the Bcl-2 BH4 domain, and established cross-resistance towards BDA-366, a putative BH4-domain antagonist of Bcl-2. However, we found that Bcl-XL, another Bcl-2-family protein, is upregulated in Riva VR, while Mcl-1 expression levels are not different in comparison with Riva WT, hinting towards an increased dependence of Riva VR cells to Bcl-XL. Indeed, Riva VR cells could be resensitized to venetoclax by A-1155463, a selective BH3 mimetic Bcl-XL inhibitor. This is underpinned by siRNA experiments, demonstrating that lowering Bcl-XL-expression levels also augmented the sensitivity of Riva VR cells to venetoclax. Overall, this work demonstrates that Bcl-XL upregulation contributes to acquired resistance of DLBCL cancer cells towards venetoclax and that antagonizing Bcl-XL can resensitize such cells towards venetoclax

Evaluation of Dutch election programs: The impact of parameter uncertainty

Shortly before the national elections in the Netherlands, the Netherlands Bureau for Economic Policy Analysis (CPB) evaluates the economic effects of the policy proposals in election programs. This paper investigates the sensitivity of this analysis to the uncertainty of parameter estimates in the economic models that are used. For this purpose, a Monte Carlo analysis of five election programs is performed, using a core version of one of the CPB models. We find that the range of projected outcomes is surprisingly small. Nonetheless, caution remains needed, especially when the estimated effects of different parties are roughly similar

Evaluation of Dutch election programs: The impact of parameter uncertainty

Shortly before the national elections in the Netherlands, the Netherlands Bureau for Economic Policy Analysis (CPB) evaluates the economic effects of the policy proposals in election programs. This paper investigates the sensitivity of this analysis to the uncertainty of parameter estimates in the economic models that are used. For this purpose, a Monte Carlo analysis of five election programs is performed, using a core version of one of the CPB models. We find that the range of projected outcomes is surprisingly small. Nonetheless, caution remains needed, especially when the estimated effects of different parties are roughly similar

Health-related quality of life in adrenocortical carcinoma:Development of the disease-specific questionnaire ACC-QOL and results from the PROFILES registry

We aimed to develop a disease-specific adrenocortical carcinoma (ACC) health-related quality of life (HRQoL) questionnaire (ACC-QOL) and assess HRQoL in a population-based cohort of patients with ACC. Development was in line with European Organization for Research and Treatment of Cancer (EORTC) guidelines, though not an EORTC product. In phase I and II, we identified 90 potential HRQoL issues using literature and focus groups, which were reduced to 39 by healthcare professionals. Pilot testing resulted in 28 questions, to be used alongside the EORTC QLQ-C30. In Phase III, 100 patients with ACC were asked to complete the questionnaires twice in the PROFILES registry (3-month interval, respondents: first 67, second 51). Confirmatory factor analysis demonstrated the structural validity of 26 questions with their scale structure (mitotane side-effects, hypercortisolism/hydrocortisone effects, emotional effects). Internal consistency and reliability were good (Cronbach's alpha 0.897, Interclass correlation coefficient 0.860). Responsiveness analysis showed good discriminative ability (AUC 0.788). Patients diagnosed more than 5 years ago reported a good HRQoL compared with the Dutch reference population, but experienced residual fatigue and emotional problems. Patients who underwent recent treatment reported a lower HRQoL and problems in several domains. In conclusion, we developed an ACC-specific HRQoL questionnaire with good psychometric properties