| 1. |
- Zhukova, Nataliya, et al.
(författare)
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WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma
- 2014
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Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of gammaH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
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| 2. |
- Alpizar, Francisco, 1974, et al.
(författare)
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Behavioral Spillovers from Targeted Incentives: Losses from Excluded Individuals Can Counter Gains from Those Selected
- 2013
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Incentives conditioned on socially desired acts such as donating blood, departing conflict or mitigating climate change have increased in popularity. Many incentives are targeted, excluding some of the potential participants based upon characteristics or prior actions. We hypothesize that pro-sociality is reduced by exclusion, in of itself (i.e., fixing prices and income), and that the rationale for exclusion influences such 'behavioral spillovers'. To test this, we use a laboratory experiment to study the effects of a subsidy to donations when participants are fully informed about why they are selected, or not, for the subsidy. We study the effects of introducing different selection rules upon changes in donations. Selecting for the subsidy those who initially acted less pro-social (i.e., gave little to start) increased donations, while random subsidies and rewarding greater pro-sociality did not. Yet a selection rule which targets lower prior pro-sociality also intentionally excludes the people who donated more initially, and only that rule reduced donations by the excluded. This shows a tradeoff between losses from excluded participants and gains from selected.
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| 3. |
- Alpizar, Francisco, 1974, et al.
(författare)
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Effects of Exclusion from a Conservation Policy: Negative Behavioral Spillovers from Targeted Incentives
- 2013
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- A critical issue in the design of incentive mechanisms is the choice of whom to target. For forests, the leading schemes: [i] target locations with high ecosystem-service density; [ii] target additionality, i.e., locations where conservation would not occur without the incentive; or, at least effectively, [iii] reward previous private choices to conserve forest. We use a field experiment to examine the changes in contributions to forest conservation when we introduce each of those three selection rules. For individuals who are selected, we find that targeting additionality (rule [ii]) is the only scheme to increase contributions. However that selection rule intentionally excludes those who contributed most previously and it is the only one to generate significant 'behavioral leakage', i.e., negative spillovers or falling contributions by those who are excluded (and face no price or income changes). Our results demonstrate a tradeoff in targeting and a challenge for optimal policy design.
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