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- 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. |
- Andersson, Claes, et al.
(författare)
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Psychosocial dysfunction is associated with recidivism in crime in paroled offenders
- 2013
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Ingår i: Alcoholism. - : John Wiley & Sons. - 0145-6008 .- 1530-0277. ; 37:s2, s. 260A-260A
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The objective of this research was to study whether automated telephony could be used in paroled offenders to perform daily assessment of variables associated with recidivismin crime, and whether there are grounds for studying the effects of a brief intervention based on these assessments during 30 days following probation. The design included a randomized controlled trial using automated daily assessments and feedback interventions based on Interactive Voice Response (IVR). Participants included paroled offenders (N = 108) during their first 30 days after leaving prison. All subjects were called daily and answered assessment questions. Based on the content of their daily assessments, the subjects in the intervention group received immediate feedback and a recommendation by IVR, and their probation officers also received a daily report by email. Main outcomemeasures (assessed daily) included Stress (Arnetz and Hasson Stress Questionnaire and a revised version of Daily Assessment of Daily Experience), Mood (SCL-8D measuring depression and anxiety), and Use and Urge to Use Alcohol and Drugs (revised version of the Alcohol Urge Questionnaire). Participants were also asked to rate the severity of their most stressful event that day. The outcome variables were analyzed using linear mixed models, presented as group differences between means, 95%CI. Results indicated that the intervention group showed greater improvement than the control group in stress (9.6, 0.5; 18.7, p = 0.038), depression/anxiety (4.6, 0.2; 9.0, p = 0.042), alcohol use (0.8, 0.1; 1.4, p = 0.031), drug use (1.0, 0.5; 1.6, p = 0.000), and in the severity of themost stressful daily event (1.9, 1.1; 2.7, p = 0.000). There were no differences between the groups in the Stress scale and in craving for alcohol and drugs. Overall, the research suggests that in paroled offenders, automated telephony is an effective technology thatmay be used to follow up and to give interventions, resulting in reduced stress and drug use.
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