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- Stuparu, Andreea D., et al.
(författare)
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Mechanisms of Resistance to Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer
- 2021
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505. ; 62:7, s. 989-995
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Tidskriftsartikel (refereegranskat)abstract
- Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is effective against prostate cancer (PCa), but all patients relapse eventually. Poor understanding of the underlying resistance mechanisms represents a key barrier to development of more effective RLT. We investigate the proteome and phosphoproteome in a mouse model of PCa to identify signaling adaptations triggered by PSMA RLT. Methods: Therapeutic efficacy of PSMA RLT was assessed by tumor volume measurements, time to progression, and survival in C4-2 or C4-2 TP53-/- tumor-bearing nonobese diabetic scid γ-mice. Two days after RLT, the proteome and phosphoproteome were analyzed by mass spectrometry. Results: PSMA RLT significantly improved disease control in a dose-dependent manner. Proteome and phosphoproteome datasets revealed activation of genotoxic stress response pathways, including deregulation of DNA damage/replication stress response, TP53, androgen receptor, phosphatidylinositol-3-kinase/AKT, and MYC signaling. C4-2 TP53-/- tumors were less sensitive to PSMA RLT than were parental counterparts, supporting a role for TP53 in mediating RLT responsiveness. Conclusion: We identified signaling alterations that may mediate resistance to PSMA RLT in a PCa mouse model. Our data enable the development of rational synergistic RLT-combination therapies to improve outcomes for PCa patients.
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- Stuparu, Andreea D., et al.
(författare)
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Targeted alpha therapy in a systemic mouse model of prostate cancer - a feasibility study
- 2020
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Ingår i: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 10:6, s. 2612-2620
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Tidskriftsartikel (refereegranskat)abstract
- 225Ac-PSMA-617 targeted-therapy has demonstrated efficacy in 75-85% of patients; however, responses are not durable. We aimed to establish translatable mouse models of disseminated prostate cancer (PCa) to evaluate effectiveness of 225Ac-PSMA-617 at various disease stages. Methods: C4-2, C4-2B, or 22Rv1 cells were injected into the left ventricle of male NSG mice. Disease progression was monitored using bioluminescence imaging (BLI). For treatment, mice were injected with 40 kBq 225Ac-PSMA-617 at one (early treatment cohort) or three weeks (late treatment cohort) post-inoculation. Treatment efficacy was monitored by BLI of whole-body tumor burden. Mice were sacrificed based on body conditioning score. Results: C4-2 cells yielded metastases in liver, lungs, spleen, stomach, bones, and brain - achieving a clinically relevant model of widespread metastatic disease. The disease burden in the early treatment cohort was stable over 27 weeks in 5/9 mice and progressive in 4/9 mice. These mice were sacrificed due to brain metastases. Median survival of the late treatment cohort was superior to controls (13 vs. 7 weeks; p<0.0001) but inferior to that in the early treatment cohort (13 vs. 27 weeks; p<0.001). Late cohort mice succumbed to extensive liver involvement. The 22Rv1 and C4-2B systemic models were not used for treatment due to high kidney metastatic burden or low take rate, respectively. Conclusion: C4-2 cells reproduced metastatic cancer spread most relevantly. Early treatment with 225Ac-PSMA-617 prevented liver metastases and led to significant survival benefit. Late treatment improved survival without reducing tumor burden in the liver, the main site of metastasis. The current findings suggest that early 225Ac-PSMA-617 intervention is more efficacious in the setting of widespread metastatic PCa.
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- Ciba, Iris, et al.
(författare)
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Prevalence of different states of glucose intolerance in Sri Lankan children and adolescents with obesity and its relation to other comorbidities.
- 2021
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Ingår i: Pediatric Diabetes. - : John Wiley & Sons. - 1399-543X .- 1399-5448. ; 22:2, s. 168-181
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: South Asian adults have higher prevalence of obesity comorbidities than other ethnic groups. Whether this also is true for Sri Lankan children with obesity has rarely been investigated.OBJECTIVE: To investigate prevalence of glucose intolerance and other comorbidities in Sri Lankan children with obesity and compare them with Swedish children. To identify risk factors associated with glucose intolerance.SUBJECTS: A total of 357 Sri Lankan children (185 boys), aged 7 to 17 years with BMI-SDS ≥2.0 from a cross-sectional school screening in Negombo. A total of 167 subjects from this study population were matched for sex, BMI-SDS and age with 167 Swedish subjects from the ULSCO cohort for comparison.METHODS: After a 12 hour overnight fast, blood samples were collected and oral glucose tolerance test was performed. Body fat mass was assessed by bioelectrical impedance assay. Data regarding medical history and socioeconomic status were obtained from questionnaires.RESULTS: Based on levels of fasting glucose (FG) and 2 hours-glucose (2 hours-G), Sri Lankan subjects were divided into five groups: normal glucose tolerance (77.5%, n = 276), isolated impaired fasting glucose according to ADA criteria (9.0%, n = 32), isolated impaired glucose tolerance (8.4%, n = 30), combined impaired fasting glucose (IFG) + impaired glucose tolerance (IGT) (3.1%, n = 11) and type 2 diabetes mellitus (2.0%, n = 7). FG, 2 hours-insulin and educational status of the father independently increased the Odds ratio to have elevated 2 hours-G. Sri Lankan subjects had higher percentage of body fat, but less abdominal fat than Swedish subjects.CONCLUSION: High prevalence in Sri Lankan children with obesity shows that screening for glucose intolerance is important even if asymptomatic.
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- Dahlbom, L, et al.
(författare)
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Gender and Overconfidence : Are Girls really overconfident?
- 2011
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Ingår i: Applied Economics Letters. - : Taylor & Francis. - 1350-4851 .- 1466-4291. ; 18:4, s. 325-327
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Tidskriftsartikel (refereegranskat)abstract
- Previous research finds that people are overconfident and that men are more overconfident than women. Using a very precise confidence measure, this article shows, however, that whereas boys are overconfident, girls are actually underconfident regarding their mathematics performance. We conducted a survey where 14-year-old high school students were asked what grade they thought they would get in a mathematics test a week later. These results were then compared with their actual grade. Boys were overconfident about their grades, whereas girls were underconfident.
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