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| 2. |
- Wu, Huaxing, 1987, et al.
(författare)
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Long-Term Whole Grain Wheat and Rye Intake Reflected by Adipose Tissue Alkylresorcinols and Breast Cancer: A Case-Cohort Study
- 2019
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643 .- 2072-6643. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- Whole grain rye (WGR) and whole grain wheat (WGW) have been suggested to protect against the development of breast cancer. In this study, we estimated long-term intake of WGR and WGW, using both a food frequency questionnaire (FFQ) and alkylresorcinol concentrations in adipose tissue biopsies, in relation to the risk of developing invasive breast cancer in a case-cohort study (n = 414 in the case group, n = 933 in the subcohort group) on the Danish "Diet, Cancer and Health" cohort. The median follow-up time of the subcohort was 5.3 years. Total WGR and WGW intake estimated with FFQ or reflected by total alkylresorcinol concentration in adipose tissue was not significantly associated with risk of breast cancer. However, after adjustment for total WGR and WGW intake, women in the highest quartile of relative WGR intake, reflected by the alkylresorcinol C17:0/C21:0 ratio, had a higher risk of overall breast cancer and estrogen-receptor-positive (ER+) breast cancer than women in the lowest quartile of relative WGR intake, while the risk of estrogen-receptor-negative (ER-) breast cancer incidence was unaffected. Similar results were obtained with the FFQ data. Based on these data, further investigation of the role of specific grain types in reducing or increasing breast cancer risk, and their overall impact on health, is warranted.
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| 3. |
- Bahram, Fuad, et al.
(författare)
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Interferon-γ-induced p27KIP1 binds to and targets MYC for proteasome-mediated degradation.
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:3, s. 2837-2854
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Tidskriftsartikel (refereegranskat)abstract
- The Myc oncoprotein is tightly regulated at multiple levels including ubiquitin-mediated protein turnover. We recently demonstrated that inhibition of Cdk2-mediated phosphorylation of Myc at Ser-62 pharmacologically or through interferon (IFN)-γ-induced expression of p27Kip1 (p27) repressed Myc's activity to suppress cellular senescence and differentiation. In this study we identified an additional activity of p27 to interfere with Myc independent of Ser-62 phosphorylation. p27 is required and sufficient for IFN-γ-induced turnover of Myc. p27 interacted with Myc in the nucleus involving the C-termini of the two proteins, including Myc box 4 of Myc. The C-terminus but not the Cdk2 binding fragment of p27 was sufficient for inducing Myc degradation. Protein expression data of The Cancer Genome Atlas breast invasive carcinoma set revealed significantly lower Myc protein levels in tumors with highly expressed p27 lacking phosphorylation at Thr-157 - a marker for active p27 localized in the nucleus. Further, these conditions correlated with favorable tumor stage and patient outcome. This novel regulation of Myc by IFN-γ/p27KIP1 potentially offers new possibilities for therapeutic intervention in tumors with deregulated Myc.
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| 4. |
- Cardilin, Tim, 1989, et al.
(författare)
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Model-based evaluation of radiation and radiosensitizing agents in oncology
- 2018
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Ingår i: CPT: Pharmacometrics and Systems Pharmacology. - : Wiley. - 2163-8306. ; 7:1, s. 51-58
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 ASCPT. Radiotherapy is one of the major therapy forms in oncology, and combination therapies involving radiation and chemical compounds can yield highly effective tumor eradication. In this paper, we develop a tumor growth inhibition model for combination therapy with radiation and radiosensitizing agents. Moreover, we extend previous analyses of drug combinations by introducing the tumor static exposure (TSE) curve. The TSE curve for radiation and radiosensitizer visualizes exposure combinations sufficient for tumor regression. The model and TSE analysis are then tested on xenograft data. The calibrated model indicates that the highest dose of combination therapy increases the time until tumor regrowth 10-fold. The TSE curve shows that with an average radiosensitizer concentration of 1.0μg/mL the radiation dose can be decreased from 2.2 Gy to 0.7 Gy. Finally, we successfully predict the effect of a clinically relevant treatment schedule, which contributes to validating both the model and the TSE concept.
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| 5. |
- Cardilin, Tim, 1989, et al.
(författare)
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Modeling long-term tumor growth and kill after combinations of radiation and radiosensitizing agents
- 2019
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 83:6, s. 1159-1173
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Radiation therapy, whether given alone or in combination with chemical agents, is one of the cornerstones of oncology. We develop a quantitative model that describes tumor growth during and after treatment with radiation and radiosensitizing agents. The model also describes long-term treatment effects including tumor regrowth and eradication. Methods: We challenge the model with data from a xenograft study using a clinically relevant administration schedule and use a mixed-effects approach for model-fitting. We use the calibrated model to predict exposure combinations that result in tumor eradication using Tumor Static Exposure (TSE). Results: The model is able to adequately describe data from all treatment groups, with the parameter estimates taking biologically reasonable values. Using TSE, we predict the total radiation dose necessary for tumor eradication to be 110 Gy, which is reduced to 80 or 30 Gy with co-administration of 25 or 100 mg kg −1 of a radiosensitizer. TSE is also explored via a heat map of different growth and shrinkage rates. Finally, we discuss the translational potential of the model and TSE concept to humans. Conclusions: The new model is capable of describing different tumor dynamics including tumor eradication and tumor regrowth with different rates, and can be calibrated using data from standard xenograft experiments. TSE and related concepts can be used to predict tumor shrinkage and eradication, and have the potential to guide new experiments and support translations from animals to humans.
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| 6. |
- Engström, Wilhelm, et al.
(författare)
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The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling
- 2015
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 36, s. S38-S60
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Forskningsöversikt (refereegranskat)abstract
- The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span.
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| 7. |
- Eriksen, Anne Kirstine, et al.
(författare)
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Prediagnostic enterolactone concentrations and mortality among Danish men diagnosed with prostate cancer
- 2017
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Ingår i: European Journal of Clinical Nutrition. - : Springer Science and Business Media LLC. - 0954-3007 .- 1476-5640. ; 71:10, s. 1235-1240
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/OBJECTIVES: Evidence on the role of diet in relation to prostate cancer progression is sparse. Foods rich in lignans have shown beneficial effects on prostate cancer progression in both animal studies and small human intervention studies, including beneficial effects on prostate-specific antigen levels and tumour growth. The lignan metabolite, enterolactone, has further shown to slow prostate cancer cell growth in vitro. The aim was to investigate the association between prediagnostic enterolactone concentrations and mortality among men with prostate cancer. SSUBLJECTS/METHODS: Prediagnostic plasma concentrations of enterolactone from 1390 men diagnosed with prostate cancer from the Danish Diet, Cancer and Health cohort were related to all-cause or prostate cancer-specific death, using Cox proportional hazards models with follow-up time (from the date of diagnose until the date of death, emigration or end of follow-up by December 2013) as the underlying time axis. RESULTS: The hazard ratios for enterolactone concentrations assessed linearly by 20 nmol/l increments was 0.95 (0.90, 1.02) for all-cause mortality and 0.98 (0.92, 1.05) for prostate cancer-specific mortality. Categorisation of enterolactone concentrations into quartiles did not reveal a different pattern. No effect modifications by smoking, body mass index or sport were observed, and the associations did not differ by prostate cancer aggressiveness. CONCLUSIONS: We found no association between enterolactone concentrations and mortality among men diagnosed with prostate cancer.
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| 8. |
- Eriksson, Staffan, et al.
(författare)
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Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead
- 2015
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 36, s. S254-S296
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Forskningsöversikt (refereegranskat)abstract
- Low-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
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| 9. |
- Eriksson, Staffan
(författare)
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Thymidine kinase 1 expression in ovarian serous adenocarcinoma is superior to Ki-67: A new prognostic biomarker
- 2017
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Ingår i: Tumor Biology. - : IOS Press. - 1010-4283 .- 1423-0380. ; 39
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is a disease with abnormally proliferating cells and therefore proliferation rate is an important index for assessing tumour growth. Ki-67 is a commonly used proliferation marker considered to be an unfavourable prognostic marker in some tumors, while Thymidine kinase 1 (TK1) is an interesting proliferation marker because its levels are highly dependent on the growth stage of cells. To define the immunohistochemistry (IHC) expression of the TK1 in patients with ovarian serous adenocarcinoma and establish its potential role as a new biomarker for progressive disease, we analyzed the expression patterns of TK1 and Ki-67 in 109 patients with ovarian serous adenocarcinoma. TK1 and Ki-67 expression both showed a statistically significant correlation to MD Anderson Cancer Center (MDACC) grade, but not to age, tumour size, lymph node metastasis or pathological TNM (pTNM) stages. TK1 expression, MDACC grades, pathological stages and lymph node metastasis correlate to relapse incident rate and overall survival, but Ki-67 does not. Although TK1 expression, MDACC grade, pTNM stage and lymph node metastasis significantly correlate to relapse in the Cox univariate analysis, in the multivariate Cox analysis only TK1 expression and lymph node metastasis were independent prognostic factors. The overall survival also correlated significantly to TK1 expression, MDACC grade, pTNM stage and lymph node metastasis in the Cox univariate analysis. However, only the pTNM stage was found to be an independent prognostic factor for survival in the Cox multivariate analysis. Therefore, though TK1 expression was an independent prognostic factor for relapse, but not for survival, TK1 is a more informative expression than Ki-67 for LI, relapse and overall survival rates. Thus, when TK1 is combined with MDACC grading, pTNM staging and lymph node metastasis, IHC determination of TK1 expression may improve the overall prediction of prognosis in patients with ovarian cancer.
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| 10. |
- Fryknäs, Mårten, et al.
(författare)
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Iron chelators target both proliferating and quiescent cancer cells
- 2016
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells.
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