RESUMEN
Specifying the role of genetic mutations in cancer development is crucial for effective screening or targeted treatments for people with hereditary cancer predispositions. Our goal here is to find the relationship between a number of cancerogenic mutations and the probability of cancer induction over the lifetime of cancer patients. We believe that the Avrami-Dobrzynski biophysical model can be used to describe this mechanism. Therefore, clinical data from breast and ovarian cancer patients were used to validate this model of cancer induction, which is based on a purely physical concept of the phase-transition process with an analogy to the neoplastic transformation. The obtained values of model parameters established using clinical data confirm the hypothesis that the carcinogenic process strongly follows fractal dynamics. We found that the model's theoretical prediction and population clinical data slightly differed for patients with the age below 30 years old, and that might point to the existence of an ancillary protection mechanism against cancer development. Additionally, we reveal that the existing clinical data predict breast or ovarian cancers onset two years earlier for patients with BRCA1/2 mutations.
Asunto(s)
Neoplasias de la Mama , Neoplasias Ováricas , Humanos , Femenino , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/epidemiología , Mutación , Predisposición Genética a la Enfermedad , Neoplasias de la Mama/genéticaRESUMEN
The priming dose effect, called also the Raper-Yonezawa effect or simply the Yonezawa effect, is a special case of the radiation adaptive response phenomenon (radioadaptation), which refers to: (a) faster repair of direct DNA lesions (damage), and (b) DNA mutation frequency reduction after irradiation, by applying a small priming (conditioning) dose prior to the high detrimental (challenging) one. This effect is observed in many (but not all) radiobiological experiments which present the reduction of lesion, mutation or even mortality frequency of the irradiated cells or species. Additionally, the multi-parameter model created by Dr. Yonezawa and collaborators tried to explain it theoretically based on experimental data on the mortality of mice with chronic internal irradiation. The presented paper proposes a new theoretical approach to understanding and explaining the priming dose effect: it starts from the radiation adaptive response theory and moves to the three-parameter model, separately for two previously mentioned situations: creation of fast (lesions) and delayed damage (mutations). The proposed biophysical model was applied to experimental data-lesions in human lymphocytes and chromosomal inversions in mice-and was shown to be able to predict the Yonezawa effect for future investigations. It was also found that the strongest radioadaptation is correlated with the weakest cellular radiosensitivity. Additional discussions were focussed on more general situations where many small priming doses are used.
Asunto(s)
Daño del ADN , Tolerancia a Radiación , Animales , ADN , Relación Dosis-Respuesta en la Radiación , Ratones , Mutación , Tolerancia a Radiación/fisiologíaRESUMEN
The nucleation and growth theory, described by the Avrami equation (also called Johnson-Mehl-Avrami-Kolmogorov equation), and usually used to describe crystallization and nucleation processes in condensed matter physics, was applied in the present paper to cancer physics. This can enhance the popular multi-hit model of carcinogenesis to volumetric processes of single cell's DNA neoplastic transformation. The presented approach assumes the transforming system as a DNA chain including many oncogenic mutations. Finally, the probability function of the cell's cancer transformation is directly related to the number of oncogenic mutations. This creates a universal sigmoidal probability function of cancer transformation of single cells, as observed in the kinetics of nucleation and growth, a special case of a phase transition process. The proposed model, which represents a different view on the multi-hit carcinogenesis approach, is tested on clinical data concerning gastric cancer. The results also show that cancer transformation follows DNA fractal geometry.
Asunto(s)
ADN , Neoplasias , Carcinogénesis/genética , Cristalización , Humanos , CinéticaRESUMEN
p28 is a 28-amino acid peptide fragment of the cupredoxin azurin derived from Pseudomonas aeruginosa that preferentially penetrates cancerous cells and arrests their proliferation in vitro and in vivo. Its antitumor activity reportedly arises from post-translational stabilization of the tumor suppressor p53 normally downregulated by the binding of several ubiquitin ligases. This would require p28 to specifically bind to p53 to inhibit specific ligases from initiating proteosome-mediated degradation. In this study, atomic force spectroscopy, a nanotechnological approach, was used to investigate the interaction of p28 with full-length p53 and its isolated domains at the single molecule level. Analysis of the unbinding forces and the dissociation rate constant suggest that p28 forms a stable complex with the DNA-binding domain of p53, inhibiting the binding of ubiquitin ligases other than Mdm2 to reduce proteasomal degradation of p53.