Modeling tumor growth in the presence of a therapy with an effect on rate growth and variability by means of a modified Gompertz diffusion process.

In experimental studies on tumor growth, whenever the time evolution of the relative volume of a tumor in an untreated (control) group can be fitted by a Gompertz diffusion process there is a possibility that an antiproliferative therapy, which modifies the growth rate of the process that fits the treated group, may also affect its variability. The present paper proposes several procedures for the estimation of the time function included in the infinitesimal variance of the new process, as well as the time function affecting the growth rate (which is included in the infinitesimal mean). Also, a hypothesis testing is designed to confirm or refute the need for including such a time-dependent function in the infinitesimal variance. In order to validate and compare the proposed procedures a simulation study has been carried out. In addition, a proposal is made for a strategy aimed at finding the optimal combination of procedures for each case. A real data application concerning the effects of cisplatin on a patient-derived xenograft (PDX) tumor model showcases the advantages of this model over others that have been used in the past.

Photoreactivity of furocoumarins and DNA in PUVA therapy: formation of psoralen-thymine adducts.

The mechanism of the [2+2] cycloaddition photoreaction of psoralen and a DNA nucleobase, thymine, cornerstone of the furocoumarin-based PUVA (psoralen+UVA radiation) phototherapy, has been studied by the quantum-chemical multiconfigurational CASPT2 method. Triplet- and singlet-mediated mono- and diadduct formations have been determined to take place via singlet-triplet crossings and conical intersections, correlated with the initially promoted triplet or singlet states in different possible reactive orientations. Pyrone-side monoadducts are suggested to be formed in the triplet manifold of the system, and to be less prone to yield diadducts because of the properties of the monoadduct lowest triplet state and the minor accessibility of its excited singlet states. Furan-side monoadducts are better produced in the singlet manifold after reaching a conical intersection with the ground state of the system. From there, the absorption of a second photon would in this case trigger the formation of the diadduct. The proposed mechanisms enable rationalizing the phototherapeutic behavior of several furocoumarins.

Theoretical insight into the intrinsic ultrafast formation of cyclobutane pyrimidine dimers in UV-irradiated DNA: thymine versus cytosine.

The higher formation yields measured in the ultrafast photoinduced formation of cyclobutane thymine dimers (T<>T) with respect to those of cytosine (C<>C) are explained, on the basis of ab initio CASPT2 results, by the existence in thymine of more reactive orientations and a less efficient photoreversibility, whereas in cytosine the funnel toward the photolesion becomes competitive with that mediating the internal conversion of the excited-cytosine monomer.

On the intrinsic population of the lowest triplet state of thymine.

The population of the lowest triplet state of thymine after near-UV irradiation has been established, on the basis of CASPT2//CASSCF quantum chemical calculations, to take place via three distinct intersystem crossing mechanisms from the initially populated singlet bright 1pipi* state. Two singlet-triplet crossings have been found along the minimum-energy path for ultrafast decay of the singlet state at 4.8 and 4.0 eV, involving the lowest 3npi* and 3pipi* states, respectively. Large spin-orbit coupling elements predict efficient intersystem crossing processes in both cases. Another mechanism involving energy transfer from the lowest 1npi* state with much larger spin-orbit coupling terms can also be proposed. The wavelength dependence measured for the triplet quantum yield of pyrimidine nucleobases is explained by the location and accessibility of the singlet-triplet crossing regions.

A theoretical insight into the photophysics of psoralen.

Psoralen photophysics has been studied on quantum chemistry grounds using the multiconfigurational second-order perturbation method CASPT2. Absorption and emission spectra of the system have been rationalized by computing the energies and properties of the low-lying singlet and triplet excited states. The S1 pipi* state has been determined to be responsible of the lowest absorption and fluorescence bands and to initially carry the population in the photophysical processes related to the phototherapeutic properties of psoralen derivatives. The low-lying T1 pipi* state is, on the other hand, protagonist of the phosphorescence, and its prevalent role in the reactivity of psoralen is suggested to be related to the elongation of the pyrone ring C3-C4 bond, where the spin density is distributed on both carbon atoms. Analysis of energy gaps and spin-orbit coupling elements indicates that the efficient photophysical process leading to the population of the lowest triplet state does not take place at the Franck-Condon region but along the S1 relaxation path.