Xeroderma pigmentosum complementation group C (XPC), a DNA repair protein, plays an important role in the maintenance of genomic integrity and is essential for the nucleotide excision repair pathway. Polymorphisms in the XPC gene may alter DNA repair leading to genetic instability and oncogenesis. The present study aimed to assess the relationship between the XPC Ala499Val (rs2228000 C>T) and Lys939Gln (rs2228001 A>C) non-synonymous polymorphisms and susceptibility to chronic myeloid leukemia (CML) pathogenesis, disease progression and the response to targeted therapeutic regimen, imatinib mesylate.
This case-control study included 212 cases and 212 controls, and the genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism assays.
Our results showed significant association of variant CT (odds ratio = 1.92, 95% confidence interval = 1.21-3.06, p = 0.003) and TT (odds ratio = 2.84, 95% confidence interval = 1.22-6.71, p = 0.007) genotypes in patients with the XPC Ala499Val polymorphism and CML risk. In addition, these genotypes were associated with CML progression to advanced phases (p = 0.006), splenomegaly (p = 0.017) and abnormal lactate dehydrogenase levels (p = 0.03). XPC Lys939Gln was found to correlate with a poor response to therapy, showing borderline significant association with minor cytogenetic response (p = 0.08) and a poor molecular response (p = 0.06). Significant association of the Ala499Val and Lys939Gln polymorphisms with prognosis was observed (Hasford high risk, p = 0.031 and p = 0.019, respectively). Haplotype analysis showed a strong correlation of variant TC haplotype with poor therapy responses (minor cytogenetic response, p = 0.019; poor molecular response, p < 0.0001).
In conclusion, our results suggest that XPC Ala499Val is a high-penetrance CML susceptibility polymorphism. Both polymorphisms studied are considered as genetic markers with respect to assessing disease progression, therapy response and prognosis in CML patients.

Imatinib, the first Tyrosine Kinase Inhibitor (TKI) used for the treatment of chronic myeloid leukaemia (CML) has revolutionized the management by inhibiting BCR-ABL tyrosine kinase. According to earlier reports there are concerns regarding the adverse effect of imatinib on haemostasis by causing platelet dysfunction. Here we studied platelet function using platelet aggregometry, in 19 CML chronic phase (CML-CP) patients on imatinib therapy, in complete haematologic response (CHR). The median duration of imatinib therapy before performing the test was 154 days. This study reveals that there are large inter-individual variations in platelet functions among imatinib treated patients and different levels of variability have been seen for different agonists. Most common aggregation abnormality (< 50% aggregation) was seen with low dose collagen (1 μg/ml) in 31.57% patients. Despite in-vitro platelet aggregation defects, none of the patients showed any bleeding symptoms. This enigma can possibly be explained by the fact that platelet specific agonists, epinephrine and collagen act in synergy for platelet aggregation compared against individual low dose agonists, supported by ex-vivo experiments in normal healthy control group (n = 5) (p value < 0.0004 for epinephrine, p value < 0.0001 for collagen). This experiment was also confirmed in a CML-CP patient. In future, more studies are needed to find out the exact mechanism of this inhibition.

The mathematical design of optimal therapies to fight cancer is an important research field in today\'s Biomathematics and Biomedicine given its relevance to formulate patient-specific treatments. Until now, however, cancer optimal therapies have considered that malignancy exclusively depends on the drug concentration and the number of cancer cells, ignoring that the faster the cancer grows the worse the cancer is, and that early drug doses are more prejudicial. Here, we analyze how optimal therapies are affected when the time evolution of treated cancer is envisaged as an additional element determining malignancy, analyzing in detail the implications for imatinib-treated Chronic Myeloid Leukemia.
Taking as reference a mathematical model describing Chronic Myeloid Leukemia dynamics, we design an optimal therapy problem by modifying the usual malignancy objective function, unaware of any temporal dimension of cancer malignance. In particular, we introduce a time valuation factor capturing the increase of malignancy associated to the quick development of the disease and the persistent negative effects of initial drug doses. After assigning values to the parameters involved, we solve and simulate the model with and without the new time valuation factor, comparing the results for the drug doses and the evolution of the disease.
Our computational simulations unequivocally show that the consideration of a time valuation factor capturing the higher malignancy associated with early growth of cancer and drug administration allows more efficient therapies to be designed. More specifically, when this time valuation factor is incorporated into the objective function, the optimal drug doses are lower, and do not involve medically relevant increases in the number of cancer cells or in the disease duration.
In the light of our simulations and as biomedical evidence strongly suggests, the existence of a time valuation factor affecting malignancy in treated cancer cannot be ignored when designing cancer optimal therapies. Indeed, the consideration of a time valuation factor modulating malignancy results in significant gains of efficiency in the optimal therapy with relevant implications from the biomedical perspective, specially when designing patient-specific treatments.