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Aspartate transcarbamoylase catalyzes the second step of de-novo pyrimidine biosynthesis. As malarial parasites lack pyrimidine salvage machinery and rely on de-novo production for growth and proliferation, this pathway is a target for drug discovery. Previously, an apo crystal structure of aspartate transcarbamoylase from Plasmodium falciparum (PfATC) in its T-state has been reported. Here we present crystal structures of PfATC in the liganded R-state as well as in complex with the novel inhibitor, 2,3-napthalenediol, identified by high-throughput screening. Our data shows that 2,3-napthalediol binds in close proximity to the active site, implying an allosteric mechanism of inhibition. Furthermore, we report biophysical characterization of 2,3-napthalenediol. These data provide a promising starting point for structure based drug design targeting PfATC and malarial de-novo pyrimidine biosynthesis.

Investigate the clinical utility of serum interleukin dosages of IL-2, IL-2R, IL-4, IL-6, IL-6R, IL-8, IL-10 and IL-12 in the diagnosis and characterization of patients with DTC. In particular, verify ILs utility in the identification of individuals who are evolving disease-free or with the active disease.We evaluated 200 patients with malignant nodules (100 patients disease-free and 100 patients with recurrence/active disease); 60 benign nodules and 100 healthy controls, serum levels were assessed by ELISA.All ILs, but not IL-4, differentiated these three groups. We observed that IL-2, 2R and 10 serum concentrations were associated with thyroglobulin levels. Serum IL-2 was able to differentiate patients with active disease from the disease-free with a sensitivity of 98%, specificity of 58%, positive predictive value (PPV) of 70% and negative predictive value (NPV) of 97% (p=0.0007). IL-6R levels differentiated patients with active disease from the disease-free patients with 56% sensitivity, 63% specificity, PPV of 60% and NPV of 59% (p0.0001). IL-8 values also distinguished patients with active disease from the disease-free ones with sensitivity of 50%, specificity of 76%, PPV of 68% and NPV of 60% (p=0.0025); using IL-12, we obtained a sensitivity value of 73%, specificity of 66%, PPV of 68% and NPV of 71% (p0.0001). Furthermore, interleukin levels showed association with some tumor characteristics of aggressiveness.We suggest that the serum concentration of ILs may assist in the diagnosis and characterization of tumor malignancy helping identify patients with active disease who deserve closer medical attention.

Objectives To investigate polymorphisms of IL-2 and IL-6R genes in patients with differentiated thyroid cancer (DTC), correlating them to previously obtained data on serum levels of IL-2 and IL-6R with DTC. Methods We evaluated the polymorphic inheritance of 300 malignant thyroid nodule patients and 300 healthy controls, including 200 patients with malignant nodules and 100 healthy controls previously investigated by ELISA for serum IL-2 and IL-6R levels. Results The genotypic distribution of IL-2 and IL-6R did not differ between cases and controls. Six haplotypes were generated for IL-6R SNPs, none of the haplotypes showed significance with the risk for thyroid cancer. Significant correlation was observed between all investigated polymorphisms and the serologic levels of the corresponding interleukins. Patients who had the IL-2 gene TT genotype of rs2069762 had higher serum levels of IL-2. Individuals with the CC genotype of rs2228145, the GG genotype of the rs4845622 and the AA genotype of the rs6684439 correlated with a higher serum production of IL-6R. Conclusion We demonstrated that IL-2 SNPs rs2069762, IL-6R rs2228145, IL-6R rs4845622 and IL-6R rs6684439 are associated with differences in the concentrations of the respective interleukins and these concentrations suggesting they may have a clinical utility distinguishing patient with active-disease.