Novel recurrently mutated genes in African American colon cancers.

We used whole-exome and targeted sequencing to characterize somatic mutations in 103 colorectal cancers (CRC) from African Americans, identifying 20 new genes as significantly mutated in CRC. Resequencing 129 Caucasian derived CRCs confirmed a 15-gene set as a preferential target for mutations in African American CRCs. Two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly likely African American CRC driver genes.

Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation.

Two boron-containing, ortho-icosahedral carborane lipophilic antifolates were synthesized, and the crystal structures of their ternary complexes with human dihydrofolate reductase (DHFR) and dihydronicotinamide adenine dinucleotide phosphate were determined. The compounds were screened for activity against DHFR from six sources (human, rat liver, Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and Lactobacillus casei) and showed good to modest activity against these enzymes. The compounds were also tested for antibacterial activity against L.

On systems and control approaches to therapeutic gain.

Background: Mathematical models of cancer relevant processes are being developed at an increasing rate. Conceptual frameworks are needed to support new treatment designs based on such models.

Methods: A modern control perspective is used to formulate two therapeutic gain strategies.

A role for DNA mismatch repair in sensing and responding to fluoropyrimidine damage.

The phenomenon of damage tolerance, whereby cells incur DNA lesions that are nonlethal, largely ignored, but highly mutagenic, appears to play a key role in carcinogenesis. Typically, these lesions are generated by alkylation of DNA or incorporation of base analogues. This tolerance is usually a result of the loss of specific DNA repair processes, most often DNA mismatch repair (MMR).

Mismatch repair and drug responses in cancer.

Defects in mismatch repair contribute to development of approximately 15% of colon cancers and to origination of endometrial, gastric and other cancers. Tumors with defects in mismatch repair exhibit marked resistance to alkylators and a variety of anticancer agents that modify DNA to create substrates for the mismatch repair system. These altered drug responses appear to derive from requirements for mismatch repair proteins in signalling apoptosis, altered cell cycle checkpoint behaviour and/or loss of mismatch repair dependent toxicity arising from futile repair cycling.