TREX1, originally designated DNase III, was isolated as a major nuclear DNA-specific 335 exonuclease that is widely distributed in both proliferating and nonproliferating mammalian tissues. The cognate cDNA shows homology to the editing subunit of the Escherichia coli replicative DNA polymerase III holoenzyme and encodes an exonuclease which was able to serve a DNA-editing function in vitro, promoting rejoining of a 3 mismatched residue in a reconstituted DNA base excision repair system. Here we report the generation of genetargeted Trex1؊/؊ mice. The null mice are viable and do not show the increase in spontaneous mutation frequency or cancer incidence that would be predicted if Trex1 served an obligatory role of editing mismatched 3 termini generated during DNA repair or DNA replication in vivo. Unexpectedly, Trex1 ؊/؊ mice exhibit a dramatically reduced survival and develop inflammatory myocarditis leading to progressive, often dilated, cardiomyopathy and circulatory failure.Two distinct nuclear exonucleases account for the major part of the total exonucleolytic activity on DNA observed in mammalian cell extracts (24, 25). They were identified as a 3Ј35Ј exonuclease acting preferentially on single-stranded DNA and a 5Ј33Ј exonuclease specific for double-stranded DNA that could remove a single-stranded 5Ј overhang as an oligonucleotide. These nuclear enzymes were designated DNase III and DNase IV, as they are distinct from the pancreatic and macrophage lysosomal DNA endonucleases DNase I and DNase II. DNase IV was later renamed flap endonuclease 1 (FEN1) (23), and its main function is processing displaced 5Ј single strands that arise during lagging-strand DNA replication, as well as during DNA repair, recombination, and triplet repeat expansion. The elimination of Fen1 activity leads to early embryonic lethality in mice, consistent with an essential role of the enzyme in DNA replication (20). In contrast, DNase III is expressed at similar levels in nonproliferating and proliferating tissues; it was isolated as the major nuclear 3Ј35Ј DNA exonuclease from the adult rabbit liver (14) and also from the calf thymus and human myoblasts, where it was designated TREX1 (37, 38).The human TREX1/DNase III cDNA (14, 29) shares amino acid sequence homology with the Escherichia coli DnaQ/MutD editing subunit of the replicative DNA polymerase III holoenzyme, which can increase the fidelity of an exonuclease-deficient mammalian DNA polymerase in vitro (36). The TREX1/ DNase III cDNA encodes a nonprocessive 3Ј35Ј DNA-specific exonuclease, with a preference for single-stranded DNA or mispaired 3Ј termini; like the native protein isolated from mammalian cells, it forms homodimers (14, 29, 30). Since two of the major mammalian nuclear DNA polymerases, Pol␣ and Pol␤, do not have an intrinsic 3Ј exonuclease function, it was proposed that TREX1/DNase III may serve to edit mismatched deoxyribonucleotides during lagging-strand DNA synthesis or gap filling in DNA base excision repair, which are conducted by Pol␣ and Pol␤, respectively...

We therefore believe that FLIM has a potential future clinical role in imaging BCCs for rapid and noninvasive tumour delineation and as an aid to determine adequate excision margins with best preservation of normal tissue.

Lung cancer is the commonest cancer killer. Small cell lung cancer (SCLC) is initially chemosensitive, but rapidly relapses in a chemoresistant form with an overall survival of <5%. Consequently, novel therapies are urgently required and will likely arise from an improved understanding of the disease biology. Our previous work showed that fibroblast growth factor-2 induces proliferation and chemoresistance in SCLC cells. Here, we show that the selective fibroblast growth factor receptor (FGFR) inhibitor PD173074 blocks H-510 and H-69 SCLC proliferation and clonogenic growth in a dose-dependent fashion and prevents FGF-2-induced chemoresistance. These effects correlate with the inhibition of both FGFR1 and FGFR2 transphosphorylation. We then determined the efficacy of daily oral administration of PD173074 for 28 days in two human SCLC models. In the H-510 xenograft, tumor growth was impaired similar to that seen with single-agent cisplatin administration, increasing median survival compared with control sham-treated animals. Crucially, the effect of cisplatin was significantly potentiated by coadministration of PD173074. More dramatically, in H-69 xenografts, PD173074 induced complete responses lasting >6 months in 50% of mice. These effects were not a consequence of disrupted tumor vasculature but instead correlated with increased apoptosis (caspase 3 and cytokeratin 18 cleavage) in excised tumors. Moreover, in vivo imaging with 3′-deoxy-3′-