We have characterized at the nucleotide level a 4.8-kilobase pair segment of the third chromosome of Drosophila melanogaster, which contains a cluster of three chorion genes, s18-1, s15-1 and s19-1. These genes are tandemly oriented and share the same basic organization: a small and a large exon separated by a short intron in the signal peptide region. In the coding region, limited similarities at the DNA and protein level suggest a common but distant evolutionary origin. The flanking sequences were searched for elements that might be involved in controlling the tissue-specific and temporally regulated expression and the selective amplification of the chorion genes. A good candidate for a cis-regulatory element is the hexamer, TCACGT, which is found in all three genes in a highly significant position, 23 to 27 nucleotides upstream of the TATA-box, accompanied by additional, less exact similarities. Palindromes and short inverted repeats that are found in the vicinity of their complement are non-uniformly distributed: they are most concentrated in the 3' flanking part of all three genes, in and near regions of unusually high A and T content. The highest number of dyad symmetries, reminiscent of sequences that function as viral replication origins, is found associated with the T- and A-rich regions between genes s18-1 and s15-1.
243 Background: The benefit of salvage chemotherapy such as weekly paclitaxel (TAX) is modest in metastatic (met) urothelial ca, with median TTP of ≤3 months and ORR of 10% (95% CI 4-18% [combined results, Vaughn 2002; Joly, 2009]). Cetuximab (CET) is a monoclonal antibody against the epidermal growth factor receptor (EGFR). High-grade urothelial cancer overexpress EGFR. We conducted a multicenter randomized, noncomparative phase II study to measure the efficacy of CET ± TAX in patients (pts) with previously treated met urothelial cancer. Methods: Pts with met urothelial cancer who received one line of chemotherapy in the adjuvant, neoadjvuant, or met setting were enrolled. Pts were randomized to CET 250mg/m2 (after 400 mg/m2 load) ± TAX 80 mg/m2 weekly. A cycle was 4 weeks (wks). Response (RECIST) was assessed by imaging every 8 wks. We used early progression to assess futility (Litwin Stats Med 2007). Either arm would close if 7 of the initial 15 pts in that arm progressed at the first disease evaluation. Either arm would be considered promising if ≥9/28 patients had PFS>16 wks (90.4% power to detect an improvement in Median [Med] PFS from 8 to 16 wks with a 7.1% type 1 error). Results: We enrolled 39 evaluable pts (30 male). Median age was 69 years (range 49-79). All pts received prior platinum-based chemotherapy. CET arm closed after 9 of the first 11 pts progressed by 8 wks (ASCO GU 2009). CET-TAX arm completed full accrual (28 pts), of which 11 had visceral disease and 13 received chemo for met disease. 10/28 pts had PFS>16 wks. Overall RR was 28.5%, (8/28 pts, 95% CI 13-49%) (2 CR, 6PR). 4 additional pts had unconfirmed PR. 2 pts have maintained PR 3 and 4 months after discontinuing CET-TAX. Med PFS for the CET-TAX was 115 days (16 weeks)(95% CI 58-174 days). Med PFS for pts with visceral disease was 84 days (95%CI 50-NR). Med PFS for pts who received prior chemo for met disease was 142 days (95% 58-NR). Med number of cycles for the CET-TAX was 3 (range 0-25). Grade 3 AEs occurring in more than 2 pts were rash (5), fatigue (4), anemia (4), low magnesium (3). Conclusions: EGFR inhibition with CET appears to augment the antitumor activity of TAX in pts with previously treated urothelial cancers. The CET-TAX combination merits further study to establish its role in treatment of urothelial cancers. [Table: see text]
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