Type 4 fimbriae are produced by a variety of pathogens, in which they appear to function in adhesion to epithelial cells, and in a form of surface translocation called twitching motility. Using transposon mutagenesis of Pseudomonas aeruginosa, we have identified a new locus required for fimbrial assembly. This locus contains the gene pilQ which encodes a 77 kDa protein with an N-terminal hydrophobic signal sequence characteristic of secretory proteins. pilQ mutants lack the spreading colony morphology characteristic of twitching motility, are devoid of fimbriae, and are resistant to the fimbrial-specific bacteriophage PO4. The pilQ gene was mapped to Spel fragment 2, which is located at 0-5 minutes on the P. aeruginosa PAO1 chromosome, and thus it is not closely linked to the previously characterized pilA-D, pilS,R or pilT genes. The pilQ region also contains ponA, aroK and aroB-like genes in an organization very similar to that of corresponding genes in Escherichia coli and Haemophilus influenzae. The predicted amino acid sequence of PilQ shows homology to the PulD protein of Klebsiella oxytoca and related outer membrane proteins which have been found in association with diverse functions in other species including protein secretion, DNA uptake and assembly of filamentous phage. PilQ had the highest overall homology to an outer membrane antigen from Neisseria gonorrhoeae, encoded by omc, that may fulfil the same role in type 4 fimbrial assembly in this species.
Sry is the Y-chromosomal gene that is pivotal in the determination of sex in mammals, however the structure of the Sry transcript produced in the embryo has not been determined. We show here that the transcript expressed in the developing mouse gonad at the sex determining stage of development is linear, polyadenylated and encoded by a single exon, in contrast to the circular, apparently untranslated transcript produced in adult testes. The linear transcript was not detected in any other fetal tissue nor in any adult tissue tested, and was expressed only in the genital ridge portion of the urogenital ridge. The spatial and temporal profile of Sry expression suggests that its role in the mouse fetus is limited to initiating Sertoli cell development during testis determination.
This study provides further evidence for linkage of FH-II to 7p22, refines the locus, and supports the notion that FH-II may be genetically heterogeneous.
Purpose
Brivanib, an oral, multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR) was investigated as a single agent in a phase II trial to assess the activity and tolerability in recurrent or persistent endometrial cancer (EMC).
Patients and Methods
Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and performance status of ≤2. Treatment consisted of brivanib 800 mg orally every day until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at six months and objective tumor response. Expression of multiple angiogenic proteins and FGFR2 mutation status was assessed.
Results
Forty-five patients were enrolled. Forty-three patients were eligible and evaluable. Median age was 64 years. Twenty-four patients (55.8%) received prior radiation. Median number of cycles was two (range 1–24). No GI perforations but one rectal fistula were seen. Nine patients had grade 3 hypertension, with one experiencing grade 4 confusion. Eight patients (18.6%; 90% CI 9.6–31.7%) had responses (one CR and seven PRs), and 13 patients (30.2%; 90% CI 18.9–43.9%) were PFS at six months. Median PFS and overall survival (OS) were 3.3 and 10.7 months, respectively. When modeled jointly, VEGF and Angiopoietin-2 expression may diametrically predict PFS. Estrogen receptor-α (ER) expression was positively correlated with OS.
Conclusion
Brivanib is reasonably well tolerated and worthy of further investigation based on PFS at six months in recurrent or persistent EMC.
In 33 Australian children with CPHD we have identified POU1F1 mutations in two patients and no PROP1 mutations. We speculate that in the majority of children other genes must be responsible for the CPHD phenotype.
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