Urothelial carcinoma involving the ureteral orifice: a clinicopathologic analysis of 93 cases.

Although tumors involving the bladder and ureter have been well described, there are only few studies in the pathology literature specifically analyzing tumors involving the ureteral orifice (UO). A search was performed for biopsy and resection specimens (transurethral resection, radical cystectomy/cystoprostatectomy, nephroureterectomy and bladder cuff resection) of urothelial carcinoma (UCa) involving the UO. Ninety-three cases were identified. Sixty-two (67%) patients were male. Mean patient age was 71 years (range, 43-91 years). Forty-two of 93 (45%) cases were invasive UCa (41 high-grade UCa; 1 low-grade UCa); 17/42 (40%) were invasive into muscularis propria. Tumor laterality was as follows: right side, 43 (46% of cases); left side, 41 (44%); bilateral, 4 (4.5%); and in 5 cases (5.5%), the laterality was not specified by the urologist. Seven cases of UCa with variant histology were also identified. Five patients had lymph node (LN) metastasis at the time of resection, and another 3 presented with LN or distant metastasis after resection (range, 4-38 months). Although this study focused primarily on the index tumor involving the UO (Group 1 cases are those with only UO involvement), in 70/93 (75%) cases (Group 2 cases), at least one other tumor was located at another site within the bladder. The fact that the majority of cases (75%) had tumors located at other sites of the bladder, emphasizes that careful examination of the UO needs to be performed by both urologists and pathologists when examining cases of UCa of the bladder.

Pulmonary vasculature directed adenovirus increases epithelial lining fluid alpha-1 antitrypsin levels.

BACKGROUND: Gene therapy for inherited serum deficiency disorders has previously been limited by the balance between obtaining adequate expression and causing hepatic toxicity. Our group has previously described modifications of a replication deficient human adenovirus serotype 5 that increase pulmonary vasculature transgene expression. METHODS: In the present study, we use a modified pulmonary targeted adenovirus to express human alpha-1 antitrypsin (A1AT) in C57BL/6 J mice. RESULTS: Using the targeted adenovirus, we were able to achieve similar increases in serum A1AT levels with less liver viral uptake. We also increased pulmonary epithelial lining fluid A1AT levels by more than an order of magnitude compared to that of untargeted adenovirus expressing A1AT in a mouse model. These gains are achieved along with evidence of decreased systemic inflammation and no evidence for increased inflammation within the vector-targeted end organ. CONCLUSIONS: In addition to comprising a step towards clinically viable gene therapy for A1AT, maximization of protein production at the site of action represents a significant technical advancement in the field of systemically delivered pulmonary targeted gene therapy. It also provides an alternative to the previous limitations of hepatic viral transduction and associated toxicities.

Genome-Wide DNA Methylation Study Identifies Significant Epigenomic Changes in Osteoarthritic Subchondral Bone and Similarity to Overlying Cartilage.

OBJECTIVE: To perform a genome-wide DNA methylation study to identify differential DNA methylation patterns in subchondral bone underlying eroded and intact cartilage from patients with hip osteoarthritis (OA) and to compare these with DNA methylation patterns in overlying cartilage. METHODS: Genome-wide DNA methylation profiling using Illumina HumanMethylation 450 arrays was performed on eroded and intact cartilage and subchondral bone from within the same joint of 12 patients undergoing hip arthroplasty. Genes with differentially methylated CpG sites were analyzed to identify shared pathways, upstream regulators, and overrepresented gene ontologies, and these patterns were compared with those of the overlying cartilage. Histopathology was graded by modified Mankin score and assessed for correlation with DNA methylation. RESULTS: We identified 7,316 differentially methylated CpG sites in subchondral bone underlying eroded cartilage, most of which (∼75%) were hypomethylated, and 1,397 sites in overlying eroded cartilage, 126 of which were shared. Samples clustered into 3 groups with distinct histopathologic scores. We observed differential DNA methylation of genes including the RNA interference-processing gene AGO2, the growth factor TGFB3, the OA suppressor NFATC1, and the epigenetic effector HDAC4. Among known susceptibility genes in OA, 32 were differentially methylated in subchondral bone, 8 were differentially methylated in cartilage, and 5 were shared. Upstream regulator analysis using differentially methylated genes in OA subchondral bone showed a strong transforming growth factor ß1 signature (P = 1 × 10(-40) ) and a tumor necrosis factor family signature (P = 3.2 × 10(-28) ), among others. CONCLUSION: Our data suggest the presence of an epigenetic phenotype associated with eroded OA subchondral bone that is similar to that of overlying eroded OA cartilage.

Genome-wide DNA methylation study identifies significant epigenomic changes in osteoarthritic cartilage.

OBJECTIVE: To perform a genome-wide DNA methylation study to identify DNA methylation changes in osteoarthritic (OA) cartilage tissue. METHODS: The contribution of differentially methylated genes to OA pathogenesis was assessed by bioinformatic analysis, gene expression analysis, and histopathologic severity correlation. Genome-wide DNA methylation profiling of >485,000 methylation sites was performed on eroded and intact cartilage from within the same joint of 24 patients undergoing hip arthroplasty for OA. Genes with differentially methylated CpG sites were analyzed to identify overrepresented gene ontologies, pathways, and upstream regulators. The messenger RNA expression of a subset of differentially methylated genes was analyzed by reverse transcription-polymerase chain reaction. Histopathology was graded by modified Mankin score and correlated with DNA methylation. RESULTS: We identified 550 differentially methylated sites in OA. Most (69%) were hypomethylated and enriched among gene enhancers. We found differential methylation in genes with prior links to OA, including RUNX1, RUNX2, DLX5, FURIN, HTRA1, FGFR2, NFATC1, SNCAIP, and COL11A2. Among these, RUNX1, HTRA1, FGFR2, and COL11A2 were also differentially expressed. Furthermore, we found differential methylation in approximately one-third of known OA susceptibility genes. Among differentially methylated genes, upstream regulator analysis showed enrichment of TGFB1 (P = 4.40 × 10(-5) ) and several microRNAs including miR-128 (P = 4.48 × 10(-13) ), miR-27a (P = 4.15 × 10(-12) ), and miR-9 (P = 9.20 × 10(-10) ). Finally, we identified strong correlations between 20 CpG sites and the histologic Mankin score in OA. CONCLUSION: Our data implicate epigenetic dysregulation of a host of genes and pathways in OA, including a number of OA susceptibility genes. Furthermore, we identified correlations between CpG methylation and histologic severity in OA.