Gene expression relationship between prostate cancer cells of Gleason 3, 4 and normal epithelial cells as revealed by cell type-specific transcriptomes

Background: Prostate cancer cells in primary tumors have been typed CD10(-)/CD13(-)/CD24(hi)/CD26(+)/CD38(lo)/CD44(-)/CD104(-). This CD phenotype suggests a lineage relationship between cancer cells and luminal cells. The Gleason grade of tumors is a descriptive of tumor glandular differentiation. Higher Gleason scores are associated with treatment failure. Methods: CD26(+) cancer cells were isolated from Gleason 3+3 (G3) and Gleason 4+4 (G4) tumors by cell sorting, and their gene expression or transcriptome was determined by Affymetrix DNA array analysis. Dataset analysis was used to determine gene expression similarities and differences between G3 and G4 as well as to prostate cancer cell lines and histologically normal prostate luminal cells. Results: The G3 and G4 transcriptomes were compared to those of prostatic cell types of non-cancer, which included luminal, basal, stromal fibromuscular, and endothelial. A principal components analysis of the various transcriptome datasets indicated a closer relationship between luminal and G3 than luminal and G4. Dataset comparison also showed that the cancer transcriptomes differed substantially from those of prostate cancer cell lines. Conclusions: Genes differentially expressed in cancer are potential biomarkers for cancer detection, and those differentially expressed between G3 and G4 are potential biomarkers for disease stratification given that G4 cancer is associated with poor outcomes. Differentially expressed genes likely contribute to the prostate cancer phenotype and constitute the signatures of these particular cancer cell types.National Institutes of Health (NIH)[CA111244]National Institutes of Health (NIH)[CA98699]National Institutes of Health (NIH)[CA85859]National Institutes of Health (NIH)[DK63630][P50-GMO-76547

Gene expression down-regulation in CD90+ prostate tumor-associated stromal cells involves potential organ-specific genes

<p>Abstract</p> <p>Background</p> <p>The prostate stroma is a key mediator of epithelial differentiation and development, and potentially plays a role in the initiation and progression of prostate cancer. The tumor-associated stroma is marked by increased expression of CD90/THY1. Isolation and characterization of these stromal cells could provide valuable insight into the biology of the tumor microenvironment.</p> <p>Methods</p> <p>Prostate CD90⁺stromal fibromuscular cells from tumor specimens were isolated by cell-sorting and analyzed by DNA microarray. Dataset analysis was used to compare gene expression between histologically normal and tumor-associated stromal cells. For comparison, stromal cells were also isolated and analyzed from the urinary bladder.</p> <p>Results</p> <p>The tumor-associated stromal cells were found to have decreased expression of genes involved in smooth muscle differentiation, and those detected in prostate but not bladder. Other differential expression between the stromal cell types included that of the CXC-chemokine genes.</p> <p>Conclusion</p> <p>CD90⁺prostate tumor-associated stromal cells differed from their normal counterpart in expression of multiple genes, some of which are potentially involved in organ development.</p

Association of follow-up infarct volume with functional outcome in acute ischemic stroke: a pooled analysis of seven randomized trials.

BACKGROUND: Follow-up infarct volume (FIV) has been recommended as an early indicator of treatment efficacy in patients with acute ischemic stroke. Questions remain about the optimal imaging approach for FIV measurement. OBJECTIVE: To examine the association of FIV with 90-day modified Rankin Scale (mRS) score and investigate its dependency on acquisition time and modality. METHODS: Data of seven trials were pooled. FIV was assessed on follow-up (12 hours to 2 weeks) CT or MRI. Infarct location was defined as laterality and involvement of the Alberta Stroke Program Early CT Score regions. Relative quality and strength of multivariable regression models of the association between FIV and functional outcome were assessed. Dependency of imaging modality and acquisition time (≤48 hours vs >48 hours) was evaluated. RESULTS: Of 1665 included patients, 83% were imaged with CT. Median FIV was 41 mL (IQR 14-120). A large FIV was associated with worse functional outcome (OR=0.88(95% CI 0.87 to 0.89) per 10 mL) in adjusted analysis. A model including FIV, location, and hemorrhage type best predicted mRS score. FIV of ≥133 mL was highly specific for unfavorable outcome. FIV was equally strongly associated with mRS score for assessment on CT and MRI, even though large differences in volume were present (48 mL (IQR 15-131) vs 22 mL (IQR 8-71), respectively). Associations of both early and late FIV assessments with outcome were similar in strength (ρ=0.60(95% CI 0.56 to 0.64) and ρ=0.55(95% CI 0.50 to 0.60), respectively). CONCLUSIONS: In patients with an acute ischemic stroke due to a proximal intracranial occlusion of the anterior circulation, FIV is a strong independent predictor of functional outcome and can be assessed before 48 hours, oneither CT or MRI

Protocol for the perfusion and angiography imaging sub-study of the Third International Stroke Trial (IST-3) of alteplase treatment within six-hours of acute ischemic stroke

RATIONALE: Intravenous thrombolysis with recombinant tissue Plasminogen Activator improves outcomes in patients treated early after stroke but at the risk of causing intracranial hemorrhage. Restricting recombinant tissue Plasminogen Activator use to patients with evidence of still salvageable tissue, or with definite arterial occlusion, might help reduce risk, increase benefit and identify patients for treatment at late time windows. AIMS: To determine if perfusion or angiographic imaging with computed tomography or magnetic resonance help identify patients who are more likely to benefit from recombinant tissue Plasminogen Activator in the context of a large multicenter randomized trial of recombinant tissue Plasminogen Activator given within six-hours of onset of acute ischemic stroke, the Third International Stroke Trial. DESIGN: Third International Stroke Trial is a prospective multicenter randomized controlled trial testing recombinant tissue Plasminogen Activator (0·9 mg/kg, maximum dose 90 mg) started up to six-hours after onset of acute ischemic stroke, in patients with no clear indication for or contraindication to recombinant tissue Plasminogen Activator. Brain imaging (computed tomography or magnetic resonance) was mandatory pre-randomization to exclude hemorrhage. Scans were read centrally, blinded to treatment and clinical information. In centers where perfusion and/or angiography imaging were used routinely in stroke, these images were also collected centrally, processed and assessed using validated visual scores and computational measures. STUDY OUTCOMES: The primary outcome in Third International Stroke Trial is alive and independent (Oxford Handicap Score 0-2) at 6 months; secondary outcomes are symptomatic and fatal intracranial hemorrhage, early and late death. The perfusion and angiography study additionally will examine interactions between recombinant tissue Plasminogen Activator and clinical outcomes, infarct growth and recanalization in the presence or absence of perfusion lesions and/or arterial occlusion at presentation. The study is registered ISRCTN25765518