Citations

Abstract We have recently shown that effective cytokine gene therapy of solid tumors in HLA-A2 transgenic (HHD) mice lacking murine MHC class I molecule expression results in the generation of HLA-A2–restricted CD8+ T effector cells selectively recognizing tumor blood vessel-associated pericytes and/or vascular endothelial cells. Using an HHD model in which HLA-A2neg tumor (MC38 colon carcinoma or B16 melanoma) cells are not recognized by the CD8+ T cell repertoire, we now show that vaccines on the basis of tumor-associated blood vessel Ags (TBVA) elicit protective Tc1-dependent immunity capable of mediating tumor regression or extending overall survival. Vaccine efficacy was not observed if (HLA-A2neg) wild-type C57BL/6 mice were instead used as recipient animals. In the HHD model, effective vaccination resulted in profound infiltration of tumor lesions by CD8+ (but not CD4+) T cells, in a coordinate reduction of CD31+ blood vessels in the tumor microenvironment, and in the “spreading” of CD8+ T cell responses to alternate TBVA that were not intrinsic to the vaccine. Protective Tc1-mediated immunity was durable and directly recognized pericytes and/or vascular endothelial cells flow-sorted from tumor tissue but not from tumor-uninvolved normal kidneys harvested from these same animals. Strikingly, the depletion of CD8+, but not CD4+, T cells at late time points after effective therapy frequently resulted in the recurrence of disease at the site of the regressed primary lesion. This suggests that the vaccine-induced anti-TBVA T cell repertoire can mediate the clinically preferred outcomes of either effectively eradicating tumors or policing a state of (occult) tumor dormancy.

Abstract We examined the prevalence and prognostic relevance of bone marrow reticulin fibrosis in 526 patients with World Health Organization–defined polycythemia vera evaluated at the time of initial diagnosis. Seventy-four patients (14%) displayed mostly grade 1 reticulin fibrosis, with only 2 cases showing higher-grade fibrosis. Presenting clinical and laboratory characteristics, including JAK2V617F allele burden, between patients with and without fibrosis were similar for the most part, with the exception of a higher prevalence of palpable splenomegaly in patients with fibrosis (P < .01). Patients with fibrosis were less prone to experience thrombosis during their clinical course (1.1 vs 2.7 per 100 patient-years; P = .03) and more prone to develop post-polycythemia vera myelofibrosis (2.2 vs 0.8 per 100 patient-years; P = .01). There was no significant difference between the 2 groups in terms of overall or leukemia-free survival. The present study clarifies the incidence, degree, and prognostic relevance of bone marrow fibrosis obtained at time of initial diagnosis of polycythemia vera.

Context Perioperative antibiotics are widely used to improve the outcomes of endoscopic sinus surgery. Objective The aim of this study was to summarize the evidence on the effect of perioperative antibiotic prophylaxis on outcomes of endoscopic sinus surgery. Data Sources and Review Methods We searched electronic databases from inception through May 2011 for any relevant clinical trials or observational studies. Two reviewers working independently extracted study characteristics, quality, and the outcomes of interest. Random‐effects meta‐analysis was used to pool the relative risks (RRs) and the standardized mean differences (SMDs) across trials. Results We found 4 eligible trials with varying quality, of which 3 were included in the quantitative analysis. Antibiotic prophylaxis was associated with a nonsignificant reduction in the incidence of infections (relative risk, 0.76; 95% confidence interval [CI], 0.64 to 1.09), symptoms scores (SMD, −0.04; 95% CI, −0.46 to 0.38), and endoscopic scores (SMD, −0.09; 95% CI, 0.30 to 0.13). The heterogeneity associated with the analysis was significant only for the outcome of change in symptoms score (I‐squared values, 0%, 70%, and 0% for the 3 outcomes, respectively). Conclusions Trial data available to date are unable to demonstrate a statistically significant reduction in infection, symptom scores, or endoscopic scores to support the routine use of postoperative prophylactic antibiotics following endoscopic sinus surgery. Our analysis was limited by the number of published trials related to this topic.

Abstract Patients with severe acute and chronic lung diseases develop derangements in gas exchange that may result in increased levels of CO2 (hypercapnia), the effects of which on human health are incompletely understood. It has been proposed that hypercapnia may have beneficial effects in patients with acute lung injury, and the concepts of “permissive” and even “therapeutic” hypercapnia have emerged. However, recent work suggests that CO2 can act as a signaling molecule via pH-independent mechanisms, resulting in deleterious effects in the lung. Here we review recent research on how elevated CO2 is sensed by cells in the lung and the potential harmful effects of hypercapnia on epithelial and endothelial barrier, lung edema clearance, innate immunity, and host defense. In view of these findings, we raise concerns about the potentially deleterious effects hypercapnia may have in patients with acute and chronic lung diseases.

Abstract BACKGROUND Improved tests are needed for detection and management of prostate cancer. We hypothesized that differential gene expression in prostate tissue could help identify candidate blood biomarkers for prostate cancer and that blood from men with advanced prostate disease could be used to verify the biomarkers presence in circulation. METHODS We identified candidate markers using mRNA expression patterns from laser-capture microdissected prostate tissue and confirmed tissue expression using immunohistochemistry (IHC) for the subset of candidates having commercial antisera. We analyzed tissue extracts with tandem mass spectrometry (MS/MS) and measured blood concentrations using immunoassays and MS/MS of trypsin-digested, immunoextracted peptides. RESULTS We selected 35 novel candidate prostate adenocarcinoma biomarkers. For all 13 markers having commercial antisera for IHC, tissue expression was confirmed; 6 showed statistical discrimination between nondiseased and malignant tissue, and only 5 were detected in tissue extracts by MS/MS. Sixteen of the 35 candidate markers were successfully assayed in blood. Four of 8 biomarkers measured by ELISA and 3 of 10 measured by targeted MS showed statistically significant increases in blood concentrations of advanced prostate cancer cases, compared with controls. CONCLUSIONS Seven novel biomarkers identified by gene expression profiles in prostate tissue were shown to have statistically significant increased concentrations in blood from men with advanced prostate adenocarcinoma compared with controls: apolipoprotein C1, asporin, cartilage oligomeric matrix protein, chemokine (C-X-C motif) ligand 11 (CXCL11), CXCL9, coagulation factor V, and proprotein convertase subtilisin/kexin 6.