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Endothelial microparticles (EMPs) belong to a family of extracellular vesicles that are dynamic, mobile, biological effectors capable of mediating vascular physiology and function. The release of EMPs can impart autocrine and paracrine effects on target cells through surface interaction, cellular fusion, and, possibly, the delivery of intra-vesicular cargo. A greater understanding of the formation, composition, and function of EMPs will broaden our understanding of endothelial communication and may expose new pathways amenable for therapeutic manipulation.

•Patients undergoing treatment for ovarian cancer are profoundly immunosuppressed and unable to mount an adequate immune response to seasonal influenza vaccine.•The B cell compartment was significantly functionally compromised.•Monoclonal B cell lymphocytosis was seen. To examine the effect of chemotherapy for ovarian cancer on immunologic function and to define the effect on the serologic response to the influenza vaccine. Under IRB approved protocols, patients with ovarian cancer were administered seasonal trivalent killed influenza vaccines. Peripheral blood was collected for immunologic assessments. Serum was analyzed for hemagglutination inhibition (HAI) antibody titers. Peripheral blood mononuclear cells were isolated to characterize T and B cell populations and function. Thirty-one patients were recruited: 13 in remission receiving a dendritic cell vaccine with or without a single dose of low-dose cyclophosphamide, 3 in remission not receiving treatment, and 15 undergoing standard therapy. Significant effects on T cell and B cell subset distributions were seen. Functional effects were also seen. Few patients were able to mount a 4-fold HAI antibody response. A 4-fold response was observed for H1N1 in 20%, for H3N2 in 26%, and for influenza B in 6%. Pre-existing exposure to influenza was predictive of responders. Despite CDC recommendations that patients undergoing chemotherapy receive influenza vaccine, there is little evidence to support its serologic effectiveness in this population. Patients with ovarian cancer are almost uniformly unable to mount a meaningful antibody response. These findings have serious implications for future resource allocation for both seasonal and novel pandemic influenza outbreak and understanding the immunologic deficits as a result of chemotherapy may improve patient care.

A new software package called flowFP for the analysis of flow cytometry data is introduced. The package, which is tightly integrated with other Bioconductor software for analysis of flow cytometry, provides tools to transform raw flow cytometry data into a form suitable for direct input into conventional statistical analysis and empirical modeling software tools. The approach of flowFP is to generate a description of the multivariate probability distribution function of flow cytometry data in the form of a “fingerprint.” As such, it is independent of a presumptive functional form for the distribution, in contrast with model-based methods such as Gaussian Mixture Modeling. FlowFP is computationally efficient and able to handle extremely large flow cytometry data sets of arbitrary dimensionality. Algorithms and software implementation of the package are described. Use of the software is exemplified with applications to data quality control and to the automated classification of Acute Myeloid Leukemia.

Background: Post-operative cardiovascular complications cause significant morbidity and mortality. Identifying individuals at highest risk is a challenge. Previous work has demonstrated that circulating extracellular vesicles (EVs) associate with increased cardiovascular disease. Methods: We conducted a prospective multisite study of cardiovascular events in individuals undergoing major vascular surgery to test the hypothesis that cell- and vesicle-derived biomarkers predict post-operative cardiovascular outcomes. The primary endpoint was major adverse cardiovascular events and myocardial injury after non-cardiac surgery within 30 days. Panels enumerating cell subsets including progenitor cells, Th17 and Tang were developed. EV subsets were enumerated using antibodies to CD3, CD31, CD41a, CD105, CD64, CD144 and CD47. Assays were performed on a pair of modified FACSCanto Plus flow cytometers (BD Biosciences). Instrument modifications were aimed at improving detection sensitivity for small particles. Mie Theory calculations confirmed detection of EVs down to 106 nm in diameter, with a large majority smaller than 300 nm. Results: No cellular subset significantly associated with post-operative events. Of the 128 EV subsets enumerated, only CD31+CD105+CD64+ macrophage-derived EVs (MEVs) associated with events after adjusting for multiple comparisons (Padj = 5.3 x 10-3). MEVs, controlled for history and demographics, resulted in a logistic regression model with area under the receiver operating characteristic (AUROC) curve of 0.921 (95% confidence level [0.860-0.975]; P = 1.6 x 10-9) and a diagnostic odds ratio of 32.8. An existing standard-of-care algorithm (RCRI) was less informative (AUROC = 0.774 [0.666, 0.868]). Summary/Conclusion: MEVs are a novel biomarker for post-operative cardiovascular events. The association of these inflammatory vesicles with cardiovascular events provides new insights into heart disease and suggests a novel approach to preoperative risk assessment.

In trying to make sense of the Michael Adams-Vince Dooley mess, it boils down to this: For all his wonderful credentials and extensive background in education and politics, if Adams wasn't savvy enough to avoid this brouhaha with Dooley, how smart can he really be? I read recently that University of Georgia President Michael Adams told former UGA administrator Dick Bestwick of his intentions to replace Vince Dooley more than three years ago. Several years ago, Dan Parker, a former Montezuma resident, told me that \"Dooley had to go.\" Parker, a partner in a recruiting firm, was instrumental in bringing Adams to Georgia. Parker's firm is searching for an athletics director to replace Dooley.

The 31st running of the Peachtree Road Race once more proves that women are more equal than men. Lornah Kiplagat won $15,000 for having the fastest time among women. Yet she finished 40th overall with her time of 30:52. Of the 39 males who beat Kiplagat's time, only one matched her purse. So much for equal pay for equal work. You've got to hand it to Molly Ivins --- she's entertaining. She's also badly deceived. In her July 5 column (\"Holy wars: Reasoning goes to extremes), she implies that the evils of history are essentially the fault of \"fundamentalists\" for whom \"the appeal of certainty and authority is timeless.\" Well, my, my. Is Ivins certain about that? By what authority? In response to the letter from the person who had an extended visit to Cuba (\"Life is good in Cuba,\" July 4): Has the writer forgotten that Cubans were sent to Hanoi to torture U.S. POWs at the Hanoi Hilton? Does this writer remember the many pro-Communist activities in the world that had Cuban advisers and military involved?

Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169. We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15–33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.

Modeling the relationships between covariates and pharmacometric model parameters is a central feature of pharmacometric analyses. The information obtained from covariate modeling may be used for dose selection, dose individualization, or the planning of clinical studies in different population subgroups. The pharmacometric literature has amassed a diverse, complex, and evolving collection of methodologies and interpretive guidance related to covariate modeling. With the number and complexity of technologies increasing, a need for an overview of the state of the art has emerged. In this article the International Society of Pharmacometrics (ISoP) Standards and Best Practices Committee presents perspectives on best practices for planning, executing, reporting, and interpreting covariate analyses to guide pharmacometrics decision making in academic, industry, and regulatory settings.