31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Technical Note: Validation of two methods to determine contact area between breast and compression paddle in mammography

Purpose: To assess the accuracy of two methods of determining the contact area between the compression paddle and the breast in mammography. An accurate method to determine the contact area is essential to accurately calculate the average compression pressure applied by the paddle. Methods: For a set of 300 breast compressions, we measured the contact areas between breast and paddle, both capacitively using a transparent foil with indium-tin-oxide (ITO) coating attached to the paddle, and retrospectively from the obtained mammograms using image processing software (Volpara Enterprise, algorithm version 1.5.2). A gold standard was obtained from video images of the compressed breast. During each compression, the breast was illuminated from the sides in order to create a dark shadow on the video image where the breast was in contact with the compression paddle. We manually segmented the shadows captured at the time of x-ray exposure and measured their areas. Results: We found a strong correlation between the manual segmentations and the capacitive measurements [r = 0.989, 95% CI (0.987, 0.992)] and between the manual segmentations and the image processing software [r = 0.978, 95% CI (0.972, 0.982)]. Bland-Altman analysis showed a bias of -0.0038 dm(2) for the capacitive measurement (SD 0.0658, 95% limits of agreement [-0.1329, 0.1252]) and -0.0035 dm(2) for the image processing software [SD 0.0962, 95% limits of agreement (-0.1921, 0.1850)]. Conclusions: The size of the contact area between the paddle and the breast can be determined accurately and precisely, both in real-time using the capacitive method, and retrospectively using image processing software. This result is beneficial for scientific research, data analysis and quality control systems that depend on one of these two methods for determining the average pressure on the breast during mammographic compression. (C) 2017 Sigmascreening B.V. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicin

Tai chi chuan : an ancient wisdom on exercise and health promotion

A lack of consistent guidelines regarding mammographic compression has led to wide variation in its technical execution. Breast compression is accomplished by means of a compression paddle, resulting in a certain contact area between the paddle and the breast. This procedure is associated with varying levels of discomfort or pain. On current mammography systems, the only mechanical parameter available in estimating the degree of compression is the physical entity of force (daN). Recently, researchers have suggested that pressure (kPa), resulting from a specific force divided by contact area on a breast, might be a more appropriate parameter for standardization. Software has now become available which enables device-independent cross-comparisons of key mammographic metrics, such as applied compression pressure (force divided by contact area), breast density and radiation dose, between patient populations. To compare the current compression practice in mammography between different imaging sites in the Netherlands and the United States from a mechanical point of view, and to investigate whether the compression protocols in these countries can be improved by standardization of pressure (kPa) as an objective mechanical parameter. We retrospectively studied the available parameters of a set of 37,518 mammographic compressions (9188 women) from the Dutch national breast cancer screening programme (NL data set) and of another set of 7171 compressions (1851 women) from a breast imaging centre in Pittsburgh, PA (US data set). Both sets were processed using VolparaAnalytics and VolparaDensity to obtain the applied average force, pressure, breast thickness, breast volume, breast density and average glandular dose (AGD) as a function of the size of the contact area between the breast and the paddle. On average, the forces and pressures applied in the NL data set were significantly higher than in the US data set. The relative standard deviation was larger in the US data set than in the NL data set. Breasts were compressed with a force in the high range of >15 daN for 31.1% and >20 kPa for 12.3% of the NL data set versus, respectively, 1.5% and 1.7% of the US data set. In the low range we encountered compressions with a pressure of <5 daN for 21.1% and <5 kPa for 21.7% of the US data set versus, respectively, 0.05% and 0.6% in the NL data set. Both the average and the standard deviation of the AGD were higher in the US data set. (1) Current mammographic breast compression policies lead to a wide range of applied forces and pressures, with large variations both within and between clinical sites. (2) Pressure standardization could decrease variation, improve reproducibility, and reduce the risk of unnecessary pain, unnecessary high radiation doses and inadequate image qualit

Epithelial-to-mesenchymal transformation alters electrical conductivity of human epicardial cells

\u3cp\u3eThe myocardium of the developing heart tube is covered by epicardium. These epicardial cells undergo a process of epithelial-to-mesenchymal transformation (EMT) and develop into epicardium-derived cells (EPDCs). The ingrowing EPDCs differentiate into several celltypes of which the cardiac fibroblasts form the main group. Disturbance of EMT of the epicardium leads to serious hypoplasia of the myocardium, abnormal coronary artery differentiation and Purkinje fibre paucity. Interestingly, the electrophysiological properties of epicardial cells and whether EMT influences electrical conductivity of epicardial cells is not yet known. We studied the electrophysiological aspects of epicardial cells before and after EMT in a dedicatedin vitromodel, using micro-electrode arrays to investigate electrical conduction across epicardial cells. Therefore, human adult epicardial cells were placed between two neonatal rat cardiomyocyte populations. Before EMT the epicardial cells have a cobblestone (epithelium-like) phenotype that was confirmed by staining for the cell-adhesion molecule β-catenin. After spontaneous EMTin vitrothe EPDCs acquired a spindle-shaped morphology confirmed by vimentin staining. When comparing both types we observed that the electrical conduction is influenced by EMT, resulting in significantly reduced conductivity of spindle-shaped EPDCs, associated with a conduction block. Furthermore, the expression of both gap junction (connexins 40, Cx43 and Cx45) and ion channel proteins (SCN5a, CACNA1C and Kir2.1) was down-regulated after EMT. This study shows for the first time the conduction differences between epicardial cells before and after EMT. These differences may be of relevance for the role of EPDCs in cardiac development, and in EMT-related cardiac dysfunction.\u3c/p\u3

F#ck Your Family!: The Visual Jurisprudence of Automobility

This paper considers the popular visual jurisprudence of bumper stickers. Drawing upon a sample sticker/driver/vehicle assemblages observed at the Gold Coast, Australia in 2014, we argue that the meanings and messages projected by the assemblages have a significant legal dimension. The argument is located at the intersection of past research into bumper stickers, increased scholarly interest in the relation of law to automobility and especially recent considerations of the popular visual jurisprudence of the motor vehicle, its cultures and semiotics. In particular we argue that the sticker/driver/vehicle assemblage represents an engagement with law and legality. We suggest this goes beyond immediate denotations of brands with intellectual property or flags and the sovereign nation state to more essential engagement with consumer capitalisms law of the image, the friend/enemy distinction, the ouroboros of rights and the essential legality of living in a polis.Arts, Education & Law Group, School of Criminology and Criminal JusticeNo Full Tex