Sebastian Greiner

The highly attenuated vaccinia virus strain modified virus Ankara induces apoptosis in melanoma cells and allows bystander dendritic cells to generate a potent anti‐tumoral immunity

Vaccinia virus (VV) has been tested as oncolytic virus against malignant melanoma in clinical trials for more than 40 years. Until now, mainly strains comparable to viral strains used for smallpox vaccination have been probed for anti‐tumoral therapy. We have shown recently that the wild‐type strain Western Reserve (WR) can interfere with crucial functions of monocyte‐derived dendritic cells (DCs). Our aim was to examine whether viral immune evasion mechanisms might be responsible for the ineffectiveness of WR‐based vaccination strategies and whether the highly attenuated strain modified virus Ankara (MVA) differs from WR with respect to its possible immunostimulatory capacity after intratumoral injection. Using in vitro experiments, we compared the effect of both strains on melanoma cells and on local bystander DCs. We found that both VV‐strains infected melanoma cells efficiently and caused disintegration of the actin cytoskeleton, as shown by fluorescence microscopy. In addition, both VV‐strains caused apoptotic cell death in melanoma cells after infection. In contrast to MVA, WR underwent a complete viral replication cycle in melanoma cells. Bystander DCs were consecutively infected by newly generated WR virions and lost their capacity to induce allogeneic T cell proliferation. DCs in contact with MVA‐infected melanoma cells retained their capacity to induce T cell proliferation. Immature DCs were capable of phagocytosing MVA‐infected melanoma cells. Priming of autologous CD8+ T cells by DCs that had phagocytosed MVA‐infected, MelanA positive melanoma cells resulted in the induction of T cell clones specifically reactive against the model antigen MelanA as shown by enzyme‐linked immunospot (ELISPOT) analysis. We conclude that the clinical trials with oncolytic wild‐type VV failed probably because of suppression of bystander DCs and consecutive suppression of T cell‐mediated anti‐melanoma immunity. The attenuated VV‐strain MVA facilitates the generation of tumour associated antigen (TAA)‐specific T cell response as it is oncolytic for melanoma cells, but non‐toxic for DC, and should be a promising candidate for intralesional metastatic melanoma therapy.

Reliability of noninvasive assessment of systolic pulmonary artery pressure by Doppler echocardiography compared to right heart catheterization: analysis in a large patient population.

Background Pulmonary artery pressure (PAP) is an important marker in cardiovascular disorders, being closely associated with morbidity and mortality. Noninvasive assessment by Doppler echocardiography is recommended by current guidelines. So far, the reliability of this method has been assessed only in small studies with contradictory results. Therefore, the aim of this study was to analyze the reliability of noninvasive PAP assessment by Doppler echocardiography compared to invasive measurements in a large patient population. Methods and Results We retrospectively analyzed data from a large tertiary cardiology department over 6 years in order to compare invasively measured PAP to estimated PAP from echocardiography examinations. N=15 516 patients fulfilled inclusion criteria and n=1695 patients with timely matched examinations (within 5 days) were analyzed. In n=1221 (72%) patients, pulmonary hypertension (PH) was diagnosed invasively (postcapillary PH: n=1122 [66%]; precapillary PH: n=99 [6%]). Systolic pulmonary artery pressure (sPAP) was 45.3±15.5 mm Hg by Doppler echocardiography and 47.4±16.4 mm Hg by right heart catheterization. Pearsons correlation coefficient was r=0.87 (P<0.0001). Mean right atrial pressure (RAP) was 12.0±5.7 mm Hg by right heart catheterization and was estimated to be 12.1±6.6 mm Hg by echocardiography (r=0.82, P<0.0001). Bland–Altman analysis showed a bias of −2.0 mm Hg for sPAP (95% limits of agreement −18.1 to +14.1 mm Hg) and +1.0 mm Hg for RAP (95% limits of agreement +0.1 to +1.9 mm Hg). Noninvasive diagnosis of pulmonary hypertension with Doppler echocardiography had a good sensitivity (87%) and specificity (79%), positive and negative predictive values (91% and 70%), as well as accuracy (85%) for a sPAP cut‐off value of 36 mm Hg (AUC 0.91, P<0.001, CI 0.90 to 0.93). Conclusions In this study, Doppler echocardiography proved to be a reliable method for the assessment of sPAP, being well suited to establish the noninvasive diagnosis of pulmonary hypertension in patients with cardiac diseases.

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

A crucial event for the induction of an anti‐viral immune response is the coordinated, phenotype‐dependent migration of dendritic cells (DC) to sites of infection and secondary lymphoid organs. Here we show that the vaccinia virus (VV) strains Western Reserve (WR) and modified virus Ankara (MVA) inhibit directional migration of mature DC toward the lymphoid chemokines CCL19 and CXCL12 without affecting surface expression of the respective chemokine receptors or impairing undirected cellular locomotion. Instead, infection with VV results in a deficiency of extracellular signal‐regulated kinase‐1 and a disturbance of intracellular calcium mobilization, indicating a viral interference with signaling events downstream of the surface chemokine receptors. In immature DC, apart from inhibiting chemokine‐induced migration of infected DC, infection with both VV strains increases expression of the inflammatory chemokine receptors CCR1 and CXCR1 on non‐infected bystander DC, which depends on the activity of IFN‐α. Although functional, these chemokine receptors are resistant to lipopolysaccharide‐induced down‐regulation. In addition, VV‐infected and non‐infected bystander DC fail to up‐regulate the lymphoid chemokine receptor CCR7 upon activation, together pointing to a disability to undergo the chemokine receptor switch. This study shows that VV targets directional migration of professional antigen‐presenting cells at multiple functional levels, revealing a potent viral strategy of immune escape.

Prognostic relevance of elevated pulmonary arterial pressure assessed non-invasively: Analysis in a large patient cohort with invasive measurements in near temporal proximity

Background The clinical relevance of non-invasively derived pulmonary arterial pressure (PAP) by Doppler echocardiography (DE) has been questioned in the past. However, transthoracic echocardiography is used as a cornerstone examination for patients with dyspnea and suspected pulmonary hypertension (PH). This study aimed to evaluate the prognostic value of non-invasive assessed PAP in a large population of patients with known or suspected cardiopulmonary disease. Methods The analyses are based on data of patients of a tertiary cardiology center that received right heart catheterization (RHC) as well as non-invasively assessed PAP by DE within five days, and includes serological and clinical parameters in a retrospective follow-up for up to eight years. Results Of 1,237 patients, clinical follow-up was possible in 1,038 patients who were included in the statistical analysis. The mean-follow up time was 1,002 days. The composite endpoint of heart transplantation (HTx) or death occurred in n = 308 patients. Elevated PAP measured non-invasively as well as invasively had significant prognostic impact (hazard ratio (HR) 2.32; 95% confidence interval (CI) 1.78–3.04; χ2 = 37.9; p<0.001 versus HR 2.84; 95%CI 2.11–3.82; χ2 = 51.9; p<0.001, respectively). By multivariate analysis, NYHA functional class, N-terminal pro-brain natriuretic peptide, cardiac troponin T, left ventricular ejection fraction, and right ventricular dysfunction remained independently predictive. Incremental prognostic information in a multimodal approach was highly relevant. Conclusions In this comprehensive study, elevated pulmonary arterial pressure measured by DE offers similar prognostic information on survival or need for HTx as right heart catheterization. Furthermore, the addition of functional capacity and serological biomarkers delivered incremental prognostic information.

Diagnosis of cardiac involvement in systemic amyloidosis by state-of-the-art echocardiography: where are we now?

ABSTRACT Introduction: Echocardiography is the first-line imaging modality used to characterize heart compromise in systemic infiltrative diseases and to evaluate response to therapy. Cardiac amyloidosis results in progressive heart failure due to restriction of ventricular filling. However, in early stages, typical findings may not be evident, even when symptoms and signs of heart failure with preserved ejection fraction are already present. Identification of early compromise is now made possible with the advent of new echocardiography techniques as two-dimensional strain imaging. Areas covered: Diagnostic and prognostic parameters that can be assessed by echocardiography are discussed, including M-mode, two-dimensional and Doppler echocardiography, as well as by new tools as tissue Doppler imaging and strain imaging. Expert opinion: Systemic amyloidosis is a rare disorder resulting from the production of misfolded proteins, primarily light-chain (AL) immunoglobulins and transthyretin (ATTR). The prognosis of affected subjects depends mainly on the presence and the degree of cardiac involvement. Early diagnosis and treatment are mandatory in order to improve survival. We present here a proposal for structured diagnosis, an algorithm based peak systolic longitudinal left ventricular strain, combined with parameters including typical myocardial texture, increased ventricular wall thickness and the presence of some degree of left ventricular diastolic dysfunction.

Left Atrial Appendage Occluder with Recurrent Thrombus Formation Visualized by Three-Dimensional Transesophageal Echocardiography

C l i n M e d International Library Citation: Greiner S, Geis N, Mereles D, Katus HA, S Hardt (2016) Left Atrial Appendage Occluder with Recurrent Thrombus Formation Visualized by Three-Dimensional Transesophageal Echocardiography. Clin Med Rev Case Rep 3:108 Received: April 14, 2016: Accepted: May 28, 2016: Published: May 31, 2016 Copyright:

Comparison of cardiovascular magnetic resonance with real-time three-dimensional echocardiography and the right ventricular automated systolic index in the assessment of the right ventricular function

Background The right ventricular (RV) function has an important diagnostic value in many cardiopulmonary diseases and is a predictor for the long-term outcome. Cardiovascular magnetic resonance (CMR) is the gold-standard for the RV quantification as the complex anatomy of the RV, i.e. its crescentic shape, impedes reliable measurement by two-dimensional echocardiography (EC). Yet, CMR or real-time 3D echocardiography (RT3DE) measurements are time consuming. Recently, a novel EC parameter, the RV automated systolic index (RV-ASI), has been introduced which employs semi-automated whole-cycle endocardial border detection and calculates volume changes based on the sum-of-discs method (modified Simpson’s rule). In this study we evaluate the measurement agreements of two novel EC parameters, a) the RV-ASI and b) the RT3DE, with the reference standard CMR. Methods