S100A4 as a Target of the E3-Ligase Asb2β and Its Effect on Engineered Heart Tissue

Background: S100A4 has recently emerged as an important player in cardiac disease, affecting phenotype development in animal models of myocardial infarction and pathological cardiac hypertrophy, albeit it is unclear whether S100A4 exerts a detrimental or beneficial function. The goal of the current study was to analyze S100A4 expression in models of cardiac pathology, investigate its degradation by the ubiquitin-proteasome system (UPS), and furthermore examine the functional effects of S100A4 levels in a 3D model of engineered heart tissue (EHT).Methods and Results: S100A4 mRNA and protein levels were analyzed in different models of cardiac pathology via quantitative RT-PCR and Western blot, showing a higher S100A4 steady-state protein concentration in hearts of Mybpc3-knock-in (KI) hypertrophic cardiomyopathy (HCM) mice. COS-7 cells co-transfected with plasmids encoding mutant (MUT) Asb2β lacking the E3 ligase activity in combination with V5-tagged S100A4 plasmid presented higher S100A4-V5 protein steady-state concentrations than cells co-transfected with the Asb2β wild type (WT) plasmid. This effect was blunted by treatment with the specific proteasome inhibitor epoxomicin. Adeno-associated virus serotype 6 (AAV6)-mediated S100A4 overexpression in a 3D model of EHT did not affect contractile parameters. Immunofluorescence analysis showed a cytosolic and partly nuclear expression pattern of S100A4. Gene expression analysis in EHTs overexpressing S100A4-V5 showed markedly lower steady-state concentrations of genes involved in cardiac fibrosis and pathological cardiac hypertrophy.Conclusion: We showed that S100A4 protein level is higher in cardiac tissue of Mybpc3-KI HCM mice probably as a result of a lower degradation by the E3 ligase Asb2β. While an overexpression of S100A4 did not alter contractile parameters in EHTs, downstream gene expression analysis points toward modulation of signaling cascades involved in fibrosis and hypertrophy

Meta-analysis of extracorporeal membrane oxygenation in combination with intra-aortic balloon pump vs. extracorporeal membrane oxygenation only in patients with cardiogenic shock due to acute myocardial infarction

BackgroundIncidence and mortality of cardiogenic shock (CS) in patients with acute myocardial infarction (AMI) remain high despite substantial therapy improvements in acute percutaneous coronary intervention over the last decades. Unloading the left ventricle in patients with Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can be performed by using an intra-aortic balloon pumps’ (IABP) afterload reduction, which might be especially beneficial in AMI patients with CS.ObjectiveThe objective of this meta-analysis was to assess the effect of VA-ECMO + IABP vs. VA-ECMO treatment on the mortality of patients with CS due to AMI.MethodsA systematic literature search was performed using EMBASE, COCHRANE, and MEDLINE databases. Studies comparing the effect of VA-ECMO + IABP vs. VA-ECMO on mortality of patients with AMI were included. Meta-analyses were performed to analyze the effect of the chosen treatment on 30-day/in-hospital mortality.ResultsTwelve studies were identified by the literature search, including a total of 5,063 patients, 81.5% were male and the mean age was 65.9 years. One thousand one hundred and thirty-six patients received treatment with VA-ECMO in combination with IABP and 2,964 patients received VA-ECMO treatment only. The performed meta-analysis showed decreased mortality at 30-days/in-hospital after VA-ECMO + IABP compared to VA-ECMO only for patients with cardiogenic shock after AMI (OR 0.36, 95% CI 0.30–0.44, P≤0.001). Combination of VA-ECMO + IABP was associated with higher rates of weaning success (OR 0.29, 95% CI 0.16–0.53, P < 0.001) without an increase of vascular access complications (OR 0.85, 95% CI 0.35–2.08, P = 0.72).ConclusionIn this meta-analysis, combination therapy of VA-ECMO + IABP was superior to VA-ECMO only therapy in patients with CS due to AMI. In the absence of randomized data, these results are hypothesis generating only

Predictive modelling of the granulation process using a systems-engineering approach

© 2016 Elsevier B.V.The granulation process is considered to be a crucial operation in many industrial applications. The modelling of the granulation process is, therefore, an important step towards controlling and optimizing the downstream processes, and ensuring optimal product quality. In this research paper, a new integrated network based on Artificial Intelligence (AI) is proposed to model a high shear granulation (HSG) process. Such a network consists of two phases: in the first phase the inputs and the target outputs are used to train a number of models, where the predicted outputs from this phase and the target are used to train another model in the second phase to lead to the final predicted output. Because of the complex nature of the granulation process, the error residual is exploited further in order to improve the model performance using a Gaussian mixture model (GMM). The overall proposed network successfully predicts the properties of the granules produced by HSG, and outperforms also other modelling frameworks in terms of modelling performance and generalization capability. In addition, the error modelling using the GMM leads to a significant improvement in prediction

Gene expression analysis of cell death induction by Taurolidine in different malignant cell lines

<p>Abstract</p> <p>Background</p> <p>The anti-infective agent Taurolidine (TRD) has been shown to have cell death inducing properties, but the mechanism of its action is largely unknown. The aim of this study was to identify potential common target genes modulated at the transcriptional level following TRD treatment in tumour cell lines originating from different cancer types.</p> <p>Methods</p> <p>Five different malignant cell lines (HT29, Chang Liver, HT1080, AsPC-1 and BxPC-3) were incubated with TRD (100 μM, 250 μM and 1000 μM). Proliferation after 8 h and cell viability after 24 h were analyzed by BrdU assay and FACS analysis, respectively. Gene expression analyses were carried out using the <it>Agilent </it>-microarray platform to indentify genes which displayed conjoint regulation following the addition of TRD in all cell lines. Candidate genes were subjected to <it>Ingenuity Pathways Analysis </it>and selected genes were validated by qRT-PCR and Western Blot.</p> <p>Results</p> <p>TRD 250 μM caused a significant inhibition of proliferation as well as apoptotic cell death in all cell lines. Among cell death associated genes with the strongest regulation in gene expression, we identified pro-apoptotic transcription factors (EGR1, ATF3) as well as genes involved in the ER stress response (PPP1R15A), in ubiquitination (TRAF6) and mitochondrial apoptotic pathways (PMAIP1).</p> <p>Conclusions</p> <p>This is the first conjoint analysis of potential target genes of TRD which was performed simultaneously in different malignant cell lines. The results indicate that TRD might be involved in different signal transduction pathways leading to apoptosis.</p

Innovative Business Approaches for the Reduction of Extreme Poverty and Marginality?

Extreme poverty is an immense political and market failure, wasting the potential of hundreds of millions of people. Investing in the creation of markets that include the extreme poor and marginalized should thus not only be considered as a charitable activity, but promises high returns on investments - in financial and humanitarian terms. However, while the potential of innovative business approaches to target the poor that live close to the poverty line is increasingly being recognised, the question remains how far these approaches can push the margin to also include those that are extremely poor. And how can those that are marginalized from development opportunities be brought into and benefit from market-based systems to improve the quality of their lives? The impressive rise of business approaches to combating poverty stems from a long history of debates on the role of businesses in society. From an initial focus on social objectives as an external add-on, leading business thinkers have increasingly been stressing the benefits for companies of integrating social considerations into their core business strategies, for instance by targeting lowincome consumers (or 'bottom of the pyramid' markets) or strengthening supply and distribution chains through the involvement of local communities as part of inclusive business strategies. Others - most notably Muhammed Yunus along with other social entrepreneurs - are taking this argument one step further, advocating the use of business strategies primarily to address social goals rather than for financial gains. Thus, in discussions on the role of business in society, profit maximisation as the primary objective of business operations is increasingly making way for business initiatives that are guided by social objectives. This trend is also being supported by growing interest among investors in financing enterprises that promote social or environmental objectives, either as their primary aim or in parallel with seeking to generate financial returns. How suitable these different approaches are to engage the poorest and marginalized depends in part on the extent to which they are able to involve the extreme poor themselves, their flexibility to direct business objectives towards the reduction of extreme poverty and marginality, and their ability to successfully operate with non-business public and civil society partners and in sectors of particular interest to the extreme poor. Further research and action is needed to identify outcome-focused indicators and measurement tools for social value creation, examine possible government measures to support business activities for the poorest, and consider complementarities between the different business approaches. While we recognise that it is unrealistic to expect businesses to be able to reach all of the extreme poor, we believe that the boundaries of innovative business operations can be pushed much further to include a far larger number of the poorest and marginalized

Molecular mechanisms underlying cardiotoxicity of novel cancer therapeutics

Novel cancer therapeutics contribute to a steadily declining cancer mortality. However, several of these new therapies target pathways also involved in the cardiovascular system thus causing cardiotoxic side effects such as chemotherapy-induced heart failure (CIHF). This might limit the applicability of these effective treatments in a relevant number of patients. Furthermore, given the improving cancer survival rates, chemotherapy-induced cardiotoxic complications receive increasing attention given their potential impact on long-term morbidity and mortality. The understanding of molecular mechanisms that underlie CIHF is crucial for future improvement of pharmacodynamics of these therapeutics but also for developing specific interventions to prevent CIHF. Here, we discuss molecular mechanisms underlying CIHF of novel cancer therapeutics including a short synopsis on clinical management of patients suffering from CIHF

Cardiovascular complications of modern tumor therapy-the right balance

Novel cancer therapies are contributing to the steadily decreasing cancer mortality. However, many of these new therapies can have significant cardiovascular complications. These can appear during treatment and, in the worst case, may even require discontinuation of treatment. At the same time, chronic side effects of cancer therapies such as heart failure, valvular heart disease or coronary artery disease are becoming increasingly relevant due to improved long-term survival and are the most common non-cancer associated cause of death. Many of the cardiovascular complications can be treated effectively, resulting in an improved long-term survival of the patients. Knowledge of the agent-specific cardiovascular side effects and diagnostic options is essential for structured management of cardio-oncologic patients to further improve mortality and morbidity in cancer patients

Angina Pectoris in a Young Woman with Lupus Erythematosus

History and clinical findings We present a 31-year old woman with a 6-year history of cutaneous lupus erythematosus (CLE) who presented to the emergency room with typical chest pain. ECG and transthoracic echocardiography were normal. Her working diagnosis of pericarditis was made due to systemic progression of her lupus erythematosus (LE). Treatment with NSAIDs was initiated and her immunosuppressive regimen intensified. The patient was discharged after resolution of her symptoms. A week later, the patient was seen at the rheumatology clinic with recurrence and aggravation of her symptoms. She was found to have elevated troponin and cardiac enzymes and therefore underwent cardiac catheterization, revealing three vessel coronary artery disease. Therapy and course The patient underwent urgent open surgical myocardial revascularization. Despite the immunosuppressive therapy the postoperative course was uneventful. Conclusions The risk for coronary artery disease in LE patients is very high. Particularly in young women presenting with chest pain, regardless of typical cardiopulmonary manifestations of LE such as pericarditis and pleurisy, acute coronary syndrome should always be considered

Cardiovascular complications of modern tumor therapy-the right balance

Novel cancer therapies are contributing to the steadily decreasing cancer mortality. However, many of these new therapies can have significant cardiovascular complications. These can appear during treatment and, in the worst case, may even require discontinuation of treatment. At the same time, chronic side effects of cancer therapies such as heart failure, valvular heart disease or coronary artery disease are becoming increasingly relevant due to improved long-term survival and are the most common non-cancer associated cause of death. Many of the cardiovascular complications can be treated effectively, resulting in an improved long-term survival of the patients. Knowledge of the agent-specific cardiovascular side effects and diagnostic options is essential for structured management of cardio-oncologic patients to further improve mortality and morbidity in cancer patients