Combined Blockade of ADP Receptors and PI3-Kinase p110β Fully Prevents Platelet and Leukocyte Activation during Hypothermic Extracorporeal Circulation

Extracorporeal circulation (ECC) and hypothermia are used to maintain stable circulatory parameters and improve the ischemia tolerance of patients in cardiac surgery. However, ECC and hypothermia induce activation mechanisms in platelets and leukocytes, which are mediated by the platelet agonist ADP and the phosphoinositide-3-kinase (PI3K) p110β. Under clinical conditions these processes are associated with life-threatening complications including thromboembolism and inflammation. This study analyzes effects of ADP receptor P2Y12 and P2Y1 blockade and PI3K p110β inhibition on platelets and granulocytes during hypothermic ECC. Human blood was treated with the P2Y12 antagonist 2-MeSAMP, the P2Y1 antagonist MRS2179, the PI3K p110β inhibitor TGX-221, combinations thereof, or PBS and propylene glycol (controls). Under static in vitro conditions a concentration-dependent effect regarding the inhibition of ADP-induced platelet activation was found using 2-MeSAMP or TGX-221. Further inhibition of ADP-mediated effects was achieved with MRS2179. Next, blood was circulated in an ex vivo ECC model at 28°C for 30 minutes and various platelet and granulocyte markers were investigated using flow cytometry, ELISA and platelet count analysis. GPIIb/IIIa activation induced by hypothermic ECC was inhibited using TGX-221 alone or in combination with P2Y blockers (p<0.05), while no effect of hypothermic ECC or antiplatelet agents on GPIIb/IIIa and GPIbα expression and von Willebrand factor binding was observed. Sole P2Y and PI3K blockade or a combination thereof inhibited P-selectin expression on platelets and platelet-derived microparticles during hypothermic ECC (p<0.05). P2Y blockade alone or combined with TGX-221 prevented ECC-induced platelet-granulocyte aggregate formation (p<0.05). Platelet adhesion to the ECC surface, platelet loss and Mac-1 expression on granulocytes were inhibited by combined P2Y and PI3K blockade (p<0.05). Combined blockade of P2Y12, P2Y1 and PI3K p110β completely inhibits hypothermic ECC-induced activation processes. This novel finding warrants further studies and the development of suitable pharmacological agents to decrease ECC- and hypothermia-associated complications in clinical applications

Monitoring of patients treated with particle therapy using positron-emission-tomography (PET): the MIRANDA study

<p>Abstract</p> <p>Background</p> <p>The purpose of this clinical study is to investigate the clinical feasibility and effectiveness of offline Positron-Emission-Tomography (PET) quality assurance for promoting the accuracy of proton and carbon ion beam therapy.</p> <p>Methods/Design</p> <p>A total of 240 patients will be recruited, evenly sampled among different analysis groups including tumors of the brain, skull base, head and neck region, upper gastrointestinal tract including the liver, lower gastrointestinal tract, prostate and pelvic region. From the comparison of the measured activity with the planned dose and its corresponding simulated activity distribution, conclusions on the delivered treatment will be inferred and, in case of significant deviations, correction strategies will be elaborated.</p> <p>Discussion</p> <p>The investigated patients are expected to benefit from this study, since in case of detected deviations between planned and actual treatment delivery a proper intervention (e.g., correction) could be performed in a subsequent irradiation fraction. In this way, an overall better treatment could be achieved than without any in-vivo verification. Moreover, site-specific patient-population information on the precision of the ion range at HIT might enable improvement of the CT-range calibration curve as well as safe reduction of the treatment margins to promote enhanced treatment plan conformality and dose escalation for full clinical exploitation of the promises of ion beam therapy.</p> <p>Trial Registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01528670">NCT01528670</a></p

Experimental Evaluation of Gene Silencing As New Therapeutic Option in the Treatment of Gemcitabine-chemoresistant Non-small-cell Lung Cancer

The evolution of technological and therapeutic applications of siRNA since the description of the interference process in 2006 has been extremely rapid and very productive. Currently, at least ten tumor entities and ten viral infections in which siRNA-based therapy might play an auspicious role have been described. Because of the very poor prognosis of NSCLC, we examined and proposed a new therapeutic alternative for the treatment of gemcitabine-resistant lung cancer via siRNA-specific silencing of six important molecules involved in lung carcinogenesis.Methods: One hundred thousand gemcitabine-chemoresistant A549 cell lines were cultured in a humidified atmosphere containing 5 % CO2 at 37°C and were transfected with specific siRNA targeting HIF1, HIF2, STAT3, SRF, E2F1 and Survivin. The relative expression of these molecules was examined via qRT-PCR and the viability of the chemoresistant cells after siRNA transfection was analyzed using a CASY system 72 hours after specific transfection.Results: The relative expression of the examined target molecules was suppressed by up to 73 % after specific transfection, and the CASY system demonstrated a concentration-dependent reduction in the viability of chemoresistant A549 cells of up to 61 %. Therefore the obtained results were significantly better in comparison to the control group.Conclusions: siRNA complexes may induce accurate suppression of various target molecules involved in lung tumor growth, in particular in gemcitabine- chemoresistant adenocarcinoma. Therefore, siRNA-based nanotechnology might represent a productive platform for the development of new chemotherapeutic agents for advanced stages of lung cancer in the context of a personalized multimodality regimen

Does co-presence affect the way we perceive and respond to emotional interactions?

This study compared how two virtual display conditions of human body expressions influenced explicit and implicit dimensions of emotion perception and response behavior in women and men. Two avatars displayed emotional interactions (angry, sad, affectionate, happy) in a “pictorial” condition depicting the emotional interactive partners on a screen within a virtual environment and a “visual” condition allowing participants to share space with the avatars, thereby enhancing co-presence and agency. Subsequently to stimulus presentation, explicit valence perception and response tendency (i.e. the explicit tendency to avoid or approach the situation) were assessed on rating scales. Implicit responses, i.e. postural and autonomic responses towards the observed interactions were measured by means of postural displacement and changes in skin conductance. Results showed that self-reported presence differed between pictorial and visual conditions, however, it was not correlated with skin conductance responses. Valence perception was only marginally influenced by the virtual condition and not at all by explicit response behavior. There were gender-mediated effects on postural response tendencies as well as gender differences in explicit response behavior but not in valence perception. Exploratory analyses revealed a link between valence perception and preferred behavioral response in women but not in men. We conclude that the display condition seems to influence automatic motivational tendencies but not higher level cognitive evaluations. Moreover, intragroup differences in explicit and implicit response behavior highlight the importance of individual factors beyond gender

Congenital ichthyosiform erythroderma with epidermolysis due to a novel frameshift mutation in KRT10

Neonatal erythroderma (NE) is an erythema that covers at least 90% of the body surface and occurs at birth or in the first 4 postnatal weeks.1 The incidence of NE in patients in the Netherlands has been estimated by dermatologists to be 10 per 100,000 newborns.1 In congenital ichthyosiform erythroderma (CIE), the presence or absence of a collodion membrane and/or extracutaneous findings is crucial to narrow down possible differential diagnoses. Here, we describe a keratinopathic form of NE or CIE due to a mutation in the KRT10 gene. Additionally, 2 variants, 1 pathogenic and 1 of unclear significance, of FLG were detected

Predictors of individual mental health and psychological resilience after Australia’s 2019–2020 bushfires

Aims: We assessed the mental health effects of Australia’s 2019–2020 bushfires 12–18 months later, predicting psychological distress and positive psychological outcomes from bushfire exposure and a range of demographic variables, and seeking insights to enhance disaster preparedness and resilience planning for different profiles of people. Methods: We surveyed 3083 bushfire-affected and non-affected Australian residents about their experiences of bushfire, COVID-19, psychological distress (depression, anxiety, stress, post-traumatic stress disorder) and positive psychological outcomes (resilient coping, wellbeing). Results: We found high rates of distress across all participants, exacerbated by severity of bushfire exposure. For people who were bushfire-affected, being older, having less financial stress, and having no or fewer pre-existing mental disorders predicted both lower distress and higher positive outcomes. Being male or having less income loss also predicted positive outcomes. Severity of exposure, higher education and higher COVID-19-related stressors predicted both higher distress and higher positive outcomes. Pre-existing physical health diagnosis and previous bushfire experience did not significantly predict distress or positive outcomes. Recommendations: To promote disaster resilience, we recommend investment in mental health, particularly for younger adults and for those in rural and remote areas. We also recommend investment in mechanisms to protect against financial distress and the development of a broader definition of bushfire-related impacts than is currently used to capture brushfires’ far-reaching effects

The Brief Solastalgia Scale: A Psychometric Evaluation and Revision

Witnessing degradation and loss to one’s home environment can cause the negative emotional experience of solastalgia. We review the psychometric properties of the 9-item Solastalgia subscale from the Environmental Distress Scale (Higginbotham et al. (EcoHealth 3:245–254, 2006)). Using data collected from three large, independent, adult samples (N = 4229), who were surveyed soon after the 2019/20 Australian bushfires, factor analyses confirmed the scale’s unidimensionality, while analyses derived from Item Response Theory highlighted the poor psychometric performance and redundant content of specific items. Consequently, we recommend a short-form scale consisting of five items. This Brief Solastalgia Scale (BSS) yielded excellent model fit and internal consistency in both the initial and cross-validation samples. The BSS and its parent version provide very similar patterns of associations with demographic, health, life satisfaction, climate emotion, and nature connectedness variables. Finally, multi-group confirmatory factor analysis demonstrated comparable construct architecture (i.e. configural, metric, and scalar invariance) across validation samples, gender categories, and age. As individuals and communities increasingly confront and cope with climate change and its consequences, understanding related emotional impacts is crucial. The BSS promises to aid researchers, decision makers, and practitioners to understand and support those affected by negative environmental change

Hereditary epidermolytic palmoplantar keratosis due to a novel desmoglein‐1 mutation: A case report

Keratosis palmoplantaris striata type I (SPPK-I) is a rare autosomal-dominant type of hereditary epidermolytic palmoplantar keratoderma, which can be caused by mutations in desmoglein-1 (DSG-1). Patients suffer from hyperkeratotic plaques and painful palmoplantar fissures. Unfortunately, treatment options including salicylic vaseline, topical corticosteroids, phototherapy, and retinoids are inefficient. Hereditary palmoplantar keratodermas (PPKs) represent a heterogeneous group of rare skin disorders with epidermal palmoplantar hyperkeratosis. Mutations in the desmoglein 1 gene (DSG1), a transmembrane glycoprotein, have been reported primarily in striate PPKs. We report a patient with keratosis palmoplantaris striata type I (SPPK-I) with a specific pathogenic variant [c.349C>T, p.(Arg117*)] in DSG1. Despite increased understanding, effective treatment options for PPK, including SPPK-I, remain limited

Targeted panel sequencing in the routine diagnosis of mature T- and NK-cell lymphomas: report of 128 cases from two German reference centers

Diagnosing any of the more than 30 types of T-cell lymphomas is considered a challenging task for many pathologists and currently requires morphological expertise as well as the integration of clinical data, immunophenotype, flow cytometry and clonality analyses. Even considering all available information, some margin of doubt might remain using the current diagnostic procedures. In recent times, the genetic landscape of most T-cell lymphomas has been elucidated, showing a number of diagnostically relevant mutations. In addition, recent data indicate that some of these genetic alterations might bear prognostic and predictive value. Extensive genetic analyses, such as whole exome or large panel sequencing are still expensive and time consuming, therefore limiting their application in routine diagnostic. We therefore devoted our effort to develop a lean approach for genetic analysis of T-cell lymphomas, focusing on maximum efficiency rather than exhaustively covering all possible targets. Here we report the results generated with our small amplicon-based panel that could be used routinely on paraffin-embedded and even decalcified samples, on a single sample basis in parallel with other NGS-panels used in our routine diagnostic lab, in a relatively short time and with limited costs. We tested 128 available samples from two German reference centers as part of our routine work up (among which 116 T-cell lymphomas), which is the largest routine diagnostic series reported to date. Our results showed that this assay had a very high rate of technical success (97%) and could detect mutations in the majority (79%) of tested T-cell lymphoma samples