7.胃管アレルギーに於ける腸粘膜スメアーの研究(第二報)(第415回千葉医学会例会,第63回日本小児科学会千葉地方会総会)

Extended representative data set of lysosomal positioning. (a) Schematic representation of the feature “MAX Contour Position” used to quantify lysosomal positioning. (b) Representative LAMP1 immunofluorescence images for different ranges of the feature “LAMP1 MAX Contour Position” in HeLa cells treated as in Fig. 6. (JPG 3911 kb

Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib.

IL-6 is a central mediator of the immediate induction of hepatic acute phase proteins (APP) in the liver during infection and after injury, but increased IL-6 activity has been associated with multiple pathological conditions. In hepatocytes, IL-6 activates JAK1-STAT3 signaling that induces the negative feedback regulator SOCS3 and expression of APPs. While different inhibitors of IL-6-induced JAK1-STAT3-signaling have been developed, understanding their precise impact on signaling dynamics requires a systems biology approach. Here we present a mathematical model of IL-6-induced JAK1-STAT3 signaling that quantitatively links physiological IL-6 concentrations to the dynamics of IL-6-induced signal transduction and expression of target genes in hepatocytes. The mathematical model consists of coupled ordinary differential equations (ODE) and the model parameters were estimated by a maximum likelihood approach, whereas identifiability of the dynamic model parameters was ensured by the Profile Likelihood. Using model simulations coupled with experimental validation we could optimize the long-term impact of the JAK-inhibitor Ruxolitinib, a therapeutic compound that is quickly metabolized. Model-predicted doses and timing of treatments helps to improve the reduction of inflammatory APP gene expression in primary mouse hepatocytes close to levels observed during regenerative conditions. The concept of improved efficacy of the inhibitor through multiple treatments at optimized time intervals was confirmed in primary human hepatocytes. Thus, combining quantitative data generation with mathematical modeling suggests that repetitive treatment with Ruxolitinib is required to effectively target excessive inflammatory responses without exceeding doses recommended by the clinical guidelines

The Heidelberg Milestones Communication Approach (MCA) for patients with prognosis <12 months: protocol for a mixed-methods study including a randomized controlled trial

Background: The care needs of patients with a limited prognosis (<12 months median) are complex and dynamic. Patients and caregivers must cope with many challenges, including physical symptoms and disabilities, uncertainty. and compromised self-efficacy. Healthcare is often characterized by disruptions in the transition between healthcare providers. The Milestones Communication Approach (MCA) is a structured, proactive, interprofessional concept that involves physicians and nurses and is aimed at providing coherent care across the disease trajectory. This study aims to evaluate these aspects of MCA: (1) the training of healthcare professionals, (2) implementation context and outcomes, (3) patient outcomes, and (4) effects on interprofessional collaboration. Methods/design: A multiphase mixed-methods design will be used for the study. A total of 100 patients and 120 healthcare professionals in a specialized oncology hospital will be involved. The training outcomes will be documented using a questionnaire. Implementation context and outcomes will be explored through semi-structured interviews and written questionnaires with healthcare professionals and with the training participants and through a content analysis of patient files. Patient outcomes will be assessed in a pragmatic non-blinded randomized controlled trial and in qualitative interviews with patients and caregivers. Trial outcomes are supportive care needs (SCNS-SF34-G), quality of life (SeiQol and Fact-L), depression and anxiety symptoms (PHQ-4), and distress (Distress Thermometer). Qualitative semi-structured interviews on patients’ views will focus on shared decision-making, communication needs, feeling empathy, and further utilization of healthcare services. Interprofessional collaboration will be explored using the UWE-IP-D before the implementation of MCA (t0) and after 3 (t1), 9 (t2), and 12 (t3) months. Discussion: Using guideline-concordant early palliative care, MCA aims to foster patient-centered communication with shared decision-making and facilitation of advance care planning including end-of-life decisions, thus increasing patient quality of life and decreasing aggressive medical care at the end of life. It is assumed that the communication skills training and interprofessional coaching will improve the communication behavior of healthcare providers and influence team communications and team processes. Trial registration German Clinical Trials Register, DRKS00013649 and DRKS00013469. Registered on 22 December 2017

Additional file 6: Figure S6. of Time course decomposition of cell heterogeneity in TFEB signaling states reveals homeostatic mechanisms restricting the magnitude and duration of TFEB responses to mTOR activity modulation

Nuclear localization of TFEB is influenced by total levels of cellular TFEB. (a) HeLa cells were subjected or not to transfections with the indicated constructs and treated 24 hours post transfection with 2 μM Torin1 for 3 hours or left non-treated (NT). Representative images demonstrate the subcellular distribution of TFEB fluorescence for endogenous TFEB (TFEB immunofluorescence, IF), or transiently overexpressed GFP-TFEB, expressed alone or coexpressed with RFP-tagged 14-3-3 protein isoform YWHAG. The look-up-table ‘Fire’ (ImageJ) was applied to grey scale images of TFEB or GFP-TFEB fluorescence, representing ranging from high (white) to low (dark purple) intensity values, as displayed in color scale bar. Scale bars (white line), 20 μm. (b) Quantification of the number of cells with mainly nuclear TFEB fluorescence. At least 30 cells were scored per condition and experiment in three independent experiments. Statistical significance was tested using two-tailed Student’s t-test (**, p ≤ 0.01; ***, p ≤ 0.001). (JPG 1702 kb

Additional file 5: Figure S5. of Time course decomposition of cell heterogeneity in TFEB signaling states reveals homeostatic mechanisms restricting the magnitude and duration of TFEB responses to mTOR activity modulation

Negative clustering examples. (a) Example of a clustering outcome dissatisfying criterion 1, i.e., reproducibility of the dynamic distribution of cells among clusters. The result was obtained using three clusters with the following input features: area cell, concentration cell, and “Mean Pixel Nuc/Cyto”. In this case, the evolution in time of the percentage of cells in clusters 1 (blue) and 2 (black) is not reproducible. (b) Example of a clustering outcome dissatisfying criterion 2, i.e., non-redundant dynamics. The result was obtained using four clusters with the input feature “Mean Pixel Nuc/Cyto”. In this case, clusters 1 (black) and 3 (blue) follow similar dynamic responses to all treatments, indicating that the two clusters are redundant. (JPG 2839 kb

<i>CDKN2A</i> deletion in supratentorial ependymoma with <i>RELA</i> alteration indicates a dismal prognosis: a retrospective analysis of the HIT ependymoma trial cohort

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns

Heidelberger Meilenstein Kommunikation (HeiMeKOM) – Erfahrungen, Best Practice Beispiele und Empfehlungen aus dem Abschluss-Symposium am 30./31. Januar 2020

The National Cancer Plan emphasises the importance of medical communication and calls for its integration into medical education and training. In this context, the Milestone Communication Approach meets the communicative challenges in dealing with lung cancer patients. Interprofessional tandems, consisting of doctors and nurses, conduct structured conversations at defined moments with patients and their relatives. The concept aims at shared decision making, continuity in the care of lung cancer patients and the early integration of palliative care. During the symposium on the Heidelberg Milestone Communication in January 2020, recommendations on the care situation of lung cancer patients in advanced stages were developed. In addition, the further adaptability of HeiMeKOM to other settings and hospitals and to other diseases was discussed as well as the possibility of implementing such a concept in standard care. This article presents the experiences, best practice examples and recommendations discussed during the symposium in order to enable their extrapolation to other similarly oriented projects. The long-term goal is to transfer the milestone concept to other hospital, primarily certified lung cancer centers, and to ensure permanent funding. For further dissemination of the concept and, above all, to have it established in standard care, health policy awareness and support are required in addition to the integration of the concept in competence catalogues of continuing medical and nursing education