The interplay between tissue niche and macrophage cellular metabolism in obesity

Obesity is associated with the development of metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease. The presence of chronic, low-grade inflammation appears to be an important mechanistic link between excess nutrients and clinical disease. The onset of these metabolic disorders coincides with changes in the number and phenotype of macrophages in peripheral organs, particularly in the liver and adipose tissue. Macrophage accumulation in these tissues has been implicated in tissue inflammation and fibrosis, contributing to metabolic disease progression. Recently, the concept has emerged that changes in macrophage metabolism affects their functional phenotype, possibly triggered by distinct environmental metabolic cues. This may be of particular importance in the setting of obesity, where both liver and adipose tissue are faced with a high metabolic burden. In the first part of this review we will discuss current knowledge regarding macrophage dynamics in both adipose tissue and liver in obesity. Then in the second part, we will highlight data linking macrophage metabolism to functional phenotype with an emphasis on macrophage activation in metabolic disease. The importance of understanding how tissue niche influences macrophage function in obesity will be highlighted. In addition, we will identify important knowledge gaps and outstanding questions that are relevant for future research in this area and will facilitate the identification of novel targets for therapeutic intervention in associated metabolic diseases

Proteasenexpression einzelner disseminierter Tumorzellen aus Lymphknoten und Knochenmark von Patienten mit nichtkleinzelligem Bronchialkarzinom

Non-small cell lung cancer (NSCLC) is characterised by early dissemination of tumor cells resulting in a strikingly reduced overall survival despite complete surgical removal of the primary tumour. It has been suggested that proteases contribute to this apparent aggressiveness of lung cancer because they are involved in a variety of mechanisms associated with tumor progression such as invasion, migration and angiogenesis. To investigate the significance of protease expression and to identify potentially co-regulated molecules during early dissemination and in minimal residual disease, we performed cDNA array analysis of single disseminated cancer cells or small cell clusters isolated from bone marrow and lymph nodes of NSCLC patients. We obtained macroscopically tumor free lymph nodes and bone marrow aspirates from patients with operable NSCLC and enriched single disseminated cancer cells and small cell clusters by density gradient centrifugation. Subsequently, the freshly prepared cell suspensions were stained with an antibody against the epithelial surface molecule EpCAM and single positive tumour cells were isolated by micromanipulation. After global amplification of the single cell cDNA and non-radioactive labelling proteinase expression was assessed using a cDNA array consisting of several matrix metalloproteases, cathepsins, caspases, kallikreins and other serine / cysteine proteases. Until now we could isolate 46 EpCAM+ cells from 72 lymph nodes and 19 EpCAM+ cells from 71 bone marrow aspirates. For 30 cells the epithelial origin could be confirmed by the co-expression of several epithelial markers or by expression of the tumor specific MAGE antigens. Hybridisation of these cells on our protease cDNA array revealed the expression of various proteases in single cells and small cell clusters. Particularly, serine proteases, cathepsins and other cysteine proteinases are frequently expressed, while, contrary to our expectations, the transcripts of matrix metalloproteases (MMP) were rarely detected in the analysed cells

Comprehensive analysis of liver macrophage composition by flow cytometry and immunofluorescence in murine NASH

Recently, it has become evident that macrophage diversity increases in the liver during the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we provide a detailed protocol for the analysis of liver macrophage subsets in mice with non-alcoholic fatty liver disease (NAFLD) and early NASH using flow cytometry and immunofluorescence (IF). These methods can be used to assess the composition and localization of macrophage subsets during NASH. For complete details on the use and execution of this protocol, please refer to Daemen et al. (2021)

Shape trumps size : image-based morphological analysis reveals that the 3D shape discriminates intracranial aneurysm disease status better than aneurysm size

Background: To date, it remains difficult for clinicians to reliably assess the disease status of intracranial aneurysms. As an aneurysm's 3D shape is strongly dependent on the underlying formation processes, it is believed that the presence of certain shape features mirrors the disease status of the aneurysm wall. Currently, clinicians associate irregular shape with wall instability. However, no consensus exists about which shape features reliably predict instability. In this study, we present a benchmark to identify shape features providing the highest predictive power for aneurysm rupture status. Methods: 3D models of aneurysms were extracted from medical imaging data (3D rotational angiographies) using a standardized protocol. For these aneurysm models, we calculated a set of metrics characterizing the 3D shape: Geometry indices (such as undulation, ellipticity and non-sphericity); writhe- and curvature-based metrics; as well as indices based on Zernike moments. Using statistical learning methods, we investigated the association between shape features and aneurysm disease status. This processing was applied to a clinical dataset of 750 aneurysms (261 ruptured, 474 unruptured) registered in the AneuX morphology database. We report here statistical performance metrics [including the area under curve (AUC)] for morphometric models to discriminate between ruptured and unruptured aneurysms. Results: The non-sphericity index NSI (AUC = 0.80), normalized Zernike energies ZsurfN (AUC = 0.80) and the modified writhe-index WL1mean (AUC = 0.78) exhibited the strongest association with rupture status. The combination of predictors further improved the predictive performance (without location: AUC = 0.82, with location AUC = 0.87). The anatomical location was a good predictor for rupture status on its own (AUC = 0.78). Different protocols to isolate the aneurysm dome did not affect the prediction performance. We identified problems regarding generalizability if trained models are applied to datasets with different selection biases. Conclusions: Morphology provided a clear indication of the aneurysm disease status, with parameters measuring shape (especially irregularity) being better predictors than size. Quantitative measurement of shape, alone or in conjunction with information about aneurysm location, has the potential to improve the clinical assessment of intracranial aneurysms

Developmental expression and differentiation-related neuron-specific splicing of metastasis suppressor 1 (Mtss1) in normal and transformed cerebellar cells

Background: Mtss1 encodes an actin-binding protein, dysregulated in a variety of tumors, that interacts with sonic hedgehog/Gli signaling in epidermal cells. Given the prime importance of this pathway for cerebellar development and tumorigenesis, we assessed expression of Mtss1 in the developing murine cerebellum and human medulloblastoma specimens. Results: During development, Mtss1 is transiently expressed in granule cells, from the time point they cease to proliferate to their synaptic integration. It is also expressed by granule cell precursor-derived medulloblastomas. In the adult CNS, Mtss1 is found exclusively in cerebellar Purkinje cells. Neuronal differentiation is accompanied by a switch in Mtss1 splicing. Whereas immature granule cells express a Mtss1 variant observed also in peripheral tissues and comprising exon 12, this exon is replaced by a CNS-specific exon, 12a, in more mature granule cells and in adult Purkinje cells. Bioinformatic analysis of Mtss1 suggests that differential exon usage may affect interaction with Fyn and Src, two tyrosine kinases previously recognized as critical for cerebellar cell migration and histogenesis. Further, this approach led to the identification of two evolutionary conserved nuclear localization sequences. These overlap with the actin filament binding site of Mtss1, and one also harbors a potential PKA and PKC phosphorylation site. Conclusion: Both the pattern of expression and splicing of Mtss1 is developmentally regulated in the murine cerebellum. These findings are discussed with a view on the potential role of Mtss1 for cytoskeletal dynamics in developing and mature cerebellar neurons

Pediatric oncologists' perspectives on the use of complementary medicine in pediatric cancer patients in Switzerland: A national survey-based cross-sectional study

BACKGROUND There is a widespread use of complementary therapies among pediatric cancer patients. Previous studies provided evidence that communication between pediatric oncologists (POs) and patients/families about the use of these therapies is often incomplete. Furthermore, nationwide studies on this topic are rare. AIMS We assessed POs' perspectives on the use of complementary medicine (CM) in Switzerland, on the basis of an edited survey previously used in a nationwide study. METHODS AND RESULTS A link to an online survey was sent by e-mail to each of the fifty-two eligible pediatric oncologists in all nine Swiss Pediatric Oncology Group (SPOG) centers. Eligible respondents were board-certified (Switzerland or abroad) POs currently working at a SPOG center. The survey was available for a total period of 2 months. We received 29 filled questionnaires (overall response rate: 56%). Most POs (59%) indicated that they ask more than 50% of their patients about CM use. Frequent reasons for not asking about the use of CM were i) forgetting to ask (55%), ii) lack of knowledge on the subject (31%), and iii) lack of time (24%). More than every second PO (55%) reported having a lack of knowledge on the subject. A majority of POs (66% to 76%) indicated interest in learning more about specific CM topics (cannabinoids, hypnosis and relaxation, music therapy, herbal medicine, acupuncture, meditation, and yoga). More information and specific training opportunities on the use of CM was deemed important by 76% to 97% of POs. CONCLUSION POs working in Switzerland identify complementary therapies as an important subject. Swiss POs are willing to acquire more knowledge on CM. More training seems to be necessary in order to increase awareness about the topic, to enhance communication about complementary therapies and thus to improve patient care

Pediatric oncologists' perspectives on the use of complementary medicine in pediatric cancer patients in Switzerland: A national survey-based cross-sectional study.

BACKGROUND There is a widespread use of complementary therapies among pediatric cancer patients. Previous studies provided evidence that communication between pediatric oncologists (POs) and patients/families about the use of these therapies is often incomplete. Furthermore, nationwide studies on this topic are rare. AIMS We assessed POs' perspectives on the use of complementary medicine (CM) in Switzerland, on the basis of an edited survey previously used in a nationwide study. METHODS AND RESULTS A link to an online survey was sent by e-mail to each of the fifty-two eligible pediatric oncologists in all nine Swiss Pediatric Oncology Group (SPOG) centers. Eligible respondents were board-certified (Switzerland or abroad) POs currently working at a SPOG center. The survey was available for a total period of 2 months. We received 29 filled questionnaires (overall response rate: 56%). Most POs (59%) indicated that they ask more than 50% of their patients about CM use. Frequent reasons for not asking about the use of CM were i) forgetting to ask (55%), ii) lack of knowledge on the subject (31%), and iii) lack of time (24%). More than every second PO (55%) reported having a lack of knowledge on the subject. A majority of POs (66% to 76%) indicated interest in learning more about specific CM topics (cannabinoids, hypnosis and relaxation, music therapy, herbal medicine, acupuncture, meditation, and yoga). More information and specific training opportunities on the use of CM was deemed important by 76% to 97% of POs. CONCLUSION POs working in Switzerland identify complementary therapies as an important subject. Swiss POs are willing to acquire more knowledge on CM. More training seems to be necessary in order to increase awareness about the topic, to enhance communication about complementary therapies and thus to improve patient care

Positive Behavior Support Systems in a Rural West Texas Middle School

Positive Behavior Support (PBS) programs are being implemented in schools in the United States to support faculty, staff, and students. The purpose of this study was to evaluate a PBS system at a rural west Texas middle school to discover what improvements are necessary for district-wide implementation and sustainability. The study drew on Bandura\u27s social learning theory, which posits that people learn from each other through observation, imitation, and modeling. PBS systems provide the framework for exhibiting specific behavior expectations so students and teachers can get the most from their educational experiences. A program evaluation was completed using discipline data from 2008-2012 from the middle school, observations at the middle school, and archival campus improvement plan results from the campus needs assessment from 2012. The research instrument used to assess the information was a pre-established PBS evaluation system called the School-Wide Evaluation Tool (SET) designed for programmatic assessment. The SET assessment tool guided the evaluation of information gathered from 100 students, 15 teachers, and an administrative team survey to highlight the strengths and weaknesses of the PBS program in the school and district, identify necessary changes to improve its effectiveness, and determine how to best implement the system district-wide. These findings were used to inform a white paper outlining how to implement a successful program and how to maintain the program over time. This evaluation provided specific steps to strengthen each component of a PBS program to ensure school-wide application and sustainability. A positive social change is experienced by students, teachers, and parents by the enhancement of a PBS system that improves student behavior in the school and district