Characterisation of ADAM15-mediated changes to cellular behaviour in breast cancer cells

ADAM15 is a multidomain multifunction transmembrane protein. It participates in protein ectodomain shedding via the metalloproteinase domain. ADAM15 also interacts with integrins via the disintegrin domain. ADAM15 mRNA is subject to complex processing, generating different isoforms as a result of alternative splicing. The splicing affects the intracellular domain (ICD) of the protein, generating distinct SH3 domain binding regions. The expression of specific splice forms correlates with breast cancer prognosis. We aimed to test if ADAM15 isoforms have distinct functions that may affect multiple aspects of cell behaviour in isoform-specific unique ways. We generated an isogenic panel expressing each ADAM15 isoform in MDA-MB-231 acells. Comparative characterisation of the panel demonstrated distinct differences between isoforms, such as catalytic function dependant or independent effects on proliferation rate, changes in cell size, isoform-specific reorganisation of the actin cytoskeleton. We discovered ADAM15 isoform-dependant upregulation of tight junction protein claudin1. Immunofluorescence analysis demonstrated co-localisation of ADAM15 with claudin1 and another tight junction protein ZO1 at cell-cell junctions. Further immunoprecipitation analysis showed potential complex formation with ADAM15 and ZO1. Pharmacological analysis showed claudin1 upregulation is mediated via PI3K/mTOR-pathway. Claudin1 upregulation depended on the metalloproteinase catalytic function of ADAM15, suggesting that ADAM15 isoforms have distinct substrates. Claudin1 was also found in the nucleus of MDA/ADAM15 A expressing cells where it could potentially function as a transcription factor. Focal adhesion (FA) turnover was influenced by ADAM15 isoform expression. In MDA/ADAM15 C expressing cells impairment of FA reassembling was observed, while ADAM15 D expression showed reduced FA disassembly. Comparison of spreading of ADAM15 isoform expressing cells on fibronectin (FN) and vitronectin (VN) revealed that most cell lines preferred FN over VN. Expression of ADAM15 E reduced this preference while ADAM15 A altered it in favour of VN over FN. Changes in subcellular localisation of β3, but not β1-integrin was observed

Estimating and abstracting the 3D structure of feline bones using neural networks on X-ray (2D) images

Computing 3D bone models using traditional Computed Tomography (CT) requires a high-radiation dose, cost and time. We present a fully automated, domain-agnostic method for estimating the 3D structure of a bone from a pair of 2D X-ray images. Our triplet loss-trained neural network extracts a 128-dimensional embedding of the 2D X-ray images. A classifier then finds the most closely matching 3D bone shape from a predefined set of shapes. Our predictions have an average root mean square (RMS) distance of 1.08 mm between the predicted and true shapes, making our approach more accurate than the average achieved by eight other examined 3D bone reconstruction approaches. Each embedding extracted from a 2D bone image is optimized to uniquely identify the 3D bone CT from which the 2D image originated and can serve as a kind of fingerprint of each bone; possible applications include faster, image content-based bone database searches for forensic purposes

Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance

In breast cancer, overexpression of the transmembrane tyrosine kinase ERBB2 is an adverse prognostic marker, and occurs in almost 30% of the patients. For therapeutic intervention, ERBB2 is targeted by monoclonal antibody trastuzumab in adjuvant settings; however, de novo resistance to this antibody is still a serious issue, requiring the identification of additional targets to overcome resistance. In this study, we have combined computational simulations, experimental testing of simulation results, and finally reverse engineering of a protein interaction network to define potential therapeutic strategies for de novo trastuzumab resistant breast cancer.First, we employed Boolean logic to model regulatory interactions and simulated single and multiple protein loss-of-functions. Then, our simulation results were tested experimentally by producing single and double knockdowns of the network components and measuring their effects on G1/S transition during cell cycle progression. Combinatorial targeting of ERBB2 and EGFR did not affect the response to trastuzumab in de novo resistant cells, which might be due to decoupling of receptor activation and cell cycle progression. Furthermore, examination of c-MYC in resistant as well as in sensitive cell lines, using a specific chemical inhibitor of c-MYC (alone or in combination with trastuzumab), demonstrated that both trastuzumab sensitive and resistant cells responded to c-MYC perturbation.In this study, we connected ERBB signaling with G1/S transition of the cell cycle via two major cell signaling pathways and two key transcription factors, to model an interaction network that allows for the identification of novel targets in the treatment of trastuzumab resistant breast cancer. Applying this new strategy, we found that, in contrast to trastuzumab sensitive breast cancer cells, combinatorial targeting of ERBB receptors or of key signaling intermediates does not have potential for treatment of de novo trastuzumab resistant cells. Instead, c-MYC was identified as a novel potential target protein in breast cancer cells

Ein Medium namens McLuhan

„If you don‘t like my arguments, I‘ve got some more.“ (Marshall McLuhan) Wie aber steht es um den Klassiker der Medienwissenschaften im 21. Jahrhundert? Diese Frage diskutieren 37 zeitgenössische Medienwissenschaftler_innen. Ihre Antworten stehen in einem reizvollen Kontrast zu Interviews, die 2007 entstanden und jetzt online zugänglich gemacht worden sind. Viele der ursprünglich Befragten sind erneut beteiligt, neue Stimmen kamen hinzu. Dabei zeigt sich im Vergleich: Die Medienwissenschaften sind diverser geworden, und manche Zukunftserwartung wurde drastisch revidiert

MedShapeNet – a large-scale dataset of 3D medical shapes for computer vision

Objectives: The shape is commonly used to describe the objects. State-of-the-art algorithms in medical imaging are predominantly diverging from computer vision, where voxel grids, meshes, point clouds, and implicit surfacemodels are used. This is seen from the growing popularity of ShapeNet (51,300 models) and Princeton ModelNet (127,915 models). However, a large collection of anatomical shapes (e.g., bones, organs, vessels) and 3D models of surgical instruments is missing. Methods: We present MedShapeNet to translate datadriven vision algorithms to medical applications and to adapt state-of-the-art vision algorithms to medical problems. As a unique feature, we directly model the majority of shapes on the imaging data of real patients. We present use cases in classifying brain tumors, skull reconstructions, multi-class anatomy completion, education, and 3D printing. Results: By now, MedShapeNet includes 23 datasets with more than 100,000 shapes that are paired with annotations (ground truth). Our data is freely accessible via aweb interface and a Python application programming interface and can be used for discriminative, reconstructive, and variational benchmarks as well as various applications in virtual, augmented, or mixed reality, and 3D printing. Conclusions: MedShapeNet contains medical shapes from anatomy and surgical instruments and will continue to collect data for benchmarks and applications. The project page is: https://medshapenet.ikim.nrw/

MedShapeNet -- A Large-Scale Dataset of 3D Medical Shapes for Computer Vision

Prior to the deep learning era, shape was commonly used to describe the objects. Nowadays, state-of-the-art (SOTA) algorithms in medical imaging are predominantly diverging from computer vision, where voxel grids, meshes, point clouds, and implicit surface models are used. This is seen from numerous shape-related publications in premier vision conferences as well as the growing popularity of ShapeNet (about 51,300 models) and Princeton ModelNet (127,915 models). For the medical domain, we present a large collection of anatomical shapes (e.g., bones, organs, vessels) and 3D models of surgical instrument, called MedShapeNet, created to facilitate the translation of data-driven vision algorithms to medical applications and to adapt SOTA vision algorithms to medical problems. As a unique feature, we directly model the majority of shapes on the imaging data of real patients. As of today, MedShapeNet includes 23 dataset with more than 100,000 shapes that are paired with annotations (ground truth). Our data is freely accessible via a web interface and a Python application programming interface (API) and can be used for discriminative, reconstructive, and variational benchmarks as well as various applications in virtual, augmented, or mixed reality, and 3D printing. Exemplary, we present use cases in the fields of classification of brain tumors, facial and skull reconstructions, multi-class anatomy completion, education, and 3D printing. In future, we will extend the data and improve the interfaces. The project pages are: https://medshapenet.ikim.nrw/ and https://github.com/Jianningli/medshapenet-feedbackComment: 16 page

Health care utilization and outcomes in older adults after Traumatic Brain Injury: A CENTER-TBI study

Introduction The incidence of Traumatic Brain Injury (TBI) is increasingly common in older adults aged ≥65 years, forming a growing public health problem. However, older adults are underrepresented in TBI research. Therefore, we aimed to provide an overview of health-care utilization, and of six-month outcomes after TBI and their determinants in older adults who sustained a TBI. Methods We used data from the prospective multi-center Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. In-hospital and post-hospital health care utilization and outcomes were described for patients aged ≥65 years. Ordinal and linear regression analyses were performed to identify determinants of the Glasgow Outcome Scale Extended (GOSE), health-related quality of life (HRQoL), and mental health symptoms six-months post-injury. Results Of 1254 older patients, 45% were admitted to an ICU with a mean length of stay of 9 days. Nearly 30% of the patients received inpatient rehabilitation. In total, 554/1254 older patients completed the six-month follow-up questionnaires. The mortality rate was 9% after mild and 60% after moderate/severe TBI, and full recovery based on GOSE was reported for 44% of patients after mild and 6% after moderate/severe TBI. Higher age and increased injury severity were primarily associated with functional impairment, while pre-injury systemic disease, psychiatric conditions and lower educational level were associated with functional impairment, lower generic and disease-specific HRQoL and mental health symptoms. Conclusion The rate of impairment and disability following TBI in older adults is substantial, and poorer outcomes across domains are associated with worse preinjury health. Nonetheless, a considerable number of patients fully or partially returns to their preinjury functioning. There should not be pessimism about outcomes in older adults who survive.publishedVersio

Prognostic Models for Global Functional Outcome and Post-Concussion Symptoms Following Mild Traumatic Brain Injury: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study

After mild traumatic brain injury (mTBI), a substantial proportion of individuals do not fully recover on the Glasgow Outcome Scale Extended (GOSE) or experience persistent post-concussion symptoms (PPCS). We aimed to develop prognostic models for the GOSE and PPCS at 6 months after mTBI and to assess the prognostic value of different categories of predictors (clinical variables; questionnaires; computed tomography [CT]; blood biomarkers). From the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, we included participants aged 16 or older with Glasgow Coma Score (GCS) 13-15. We used ordinal logistic regression to model the relationship between predictors and the GOSE, and linear regression to model the relationship between predictors and the Rivermead Post-concussion Symptoms Questionnaire (RPQ) total score. First, we studied a pre-specified Core model. Next, we extended the Core model with other clinical and sociodemographic variables available at presentation (Clinical model). The Clinical model was then extended with variables assessed before discharge from hospital: early post-concussion symptoms, CT variables, biomarkers, or all three categories (extended models). In a subset of patients mostly discharged home from the emergency department, the Clinical model was extended with 2-3–week post-concussion and mental health symptoms. Predictors were selected based on Akaike's Information Criterion. Performance of ordinal models was expressed as a concordance index (C) and performance of linear models as proportion of variance explained (R2). Bootstrap validation was used to correct for optimism. We included 2376 mTBI patients with 6-month GOSE and 1605 patients with 6-month RPQ. The Core and Clinical models for GOSE showed moderate discrimination (C = 0.68 95% confidence interval 0.68 to 0.70 and C = 0.70[0.69 to 0.71], respectively) and injury severity was the strongest predictor. The extended models had better discriminative ability (C = 0.71[0.69 to 0.72] with early symptoms; 0.71[0.70 to 0.72] with CT variables or with blood biomarkers; 0.72[0.71 to 0.73] with all three categories). The performance of models for RPQ was modest (R2 = 4% Core; R2 = 9% Clinical), and extensions with early symptoms increased the R2 to 12%. The 2-3-week models had better performance for both outcomes in the subset of participants with these symptoms measured (C = 0.74 [0.71 to 0.78] vs. C = 0.63[0.61 to 0.67] for GOSE; R2 = 37% vs. 6% for RPQ). In conclusion, the models based on variables available before discharge have moderate performance for the prediction of GOSE and poor performance for the prediction of PPCS. Symptoms assessed at 2-3 weeks are required for better predictive ability of both outcomes. The performance of the proposed models should be examined in independent cohorts.publishedVersio

Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research

No abstract available

Machine learning algorithms performed no better than regression models for prognostication in traumatic brain injury

Objective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury. Study Design and Setting: We performed logistic regression (LR), lasso regression, and ridge regression with key baseline predictors in the IMPACT-II database (15 studies, n = 11,022). ML algorithms included support vector machines, random forests, gradient boosting machines, and artificial neural networks and were trained using the same predictors. To assess generalizability of predictions, we performed internal, internal-external, and external validation on the recent CENTER-TBI study (patients with Glasgow Coma Scale <13, n = 1,554). Both calibration (calibration slope/intercept) and discrimination (area under the curve) was quantified. Results: In the IMPACT-II database, 3,332/11,022 (30%) died and 5,233(48%) had unfavorable outcome (Glasgow Outcome Scale less than 4). In the CENTER-TBI study, 348/1,554(29%) died and 651(54%) had unfavorable outcome. Discrimination and calibration varied widely between the studies and less so between the studied algorithms. The mean area under the curve was 0.82 for mortality and 0.77 for unfavorable outcomes in the CENTER-TBI study. Conclusion: ML algorithms may not outperform traditional regression approaches in a low-dimensional setting for outcome prediction after moderate or severe traumatic brain injury. Similar to regression-based prediction models, ML algorithms should be rigorously validated to ensure applicability to new populations