julilili42/papers huggingface dataset:
JS05.5.A INTRAOPERATIVE MRI-GUIDED RESECTION IS NOT SUPERIOR TO 5-ALA-GUIDANCE IN NEWLY DIAGNOSED GLIOBLASTOMA: A PROSPECTIVE CONTROLLED MULTICENTER CLINICAL TRIAL
2023-09-01

Abstract BACKGROUND Prospective data suggested a superiority of intraoperative MRI (iMRI) over 5-aminolevulinic acid (5-ALA) for achieving complete resections of contrast enhancement in glioblastoma surgery. We investigated this hypothesis in a prospective clinical trial and correlated residual disease volumes with clinical outcome in newly diagnosed glioblastoma. MATERIAL AND METHODS This is a prospective controlled multicenter parallel-group trial with two center-specific treatment arms (5-ALA and iMRI) and blinded evaluation. The primary endpoint was complete resection of contrast enhancement on early postoperative MRI. We assessed resectability and extent of resection by an independent blinded centralized review of pre- and post-operative MRI with 1mm slices. Secondary endpoints included progression-free (PFS) and overall survival (OS), patient-reported quality of life and clinical parameters. RESULTS We recruited 314 patients with newly diagnosed glioblastomas at eleven German centers. 127 patients in the 5-ALA and 150 in the iMRI arm were analyzed in the as treated analysis. Complete resections, defined as a residual tumor ≤0.175 cm3, were achieved in 90 patients (78%) in the 5-ALA and 115 (81%) in the iMRI arm (p=0.79). Incision-suture times (p&amp;lt;0.001) were significantly longer in the iMRI arm (316 vs. 215 [5-ALA] minutes). Median PFS and OS were comparable in both arms. The lack of any residual contrast enhancing tumor (0cm3) was a significant favorable prognostic factor for PFS (p&amp;lt;0.001) and OS (p=0.048), especially in MGMT unmethylated tumors (p=0.006). CONCLUSION We could not confirm superiority of iMRI over 5-ALA for achieving complete resections. Neurosurgical interventions in newly diagnosed glioblastoma shall aim for safe complete resections with 0 cm3 contrast-enhancing residual disease, as any other residual tumor volume is a negative predictor for PFS and OS.
P10.04.B LONGITUDINAL [18F ]FET-PET-BASED IMAGING AND PROFILING OF PDGFB-DRIVEN EXPERIMENTAL GLIOMA USING THE RCAS-TVA SYSTEM
2023-09-01

Abstract BACKGROUND Glioblastoma are aggressive and incurable primary tumors of the central nervous system. As patients present with already established tumors, longitudinal imaging by MRI and [18F]FET-PET in human glioblastoma for characterizing temporal and spatial metabolic alterations is only possible to characterize alterations during therapy, but not during tumor evolution. In this regard, genetically engineered preclinical models are very relevant. The replication-competent avian sarcoma-leukosis virus (RCAS)/tumor virus receptor-A (tva) system provides a high grade of spatial and temporal control of somatic gene delivery in vivo. In this study, we used longitudinal MRI and [18F]FET-PET to characterize the evolution and growth of platelet-derived growth factor B (PDGFB)-driven glioma model using the RCAS-tva system. MATERIAL AND METHODS DF-1 cells transfected with PDGFB were implanted into adult 129S.Tg(NES-TVA)-Cdkn2a−/− mice intracranially. Mice received MRI twice and [18F]FET-PET measurements once per week. Longitudinal growth pattern and [18F]FET-PET uptake were assessed and analyzed. We measured symptom-free survival and performed immunohistochemistry on collected tumor tissue samples. RESULTS We observed robust tumor formation with highly reproducible symptom-free survival times of treatment-naïve experimental animals. Contrast-enhanced MRI volumetry revealed exponential growth dynamics starting around day 25 after DF-1 inoculation. Here, the PDGFB-driven gliomas present an escalating [18F]FET-PET uptake as well as increasing BBB permeability over time. These imaging features match the clinical scenario, which underlines the translational relevance of this model. Histology corroborated the imaging findings and an immunogenic glioma-associated microenvironment. CONCLUSION These data provide further valuable insights into this RCAS/tva-based PDGFB-driven murine glioma model and advocates for an imaging-stratified design of preclinical therapeutic interventions.
P10.25.A ATR INHIBITION IN EXPERIMENTAL GLIOMA: DISCOVERY AND VALIDATION OF MOLECULAR TARGETS FOR FUNCTIONALLY-INSTRUCTED COMBINATION THERAPIES
2023-09-01

Abstract BACKGROUND The DNA damage response (DDR) is an important physiological network for the prevention of malignant transformation, e.g. by halting the cell cycle upon DNA damage detection and promoting DNA repair. Glioblastoma are incurable primary brain tumors that display acquired treatment resistance which might also be due to DDR dysregulation. Furthermore, we had recently investigated molecular effects of disrupting the (b)HLH network, a frequently altered and tumor-promoting transcriptional network in glioma. The identified downstream anti-tumor effects included the ataxia telangiectasia and Rad3 related (ATR) pathway. In the present study, we aimed at investigating the anti-glioma effects of ATR inhibition (ATRi) in experimental glioma and exploring potential treatment regimens for forward translation. MATERIAL AND METHODS We assessed ATRi monotherapy in the syngeneic SMA560/VM/Dk mouse model, performed acute cytotoxicity, clonogenic survival assays, cell cycle analyses by flow cytometry and apoptosis induction in vitro. Furthermore, we used RNA sequencing, DigiWest protein profiling analyses and genome-wide CRISPR/Cas9 loss-of function and activation screens. We evaluated synergistic or additive anti-glioma effects of functionally-instructed combination therapies by the Bliss and ZIP synergy models. We xenotransplanted zebrafish embryos with glioma cells to validate most promising combination approaches in vivo. RESULTS ATRi monotherapy induced prolonged latency until the onset of neurological symptoms in the SMA560/VM/Dk mouse model. ATRi reduced viability and clonogenic survival in vitro and ex vivo. Molecular analyses revealed differential patterns of gene expression, e.g. p53 signaling, differing modes of cell cycle and apoptosis regulation, arguing for a profound context specificity of the treatment. Similarly, CRISPR/Cas-9 genome-wide knockout and activation screens revealed distinct genetic vulnerabilities. Based on these RESULTS , we designed a drug library for investigating potential functionally-instructed modifiers of response to ATRi in experimental glioma in vitro, ex vivo and in vivo. CONCLUSION In summary, we present a workflow in experimental glioma for target discovery and validation leading to the design of novel combination therapies. We identify potential combination therapies involving ATRi in experimental glioma that could inform future early phase clinical trials and preclinical studies.
OS09.7.A THE ROLE OF MICROSURGERY IN THE FIRST LINE TREATMENT OF VESTIBULAR SCHWANNOMA: IT IS ALL ABOUT THE ODDS
2023-09-01

Abstract BACKGROUND Given the risk for a deterioration of facial function (FDR), first-line (1stline) microsurgery (MS) is discouraged in vestibular schwannoma (VS). In contrast, 1stline radiosurgery (SRS) preserves facial function but has a higher recurrence rate (RR). As salvage VS surgery is very challenging, it could be reasonable to accept a slightly increased FDR of 1stline MS in favor of the lower RR. The aim of the present study was to determine the FDR and RR values of salvage surgery and to calculate the break-even point of MS in the 1stline VS treatment. MATERIAL AND METHODS This retrospective study analyzed all patients with unilateral VS undergoing microsurgery between 03/2008 and 10/2021 (n=1470). We identified patient with 2ndline MS after previous MS (MS-MS) or radiosurgery (SRS-MS) as well as patients with 3rdline MS (MS-SRS-MS). After reviewing patients’ clinical and imaging data, we determined FDR and RR for each cohort. This data was compared to a 1stline MS cohort (CTRL) with a follow-up of at least 10 years (n=572). A mathematical prediction model (MPM) was applied to calculate the odds ratio (OR) of different treatment strategies (i.e., MS-MS, SRS-MS, MS-SRS-MS) depending on different FDR and RR values. RESULTS We identified 48 patients with 2ndline and 11 patients with 3rdline MS after failed MS/SRS. Time to recurrence in relation to the initial treatment was shortest in SRS-MS (35±34 mo) compared to MS-MS (128±179 mo) and MS-SRS-MS (38±17 mo). These patients had a significant worse preoperative facial function than CTRL patients. Extent-of-resection (EOR) was diminished in 2ndline (79% and 75%) compared to 1stline MS (97%). Both the FDR and RR were significantly increased in MS-MS (FDR:17%, RR:14%) and SRS-MS (FDR:45%, RR:5%) compared to CTRL (FDR:12%, RR:4%). Notably, MS-SRS-MS was associated with the highest FDR (60%) while having the lowest GTR rate (54%). MPM indicated that FDR&amp;lt;15% and RR&amp;lt;5% justify a 1stline MS. In the present cohort, these criteria were met for Koos 1-3 tumors (FDR:0-7%, RR:0-3%). CONCLUSION Recurrent VS surgeries fare much worse considering FDR, EOR and RR than first-line surgeries. Hence, reducing the RR of the first-line VS treatment is required. In smaller VS, the surgical oncofunctional outcome can reach the break-even point favoring microsurgery over radiosurgery as first-line treatment option. However, in situations with high FDR (e.g., large or cystic VS) a more conservative surgical approach might be beneficial.
P10.29.A FUNCTIONALLY INSTRUCTED COMBINATION-TREATMENTS INVOLVING REGORAFENIB IN EXPERIMENTAL GLIOMA
2023-09-01

Abstract BACKGROUND Glioblastoma are incurable primary tumors of the central nervous system. The standard of care for newly diagnosed glioblastoma outside clinical trials includes a combination of radiation therapy, alkylating chemotherapy and tumor-treating fields. Yet, for progressive glioblastoma, only lomustine is registered in Europe. The REGOMA trial (Lombardi et al., Lancet Oncol 2019) had investigated regorafenib versus lomustine in a phase 2-trial. Furthermore, the use of regorafenib in a compassionate-use-program was recently reported (Tzaridis et al., Neuro Oncol 2019) Yet, the regorafenib arm in the Glioblastoma Adaptive Global Innovative Learning Environment (GBM Agile) master protocol was stopped after an interim analysis that showed a low probability of improvement of overall survival compared with control (press release 21 September 2022). We investigated here a functional genomics-based approach to discover and validate potential modulators of response to regorafenib treatment in experimental glioma in vitro, in vivo and ex vivo. MATERIAL AND METHODS We performed CRISPR/Cas9 activation (Calabrese P65-HSF activation library) and knockout (genome-wide knockout library Brunello) screens during treatment with regorafenib, sequenced and analyzed the genomic DNA of the remaining cells. RESULTS We discovered functionally-instructed molecular hits, designed a drug library for further validation by functional assays in vitro and combination treatments in murine glioma models in vivo. CONCLUSION Taken together, we discovered and validated functionally-instructed combination treatment options involving regorafenib. Our finalized results will be presented.
O7 Antibody-mediated delivery of plasma membrane tethered recombinant TAPBPR enables highly efficient exchange of HBV peptides across a wide range of HLA class I allotypes
2023-09-01

<h3>Background and Aims</h3> Hepatitis B (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. Immunotherapies to date have not been successful in achieving long-term immune control required for functional cure. The antigenic peptide display of HBV derived peptides on HLA class I molecules is crucial for mounting antiviral immune responses. TAPBPR functions intracellularly as an MHC class I peptide exchange catalyst promoting the loading of immunogenic peptides onto MHC-I as well as the release of suboptimal peptides. Following on from the use of recombinant soluble TAPBPR (sTAPBPR) to mediate exogenous peptide loading onto MHC class I at the cell surface, the Boyle lab demonstrated that by using recombinant TAPBPR-antibody fusion proteins (TAPBPR-Ab) we can tether TAPBPR to the plasma membrane expressed target protein resulting in superior peptide exchange when compared with sTAPBPR alone. This was observed with low peptide concentrations due to its ability to remain bound to the cell surface, thus enabling sequential binding to multiple MHC molecules. TAPBPR-Ab promoted highly efficient loading of exogenous immunogenic peptides onto tumour cells, resulting in antigen-specific CD8+ T cell responses and killing of antibody-target positive tumour cells in vivo. Here we investigate the ability of TAPBPR-Ab fusion proteins to be utilised to increase the immunogenicity of HBV infected cells. <h3>Methods</h3> Recombinant sTAPBPR fused to αGFP nanobody (TAPBPR-GFPnb) and tethered to the plasma membrane was used to perform exogenous peptide loading of fluorescently labelled HBV peptides on a panel of cells expressing the antibody target GFP and single HLA class I of choice (HLA-A*02:01, -B*08:01, -B*35:01 and Cw*06:02). <h3>Results</h3> Superior peptide binding levels were observed on target cells treated with TAPBPR-GFPnb compared to cells treated with sTAPBPR or peptide alone. This was observed on HLA class I allotypes that TAPBPR is known to exhibit a preference for such as HLA-A*02:01 and HLA B*08:01, as well as -B*35:01 and Cw*06:02 allotypes. Peptide binding was not observed in cells lacking classical HLA class I expression demonstrating that peptide loading occurs directly onto to HLA class I. Peptide binding was negligible on TAPBPR-GFPnb treated cells lacking the nanobody target, similarly to cells treated with peptide alone. <h3>Conclusion</h3> The use of TAPBPR-Ab fusion proteins is a novel approach to decorate target positive HBV infected cells with immunogenic HBV peptides on a diverse range of HLA class I. They have demonstrated an ability to trigger antigen specific immune responses, even at low peptide concentrations and thus have the exciting potential to be an important therapeutic tool for HBV functional cure, with limited off target effects.
Training and education of young physicians and engineers in the field of endoscopy and laparoscopy – a review of Germany-wide joint cooperation and training possibilities
2023-09-01

Abstract Introduction: Application-related (hands-on) training and instruction is an essential component in the advanced education of physicians in residency. To teach and train required endoscopic examinations and interventions in a standardized manner, courses are offered by various societies. Within these courses the assistant endoscopists learn and train how to use the technical equipment and how to perform the examinations and related interventions. Similarly, for graduate biomedical engineering students with a job- or research-related interest in the field of endoand laparoscopy, an early involvement and practical introduction to the instrumentation and techniques - if possible already during their studies - can generate a fundamental understanding of the technical requirements as well needs of the physicians. Objective: As various such (hands-on) training-courses for flexible and rigid endoscopy specifically addressing young physicians, surgeons as well as engineers are offered by numerous institutes, this contribution tries do provide a structured overview on/over these possibilities. Material: Known cross-institutional courses in the field of endo- and laparoscopy currently offered in Germany in cooperation of physicians and engineers are listed and briefly described. Results: A total of n = 4 crossinstitutional courses for the introduction and training in flexible and rigid endoscopy have been identified. Discussion: The cross-institutional courses for physicians and technicians in the field of endo- and laparoscopy presented serve to provide a better understanding of the subject matter and the field of either discipline. Questions that arise in the field of endoscopy from physicians can be addressed at an early stage and, if necessary, worked on with little effort. Ideas for new instruments and even new interventions can arise and be pursued through an intensive exchange between technicians and physicians. Collaborations are established on a local basis which will foster national activities in this field and which allow to develop competencies relevant for the industrial sector of medical engineering.
Archaeogenetics: Local genetic diversity and ethnic fluidity in post-Roman Pannonia
2023-09-01

During the fifth century, the Roman Empire underwent dramatic changes. New, ethnically identified polities emerged in the Mediterranean region. Historical research has highlighted the social complexities of this process. Archaeogenetics now shows the remarkably high genetic diversity of post-Roman local societies.
Exploring Ergodicity Of Associations Between Pre-exercise Readiness And Exercise-related Effort And Affective Experience
2023-09-01

Readiness states can yield insight in predicting exercise effort and experience, but existing research is limited to single-session or qualitative designs with group-level (nomothetic) analysis. To best understand target phenomena and drive person-adaptive treatment, it is critical to determine if expected relationships among variables can generalize across within- and between-person patterns (ergodicity of association). PURPOSE: Explore ergodicity of associations between readiness dimensions and volitional exercise experiences reported in natural settings. METHODS: For 5-7 weeks, six participants initiated event-contingent ecological momentary assessments using pre- and post-exercise surveys bookmarked in their smartphones (18 ± 3 bouts/person, multiple exercise types). Reports captured pre-exercise physical, cognitive, and threat-challenge states (Acute Readiness Monitoring Scale), bout duration (min), perceived exertion (Category-10 Ratio Scale), and recalled in-task affective valence (Feeling Scale). Analyses included repeated measures correlation (within-person; 107 observations) and standard bivariate correlation (between-person; 6 observations using person-specific means). Associations were interpreted as weak (<0.30), moderate (0.30-0.49), or strong (>0.50), with preliminary p-values and confidence intervals included. RESULTS: Within-person associations showed expected patterns between readiness and affect (i.e., more pleasant exercise when reporting more favorable pre-exercise states), while only nomothetic analysis yielded expected patterns of readiness states with exertion and duration (see table). CONCLUSION: This work shows proof-of-concept that associations between readiness and experiential aspects of volitional, varied exercise appear to be non-ergodic. Results align with many non-exercise-related psychological processes, warranting replication with fully-powered samples.
80: Transfer Learning Boosts Performance Of Deep Learning Model Prediction of In-Hospital Mortality In Patients Treated With Extracorporeal Membrane Oxygenation
2023-09-01

Background: The application of deep learning – a powerful but data-intensive subset of machine learning – to smaller cohorts including extracorporeal membrane oxygenation (ECMO) datasets is challenging. Transfer learning can boost the performance of deep learning models trained on smaller datasets. Methods: We applied deep learning to routinely collected electronic health record data within the Medical Information Mart for Intensive Care IV database to predict in-hospital mortality in a small cohort of subjects treated with ECMO, 24 hours prior to death. Model performance was assessed with and without pre-training on data for subjects not treated with ECMO. Results: The study dataset included 27,192 subjects admitted to one of six intensive care unit (ICUs) at a single medical center between 2008 and 2019. Seventy five (0.3%) subjects were treated with ECMO, including 58 (77%) treated with veno-arterial ECMO. In-hospital mortality in subjects treated and not treated with ECMO were 57.3% and 16.1%, respectively. The model performed poorly without pre-training, AUC 0.65 (95% CI 0.59-0.73). However, pre-training significantly improved model performance, AUC 0.82 (95% CI 0.81-0.83). Pre-training on smaller cohorts of subjects not treated with ECMO in select ICUs resulted in similar strong performances. Conclusions: A deep learning model performed well at predicting in-hospital mortality in a small cohort of patients treated with ECMO after first pre-training on data from patients not treated with ECMO. Transfer learning allows pre-trained deep learning models to be applied to smaller clinical datasets, including datasets of patients undergoing highly specialized treatments, resulting in better overall performance.
Guido Goldman: Transatlantic Bridge Builder By Martin Klingst. Translated by Brian Hanrahan. New York and Oxford: Berghahn Books, 2021. Pp. xx + 208. Paperback $34.95. ISBN: 978-1800732636.
2023-09-01

Guido Goldman: Transatlantic Bridge Builder By Martin Klingst. Translated by Brian Hanrahan. New York and Oxford: Berghahn Books, 2021. Pp. xx + 208. Paperback $34.95. ISBN: 978-1800732636. - Volume 56 Issue 3
On Photos and Drawings in Baby Books. A Comparison Based on Dining Scenes
2023-09-01

Abstract This article offers a comparative analysis of the aesthetic functions of photos vs. drawings in baby books. Baby books are understood as books for children between 0 and 3 years of age. Since the development of food intake and eating behavior is very important at this age, appropriate pictures of dining scenes can be found in many baby books. This article compares picturebooks for babies that show dining scenes, with two photo books, Trine kan... (1955) and Se hvad vi kan! (1964), and two baby books with drawings, The Picturebook for BABY (1950) and I See (1985). The null hypothesis is that photos tend more towards documentary, authentic, and objective representation, while drawings emphasize a stereotypical, expressive, and subjective perspective. Important intermittent factors are the concept of portraiture, expressed cuteness, and the position on a scale from avant-garde to kitsch. The analysis of the images and the accompanying texts (including the peritexts) shows that the representation of babies is subject to historical changes, which is related to different constructions of what it means to be a baby. In particular, the orientation towards parental or pedagogical ideals influences the respective representations.
Manifolds.jl: An Extensible Julia Framework for Data Analysis on Manifolds
2023-09-02

We present the Julia package Manifolds.jl , providing a fast and easy-to-use library of Riemannian manifolds and Lie groups. This package enables working with data defined on a Riemannian manifold, such as the circle, the sphere, symmetric positive definite matrices, or one of the models for hyperbolic spaces. We introduce a common interface, available in ManifoldsBase.jl , with which new manifolds, applications, and algorithms can be implemented. We demonstrate the utility of Manifolds.jl using Bézier splines, an optimization task on manifolds, and principal component analysis on nonlinear data. In a benchmark, Manifolds.jl outperforms all comparable packages for low-dimensional manifolds in speed; over Python and Matlab packages, the improvement is often several orders of magnitude, while over C/C++ packages, the improvement is two-fold. For high-dimensional manifolds, it outperforms all packages except for Tensorflow-Riemopt, which is specifically tailored for high-dimensional manifolds.