tbuckley/cabot-search huggingface dataset:
BIOM-19. DECIPHERING THE METHYLATION SIGNATURE OF CIRCULATING EXTRACELLULAR VESICLE DNA FOR CNS TUMOR CLASSIFICATION
Authors: Franz Ricklefs, Tammo Ricklefs, Cecile Maire, Amanda Salviano da Silva, Kathrin Wollman, Thomas Sauvigny, Lasse Dührsen, Ulrich Schüller, Manfred Westphal, Katrin Lamszus
Journal: Neuro-Oncology (2021)

Abstract Genome-wide methylation profiling has recently been developed into a tool that allows subtype tumor classification in central nervous system (CNS) tumors. We previously showed that extracellular vesicle (EV) DNA faithfully reflects the tumor methylation class, including information on the IDH mutation and MGMT promoter methylation status. Furthermore we showed that circulating plasma EVs are elevated in CNS tumor patients in comparison to non-tumor donors (HD) controls with tumor related protein profiles. We now investigated, whether the methylation signatures of circulating DNA (both EV and cfNDA) can be used in liquid biopsy approaches for CNS tumor detection and classification. We isolated DNA from circulating EVs (n=27), cfDNA (n=27) and tumor tissue DNA (n=90) of patients with glioblastoma (GBM), meningioma (MGN) and cerebral metastases (CM). Patients undergoing epilepsy surgery as well as aneurysm clipping were used as non-tumor controls (HD, n= 7). EVs were classified by nanoparticle analysis, immunoblotting, imaging flow cytometry and electron microscopy. Isolated EV-DNA comprised many sorts of molecular weight (up tp &amp;gt;10Kb) in comparison to cfDNA (130-140bp). Healthy donors and tumor patients showed not differences in their DNA size profiles. We performed genome-wide methylation profiling by 850k Illumina EPIC arrays for all DNA analytes and tumor entities. Linear models and empirical Bayes methods identified significant differentially methylated CpGs (GBM vs. HD, MGN, vs HD, CM vs. HD), that revealed tumor specific signatures to detect and discriminate different CNS tumor entities. Visualization of differentially methylated CPGs by dimension reduction (PCA, t-SNE, Umap) verified tumor specific clusters. cfDNA and EV-DNA exhibited distinctive individual CpG profiles. Our study shows that the methylation signature of circulating EV DNA and cfDNA can be used to separate healthy individuals from tumor patients and could potentially complement standard-of-care imaging to improve tumor detection, classification and surveillance.
The <i>Ccl17</i> gene encoding TARC is synergistically transactivated by PU.1 and IRF4 driven by the mammalian common promoter in dendritic cells
Authors: Naoto Ito, Fumiya Sakata, Masakazu Hachisu, Kazuki Nagata, Tomoka Ito, Kurumi Nomura, Masanori Nagaoka, Keito Inaba, Mutsuko Hara, Nobuhiro Nakano, Tadaaki Nakajima, Takuya Yashiro, Chiharu Nishiyama
Journal: Allergy (2021)

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Targeting BMI-1 in B cells restores effective humoral immune responses and controls chronic viral infection
Authors: Andrea Di Pietro, Jack Polmear, Lucy Cooper, Timon Damelang, Tabinda Hussain, Lauren Hailes, Kristy O’Donnell, Vibha Udupa, Tian Mi, Simon Preston, Areen Shtewe, Uri Hershberg, Stephen J. Turner, Nicole L. La Gruta, Amy W. Chung, David M. Tarlinton, Christopher D. Scharer, Kim L. Good-Jacobson
Journal: Nature Immunology (2021)
IMMU-07. REPROGRAMMING OF MICROGLIA/MACROPHAGES IN GLIOBLASTOMA IMPROVES ANTI-TUMOR T CELL RESPONSES
Authors: Valentina Fermi, Rolf Warta, Christine Jungk, Philip Dao Trong, Andreas Unterberg, Christel Herold-Mende
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) still remains incurable. In search for new treatment modalities immunotherapy might be attractive but highly depends on a sufficient infiltration and function of effector T cells in an immunosuppressive microenvironment. In this study, we analyzed if blocking or reprogramming M2polarized glioma-associated microglia/macrophages (GAMs) could improve spontaneous effector T cell responses and thus enhance the effectiveness of immunotherapy. This was tested by sorting patient-derived CD11b+ cells from GBM tissues and treating these GAMs with small molecule inhibitors (SMI) targeting the colony stimulating factor1 receptor (CSF1R). Especially CD11b+ cells treated with the SMI GW2580 presented with a reduced expression of the M2 marker CD163 (p &amp;lt; 0.01) and an increased expression of HLA-DR (p &amp;lt; 0.05). Conditioned media of SMI-treated GAMs also contained significantly higher levels of nitrite (p &amp;lt; 0.001) and a reduced concentration of the immunosuppressive cytokine IL-6 (p &amp;lt; 0.05). Moreover, gene expression profiles of GW2580-treated GAMs showed a shift from an immunosuppressive towards a pro-inflammatory phenotype. Most importantly, the addition of conditioned media of GW2580-treated GAMs to a co-culture of autologous tumor and T cells significantly reduced the number of live tumor cells as compared to the use of conditioned media of untreated GAMs (p &amp;lt; 0.05). Interestingly, in some cases the ability of T cells to transmigrate through a dense barrier of autologous tumor-derived endothelial cells could also be increased. In summary, we showed that CSF-1R blockade with the SMI GW2580 can reprogram GAM phenotype and thereby improve T cell activation. This strongly suggests further studies on the use of GW2580 in combination with immunotherapeutic approaches for the treatment of GBM.
Abstract 9768: Relationship of Atherogenic Lipoproteins with Insulin Resistance and Carotid Intimal Thickness in Youth at Risk for Cardiovascular Disease
Authors: Stephanie T Chung, Sheela Magge
Journal: Circulation (2021)

Introduction: Youth with obesity and abnormal glucose tolerance (AGT) have an atherogenic lipoprotein (Lp) profile (small dense HDL and small LDL) and an increased risk for atherosclerotic disease, but the relative contributions of hyperglycemia and insulin resistance to the development of subclinical atherosclerosis in youth are not well defined. Hypothesis: Atherogenic Lp concentrations (ApoB, small LDLp, small HDLp) are associated with lower insulin sensitivity (Si) and greater carotid intimal thickness (cIMT), irrespective of glycemic status. Methods: In 155 youth with obesity (14.5±1.4y (mean±SD), 50% female; 42 lean (LC: BMI 25-85%ile), 44 insulin sensitive (OIS, fasting insulin ≤20μM/mL, BMI≥95%ile), 35 insulin resistant (OIR; fasting insulin&gt;20μM/mL, BMI≥95%ile) and 34 with AGT (23 prediabetes, 11 type 2 diabetes) we compared a standard lipid panel and Lp size and number. Linear regressions were used to test the associations between lipids/ NMR-derived Lp with Si index derived from a minimal model during an intravenous glucose test. cIMT was determined by ultrasonography. In a subset of 56 youth (21 LC, 19 OIS, 10 OIR, and 7 AGT) we explored the change in Si with the change in Lp and cIMT after 2 years. Results: OIR and AGT had higher triglycerides and lower HDL compared to LC, P &lt;0.01. Total cholesterol, LDL, and cIMT were comparable among all youth. ApoB, total triglyceride-rich Lp, LDLp and small LDLp) were similar in OIS, OIR, and AbGT and higher compared to LC. Among adolescents with obesity, Si was inversely associated with ApoB (β=-0.016), total LDLp (β=-0.91), small HDLp (β=-0.11) and cIMT (β= -2.99), all P &lt;0.001. There was no effect modification by obesity group. LnSi was associated with total HDL (β=1.30), large HDLp (β= 0.23) and small HDLp (β=-0.11), all P &lt;0.01) with steeper associations between AGT vs OIR and AGT vs OIS. After 2 years, the change in insulin sensitivity was not associated with changes in lipoproteins or cIMT. Conclusions: Among youth with obesity, insulin resistance was associated with atherogenic lipoproteins and cIMT, regardless of glucose tolerance status. Alterations in HDL particle number and size were distinct early manifestations that were observed in youth with AGT compared to their peers.
TMOD-02. GENERATION OF A NOVEL MOUSE MODEL FOR BRAIN TUMORS OF THE DNA METHYLATION CLASS “GBM MYCN”
Authors: Melanie Schoof, Carolin Göbel, Dörthe Holdhof, Sina Al-Kershi, Ulrich Schüller
Journal: Neuro-Oncology (2021)

Abstract DNA methylation based classification of brain tumors has revealed a high heterogeneity between tumors and led to the description of multiple distinct subclasses. The increasing subdivision of tumors can help to understand molecular mechanisms of tumor development and to improve therapy if appropriate model systems for preclinical research are available. Multiple recent publications have described a subgroup of pediatric glioblastoma which is clearly separable from other pediatric and adult glioblastoma in its DNA methylation profile (GBM MYCN). Many cases in this group are driven by MYCN amplifications and harbor TP53 mutations. These tumors almost exclusively occur in children and were further described as highly aggressive with a median overall survival of only 14 months. In order to further investigate the biology and treatment options of these tumors, we generated hGFAP-cre::TP53 Fl/Fl ::lsl-MYCN mice. These mice carry a loss of TP53 and show aberrant MYCN expression in neural precursors of the central nervous system. The animals develop large forebrain tumors within the first 80 days of life with 100 % penetrance. These tumors resemble human GBM MYCN tumors histologically and are sensitive to AURKA and ATR inhibitors in vitro. We believe that further characterization of the model and in vivo treatment studies will pave the way to improve treatment of patients with these highly aggressive tumors.
DDRE-43. SCREENING OF FDA-APPROVED COMPOUNDS FOR THE TREATMENT OF CHORDOMA, WITH IN VIVO VALIDATION USING THREE DIFFERENT XENOGRAFT MODELS, IDENTIFIES BRIGATINIB AS A POTENTIAL TREATMENT
Authors: Philip Tatman, Tadeusz Wroblewski, Anthony Fringuello, Sam Scherer, William Foreman, Denise Damek, Samy Youssef, Kevin Lillehei, David Ormond, Michael Graner
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Chordoma is a rare malignant tumor with poor surgical control and no existing pharmacotherapies. Therefore, these tumors require additional research into novel therapeutics for their treatment. METHODS In this study we created a high-throughput drug screen and culture system to evaluate the efficacy of existing FDA-approved compounds in 10 chordoma cell lines and primary tumors. The cell lines were graciously donated by the Chordoma Foundation. Primary tumors were collected from our operating room. In vivo validation using three separate chordoma xenograft models was also performed through the Chordoma Foundation. One model was a primary clival pediatric tumor, the second was a metastatic sacral tumor, and the third model was a recurrent skull base tumor. RESULTS Using a 127 FDA-approved compound library, we screened 6 donated chordoma cell lines and 4 tumors resected from our institution. 5 of the chordomas were primary, 3 were recurrent, and 2 were metastatic. 6 chordoma were located in the sacrum, three were located in the mobile spine, and one was located in the clivus. Five tumors came from female patients and five came from male patients. After a single 72-hour 1um dose of brigatinib, the average tumor viability in our drug screen was reduced to 81.5% +/-9.5SD (p=1.61x10-13). In the in vivo studies, brigatinib achieved a full response in the metastatic sacral chordoma xenograft model (TGI=100%, p&amp;lt; 0.0001), a partial response in the recurrent skull base xenograft model (TGI=54%, p=0.3048), and no response in the primary clival pediatric xenograft model (TGI = 0%, p &amp;gt;0.9). CONCLUSIONS Brigatinib may be a viable treatment option for recurrent and metastatic chordomas.
Abstract 10605: Artificial Intelligence Effectively Measures Left Atrial Volumes and Function on Multiphasic Cardiac Cta in Patients with Atrial Fibrillation
Authors: Gilberto Aquino, Basel Yacoub, Madison Kocher, Jordan Chamberlin, Ismail Mikdat Kabakus, Selcuk Akkaya, Megan Mercer, Jeffrey Waltz, Matthew Figel, Nathan Leaphart, Athira Jacob, Mehmet A Gulsun, James Gilkes, Joseph Stephenson, Puneet Sharma, Pooyan Sahbaee, Michael E Field, Ali M Agha, Joseph Schoepf, dhiraj baruah, Tilman Emrich, Jeremy R Burt
Journal: Circulation (2021)

Introduction: This study was performed to evaluate a novel AI algorithm for fully automated measurement of LA volumes and function using cardiac CTA in patients with atrial fibrillation (AF). Methods: A prototype AI algorithm (AI-LAV), with a conditional variational auto-encoder architecture, was developed and trained using 555 manually annotated ECG-gated, contrast-enhanced cardiac CTs. A total of 79 patients (mean age 63 ± 12 years; 35 with AF and 44 controls) evaluated between 2017 and 2020 were included in this retrospective study to validate the AI model. Images were analyzed by the trained AI algorithm and experienced radiologists. Left atrial volumes were obtained at cardiac end-systole (LAVmax), end-diastole (LAVmin), and pre-atrial contraction (LAVpc), which were then used to obtain LA function indices (total, passive, and active emptying fractions). Statistical analysis was performed. Results: AI was significantly faster than manual measurement of LA volumes and function (4 s vs 10.8 min, respectively). Agreement between the manual and automated methods was good to excellent overall, and there was stronger agreement in AF patients (all ICCs ≥ 0.877; p&lt;0.001) than controls (all ICCs ≥ 0.799; p&lt;0.001). The AI comparably estimated LA volumes and function in AF patients (all within 1.3 mL and 1.7% of the manual measurement), but overestimated volumes and function by clinically negligible amounts in controls (all by ≤ 4.2 ml and ≤ 3.5%). The AI’s ability to distinguish AF patients from controls using the LA volume index was similar to the experts’ (AUC 0.81 vs 0.82, respectively; p = 0.62). Conclusion: In a validation cohort, the novel AI algorithm efficiently performed fully automated multiphasic CTA-based quantification of left atrial volume and function with similar accuracy to expert manual quantification. Figure. Scatter and Bland-Altman plots for LAVmax and LAVmin. Segmentation comparison between expert (manual) and AI on cardiac CTA.
Abstract 12220: Deep Learning Segmentation and Quantification of Epicardial Adipose Tissue in CT Calcium Score Images
Authors: Ammar Hoori, Tao Hu, Juhwan Lee, Sadeer Al-Kindi, Sanjay Rajagopalan, David Wilson
Journal: Circulation (2021)

Introduction: Studies have linked the epicardial adipose tissue (EAT) volume with the risk of adverse cardiovascular (CV) events, suggesting a role for clinical decision making. Manual quantification of EAT is time-consuming, requires specialized training, and is prone to human error, thus limiting its routine use in clinical practice. Hypothesis: Deep-learning approach can facilitate EAT quantification on archival coronary artery calcium scoring (CAC) scans. Methods: We developed a deep learning semantic segmentation method using the DeepLab-v3 plus network and applied it to gated, non-contrast cardiac CT calcium score scans. Analysts manually identified the enclosing pericardial sac using interactive visualization software. Our algorithm was trained to segment the image region enclosed by the pericardial sac. To keep the sac-increasing curvature, we segmented the heart into two halves. The lower half was analyzed from bottom-to-middle, while the slices in the upper half were analyzed from top-to-middle. Each 2D slice was associated with two consecutive slices, giving a three-slice image slab. A window/level of 350/40 Hounsfield unit (HU) was applied to axial slices providing a uniform HU-attention-window. A median filter with kernel size 3mm was applied to reduce noise. After deep learning semantic segmentation of the enclosing region, we determined EAT using the standard CT fat window [-190, -30] HU. Results: Using 89 CT scans (50 training/39 testing), our algorithm showed excellent results compared to ground-truth manual labeling. The total average Dice score was (88.52%±3.35) with a high correlation against manually derived EAT (R=98.52%, p-value&lt;0.001). The average Dice score per slice was 91.80% (with R=96.62%, p-value&lt;0.001). The average percent EAT volume error was only 5.74%±5.04. Conclusions: Our developed end-to-end deep learning segmentation approach, using HU-attention-window and slab-of-slices gives accurate EAT volume segmentation. Our results provide an important avenue for automated analysis of EAT and its relationship with CV events in large data sets.
Abstract 14365: Interrogating Diastolic Dysfunction Using a Novel Stem Cell Model of Restrictive Cardiomyopathy
Authors: David W Staudt, Ricardo Serrano, Dries Feyen, Mark Mercola
Journal: Circulation (2021)

Introduction: Diastolic dysfunction is an important cause of morbidity and mortality in both children and adults. Unfortunately, investigation of new therapies is limited by a lack of in vitro models of diastolic dysfunction. Idiopathic Restrictive Cardiomyopathy (RCM) is a serious genetic condition in which children have an isolated defect in myocardial relaxation. Though some of the genetic lesions have been identified, there is still an incomplete understanding of the mechanisms that lead to diastolic dysfunction in this condition. Hypothesis: Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) derived from patients with RCM will provide an in vitro model of diastolic dysfunction and will allow elucidation of cellular and molecular pathways involved in myocardial relaxation. Methods: Patients with RCM and a known pathogenic sarcomeric mutation were identified through speaking with providers in our heart failure and cardiac transplant program. hiPSCs were derived from patient blood samples and differentiated into cardiomyocytes. Isogenic controls were generated using CRISPR-mediated homologous directed repair. Calcium handling, contraction kinetics, and resting tension of RCM hiPSC-CMs were compared to control hiPSC-CMs on substrates with defined stiffness using high-throughput quantitative imaging techniques. Results: hiPSC-CMs derived from a patient with a pathogenic mutation in troponin T (TNNT2) display prolonged calcium kinetics and relaxation times compared to controls, as well as increased resting tension. Conclusions: RCM hiPSC-CMs represent a novel model of diastolic dysfunction that can be interrogated on a high-throughput platform. We plan to use these cells to perform proteome-scale functional screens, providing a novel opportunity to discover previously unknown contributors to diastolic dysfunction.
Abstract 13895: Impact of Coronary Revascularization on Cardiopulmonary Performance in Patients With Coronary Chronic Total Occlusion
Authors: Karim Bakry
Journal: Circulation (2021)

Background: —CTO PCI represents the tip of iceberg in interventional cardiology, however owing to lack of enough data, there is still debate about its benefit. CPET combines measurement of gas indices with standard exercise and ECG parameters giving a comprehensive way for patient evaluation also there is plenty of data about its use in many cardiovascular diseases and about its prognostic value in many occasions. So we thought of using CPET in evaluating value of CTO PCI on various CPET parameters. Hypothesis: CTO PCI improves cardiopulmonary performance evaluated by CPET. Methods: fifty nine patients underwent successful CTO PCI and CPET at baseline and at12 month follow up, of whom nine patients had suboptimal results in control angiography which is a higher than usual incidence of re-stenosis, we compared the results of the CPET pre and post-PCI in both groups. Results: In patent group, CPET at follow up revealed a significant increase of peak oxygen consumption (Peak VO 2 ) (13.47±1.53 ml/kg/min vs. 17.84±0.99 ml/kg/min p &lt;0.0001), VO 2 at anaerobic threshold (AT) (11.63 ± 1.14 ml/kg/min vs. 10.35 ±1.01ml/kg/min ( p &lt; 0.0001), peak oxygen pulse ( 16.02 ±1.34 vs. 11.15 ± 1.36, p &lt; 0.0001) and significant increase in peak cardiac index (3.78 ± 0.5 vs. 2.98 ±0.6, p &lt; 0.0001). Also there was significant decrease of Peak VE/VCO 2 (32.98 ± 3.2 vs. 42.98 ± 6.2, p &lt; 0.0001).In patients with re-stenosis, CPET at follow up revealed a significant decrease of peak oxygen consumption (Peak VO 2 ) (13.36±1.48 ml/kg/min vs. 12.41±0.97 ml/kg/min, p =0.02) and a significant increase of Peak VE/VCO 2 (42.73 ± 4.33 vs. 43.27 ± 3.29, p =0.01)also there was worse numerical values of other parameters despite not being statistically significant. Conclusions: CTO revascularization improves cardiopulmonary performance assessed by CPET in addition patients with re-occlusion after successful procedure had worse parameters even than their own baseline. CPET can provide a way for non-invasive follow-up of patients after PCI and earlier detection of in-stent re-stenosis that is more common in CTO.
EPID-20. THE RISING INCIDENCE AND PREVALENCE OF BRAIN TUMOURS: A CANADIAN EPIDEMIOLOGICAL STUDY
Authors: Mathew Voisin, Sanskriti Sasikumar, Alireza Mansouri, Gelareh Zadeh
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Primary malignant brain tumours account for over one third of all brain tumours and are associated with high morbidity and mortality. The purpose of this paper is to estimate the rate and trends of incidence and prevalence for primary malignant CNS tumours in Canada from 1992 to 2017. METHODS An epidemiological study using publicly available data from Statistics Canada: Canadian Cancer Registry (CCR) from 1992 to 2017 for all of Canada was conducted. Incidence and prevalence per 100,000, age-standardized incidence, and age-standardized prevalence per 100,000 person-years of primary malignant CNS tumours were calculated and stratified by sex and age: pediatric (0-19), adult (20-64), and elderly ( &amp;gt;64) populations. RESULTS During the study period, incidence and prevalence increased by 27.3% and 28.8%, respectively. Males accounted for 56% of all diagnoses and experienced decreased survival compared to females one year after diagnosis (p-value = 0.04). Age-standardized rates of incidence and prevalence were highest in elderly populations. CONCLUSIONS Overall, the incidence of primary malignant CNS tumours has increased from 1992 to 2017 with males and the elderly disproportionately affected. Increased healthcare resources and awareness are needed to better identify and deliver evidence-based care for these patients.