tbuckley/cabot-search huggingface dataset:
EXTH-36. BIFUNCTIONAL RNA NANOPARTICLES INDUCE ANTITUMOR IMMUNE RESPONSES AND ALLOW MRI-BASED DETECTION OF DENDRITIC CELL MIGRATION AS A BIOMARKER OF ANTITUMOR IMMUNE RESPONSE
Authors: Adam Grippin, Brandon Wummer, Elias Sayour, Adam Monsalve, Matthew Fillingim, Kyle Dyson, Tyler Wildes, Jon Dobson, Duane Mitchell
Journal: Neuro-Oncology (2018)

Cancer vaccines are a promising approach to personalized cancer immunotherapy, but the lack of meaningful biomarkers of patient response to treatment limits their development. We recently reported in a randomized and blinded pilot clinical trial that RNA-pulsed dendritic cells (DCs) combined with tetanus-diphtheria (Td) booster vaccine prolong progression-free and overall survival in patients with glioblastoma (Mitchell et al, Nature 2015). Furthermore, we demonstrated that DC migration to lymph nodes assessed by SPECT/CT imaging strongly correlates with clinical outcomes. While this finding may provide a novel imaging biomarker for response to DC vaccines, the complexity and regulatory requirements of nuclear medicine-based imaging of radiolabeled cells limits widespread utilization of this technique. We have therefore developed bi-functional RNA-loaded magnetic nanoparticles to load DCs with RNA-encoded antigens, enhance DC migration to lymph nodes, and track migration in vivo using an MRI-based imaging modality. Immune-stimulatorycationic liposomes with iron oxide nanoparticle cores were complexed with mRNA. The resulting iron oxide-loaded RNA-NPs (IO-RNA-NPs) were used to transfect DCs ex vivo in the presence of a magnetic field. IO-RNA-NP-loaded DCs were then injected intradermally into tumor-bearing C57Bl6 mice and tracked noninvasively with T2-weighted 11T MRI. The presence of iron oxide in RNA-NPs did not significantly alter particle characteristics. Additionally, inclusion of iron oxide within RNA-NPs enabled magnetically enhanced transfection through application of external magnetic fields. Compared to RNA electroporation, IO-RNA-NP loading enhanced production of inflammatory cytokines and DC migration to lymph nodes. IO-RNA-NPs also produced a reduction in T2-weighted MRI intensity and an increase in MRI-detected lymph node size that correlated directly with the number of iron oxide loaded DCs in treated lymph nodes, inhibition of tumor growth, and survival in murine tumor models. This data suggests that IO-RNA-NPs enhance DC activation and establish MRI-detected dendritic cell migration as a biomarker of antitumor vaccine response.
TMIC-03. DISSECTING GLIOMA:IMMUNE CELL INTERACTIONS AT THE SINGLE CELL LEVEL
Authors: David Baskin, Joshy George, Krish Karuturi, Kyuson Yun
Journal: Neuro-Oncology (2018)

High grade gliomas such as glioblastomas (GBMs) remain virtually incurable diseases. Recent success with immunotherapies for other solid tumors has demonstrated the power of harnessing one’s own immune system to combat malignant cancers. However, on-going clinical trials using checkpoint inhibitors and other approaches show disappointing results in glioma patients. A major known hurdle for many immune therapies is the highly immune-suppressive glioma microenvironment. There are large numbers of myeloid derived suppressive cells (MDSCs) and tumor associated macrophages (TAMs) that promote glioma growth directly and indirectly by block recruitment and infiltration of anti-tumorigenic immune cells (such as T cells). Another potential challenge is the heterogeneity of glioma:immune interactions that generate nuanced but functionally significant differences in different regions of the same patient tumor. To better understand the microenvironmental heterogeneity and glioma:immune cell interactions in different microenvironments, we analyzed cell:cell communication among GSCs, non-stem glioma cells, MDSCs and TAMs in human GBM tissues at the single cell level. We sampled multiple regions from individual GBM tumors during surgical resection to address spatial heterogeneity in immune infiltration and glioma cell genotypes and phenotypes. We performed single cell RNA-sequencing (scRNA-seq) and exome-sequencing as well as immune phenotyping by flow analyses from each fragment separately. Then, using a novel systems biology tool we recently developed, Cell-to-cell Communication Explorer (C2CCE), we systematically analyzed cell-to-cell communication among glioma cells and immune cells at the single cell level. We observed striking spatial heterogeneity of immune infiltration in some patients. We also observed specific cell:cell communication hierarchy among glioma cells, TAMs, and MDSCs. We are currently working on identifying different communication channels between glioma stem cells and non-stem cells with different immune cell types.
Abstract 16956: The Therapeutic Potential of Human iPS Cell-derived Cardiac Tissue onto a Porcine Myocardial Infarction Model
Authors: Shingo Hirao, Hidetoshi Masumoto, Hiroomi Nishio, Zipeng Li, Hideo Kanemitsu, Koji Ueyama, Kazuhiro Yamazaki, Tadashi Ikeda, Yukihiko Tabata, Jun K Yamashita, Kenji Minatoya
Journal: Circulation (2017)

Introduction: We previously generated human induced pluripotent stem cell (hiPSC)-derived cardiac tissue sheets (CTSs) including cardiomyocytes, endothelial cells and vascular mural cells, which im...
Abstract 16166: Amphiregulin Induces Cardiac Fibrosis and Aggravates Cardiac Dysfunction Post Myocardial Infarction in Mice Partly Through an EGFR-Dependent Mechanism
Authors: Liang Liu, Xian Jin, Cui-Fen Hu, Ya-Ping Zhang, Rong Li, Zhong’e Zhou, Cheng-Xing Shen
Journal: Circulation (2017)

Cardiac fibrosis, a main process leading to ventricular remodeling after myocardial infarction (MI), plays an crucial role in the patheogenesis of heart failure post MI. It is known that amphiregul...
NIMG-32. COMPARISON OF L-METHYL-11C-METHIONINE POSITRON EMISSION TOMOGRAPHY WITH MAGNETIC RESONANCE SPECTROSCOPY IN DETECTING NEWLY DIAGNOSED GLIOMA
Authors: Sied Kebir, Lazaros Lazaridis, Manuel Weber, Cornelius Deuschl, Ann-Kathrin Stoppek, Teresa Schmidt, Judith Boehm, Christoph Moenninghoff, Björn Scheffler, Kathy Keyvani, Daniela Pierscianek, Ulrich Sure, Christoph Kleinschnitz, Ken Herrmann, Martin Glas
Journal: Neuro-Oncology (2018)

Amino acid positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) are at the forefront of non-invasive imaging techniques used for detection and subtyping of glioma-suspicious lesions. No reported studies so far attempted to compare those techniques performed during one single preoperative session in their ability to predict glioma subtypes. Twenty patients with histologically confirmed newly diagnosed glioma underwent preoperative MET PET and MRS during one single diagnostic session. According to the molecular portfolio and histopathological diagnosis, patients were subdivided in isocitrate dehydrogenase (IDH) wildtype glioblastoma (GBM), IDH wildtype grade II/III glioma (IDHW), IDH mutant grade II/III glioma without 1p/19q codeletion (IDHMnc) and with 1p/19q codeletion (IDHMcod). Maximum tumor-to-brain ratio (TBRmax), creatine, choline and N-acetyl aspartate (NAA) peaks were correlated with postoperative histopathological tumor diagnoses. To gain generalizable implications from our data we subdivided the full study cohort into a development and validation subcohort. A support vector machine model was fitted to the development subcohort and evaluated on the validation subcohort. Receiver operating characteristic (ROC) curve with area under the curve (AUC) as metric served to assess model performance. TBRmax was highest in GBM patients (4.18), followed by IDHW patients (3.04). The latter TBRmax values were higher compared to those in IDHMnc patients (1.95) and in IDHMcod patients (2.79). MRS marker distribution showed no clear trend. ROC analysis revealed TBRmax to be the best performing parameter in identifying IDH status (AUC: 0.67) and all spectroscopy markers combined in identifying glioma subgroups (AUC: 0.68). CONCLUSIONS: MET PET and MRS bear limited potential in glioma subgrouping. However, MET PET appears to be slightly superior in differentiating IDH status. Investigation in a larger cohort is required to draw definite conclusions.
EXTH-21. REPURPOSING GLIOBLASTOMA EXOSOMES AS PERSONALIZED MULTI-ANTIGENIC ANTI-TUMOR VACCINE
Authors: Sophie Dusoswa, Sophie Horrevorts, Sjoerd Schetters, Tom Würdinger, Yvette Van Kooyk, Juan Garcia-Vallejo
Journal: Neuro-Oncology (2018)

The composition of glial tumor derived exosomes (TEX) reflects plasma membrane and cytosol-derived proteins of the donor cell. Therefore, TEX form interesting candidates for anti-glioma skin dendritic cell targeted vaccination. Recent literature however, reports potent immune suppressive characteristics of TEX. TEX surface glycosylation may induce C-type lectin receptor triggering and/or cargo internalization thereby modifying the immunogenic/tolerogenic balance of the cellular immune response towards an immune suppressive phenotype. The aim of this study is to investigate whether we can repurpose TEX from immune suppressive vesicles towards immunogenic vehicles for multi-antigenic vaccination by de novo glycosylation of their surface. To this end, the surface glycosylation of TEX was carefully characterized by ELISA and electron microscopy. TEX uptake and downstream routing was assessed by imaging flow cytometry analysis. Our GBM-derived TEX were 50–200 nm in size and expressed high levels of CD63. The surface glycan profile of U251, U87, and GBM8-derived TEX was dominated by α-2,3 and α-2,6 sialic acid-capped N-glycans, high mannose glycans and truncated Tn-bearing O-glycans. These TEX appeared to have low affinity for DC-SIGN and MGL, but showed significant binding to Siglec-7 and Siglec-9. We developed a chemo-enzymatic glycan-modificantion protocol with the aim to replace Siglec ligands for DC-SIGN ligands in order to target them to skin resident dendritic cells for cross-presentation. Glycan-modified TEX, which had been introduced with a high affinity ligand for DC-SIGN, were efficiently taken up by human dendritic cells and fused with the endosomal pathway. In conclusion, repurposing glioma-derived TEX through de novo glycan-modification could provide a strategy for multi-antigenic anti-glioma vaccination.
Comprehensive plasma and tissue profiling reveals systemic metabolic alterations in cardiac hypertrophy and failure
Authors: Oliver J Müller, Markus B Heckmann, Lin Ding, Kleopatra Rapti, Ashraf Y Rangrez, Thomas Gerken, Nicole Christiansen, Ulrike E E Rennefahrt, Henning Witt, Sandra González Maldonado, Philipp Ternes, Dominic M Schwab, Theresa Ruf, Susanne Hille, Anca Remes, Andreas Jungmann, Tanja M Weis, Julia S Kreußer, Hermann-Josef Gröne, Johannes Backs, Philipp Schatz, Hugo A Katus, Norbert Frey
Journal: Cardiovascular Research (2018)

Heart failure is characterized by structural and metabolic cardiac remodelling. The aim of the present study is to expand our understanding of the complex metabolic alterations in the transition from pathological hypertrophy to heart failure and exploit the results from a translational perspective.Mice were subjected to transverse aortic constriction (TAC) or sham surgery and sacrificed 2 weeks, 4 weeks, or 6 weeks after the procedure. Samples from plasma, liver, skeletal muscle, and heart were collected and analysed using metabolomics. Cardiac samples were also analysed by transcriptional profiling. Progressive alterations of key cardiac metabolic pathways and gene expression patterns indicated impaired mitochondrial function and a metabolic switch during transition to heart failure. Similar to the heart, liver, and skeletal muscle revealed significant metabolic alterations such as depletion of essential fatty acids and glycerolipids in late stages of heart failure. Circulating metabolites, particularly fatty acids, reflected cardiac metabolic defects, and deteriorating heart function. For example, inverse correlation was found between plasma and the heart levels of triacylglycerol (C18:1, C18:2, C18:3), and sphingomyelin (d18:1, C23:0) already at an early stage of heart failure. Interestingly, combining metabolic and transcriptional data from cardiac tissue revealed that decreased carnitine shuttling and transportation preceded mitochondrial dysfunction. We, thus, studied the therapeutic potential of OCTN2 (Organic Cation/Carnitine Transporter 2), an important factor for carnitine transportation. Cardiac overexpression of OCTN2 using an adeno-associated viral vector significantly improved ejection fraction and reduced interstitial fibrosis in mice subjected to TAC.Comprehensive plasma and tissue profiling reveals systemic metabolic alterations in heart failure, which can be used for identification of novel biomarkers and potential therapeutic targets.
Abstract 11776: Relative Merits of Ejection Fraction and Strain by 2D Echo, 3D Echo and Cardiac Magnetic Resonance Imaging for Image-Based Recognition of Heart Failure
Authors: Samir K Saha, Rena S Toole, Anatoli Kiotsekoglou, Jie J Cao, Nathaniel Reichek, Aasha Gopal
Journal: Circulation (2014)

Introduction: Echo and cardiac magnetic resonance imaging (CMR) are often used in evaluation of patients with heart failure (HF) whether associated with systolic dysfunction or preserved ejection fraction (EF). We evaluated the relative merits of EF (by CMR and 2D echo) versus echo strain (by 2D and 3D speckle tracking echo STE) for imaged-based recognition of patients with HF. Methods: 117 subjects (81 normals and 36 HF) were evaluated. There were no significant differences in age or gender between normals (59+/-14 yrs, 39 M) and HF (54+/-14 yrs, 29 M). 2D biplane echo and CMR provided EF while 2D and 3DSTE yielded global longitudinal (GLS %) and circumferential (GCS%) strains. Since 3DSTE was optimized for strain rather than EF, 3DEF was not evaluated. HF diagnosis was based on dyspnea, plasma N-terminal pro-B type brain natriuretic peptide and EF. Results: As expected, mean EF and strains differed between normals and HF (table). Using a backward elimination regression model, only 2DEF, CMREF, 2DGCS% and 3DGLS% were retained for further analysis. ROC-guided criterion values (for HF recognition) for 2DEF, CMREF, 2DGCS% and 3DGLS% were &gt;52%, &gt;50%, &gt;-22% and &gt;-16%, respectively. Using these values, the sensitivity, specificity, and odd-ratios for HF recognition with each parameter were computed (table). Conclusions: CMREF provided the highest sensitivity and specificity for HF recognition. The most sensitive echo measure was 3DGLS% while the most specific echo measure was 2DEF. However, in a mixed population of normals and HF, whether associated with systolic dysfunction or preserved EF, 2DGCS% and 3DGLS% had the highest odds ratios.
Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas
Authors: Marthe M. de Jonge, Aurélie Auguste, Lise M. van Wijk, Philip C. Schouten, Matty Meijers, Natalja T. ter Haar, Vincent T.H.B.M. Smit, Remi A. Nout, Mark A. Glaire, David N. Church, Harry Vrieling, Bastien Job, Yannick Boursin, Cor D. de Kroon, Etienne Rouleau, Alexandra Leary, Maaike P.G. Vreeswijk, Tjalling Bosse
Journal: Clinical Cancer Research (2018)

The elevated levels of somatic copy-number alterations (SCNAs) in a subset of high-risk endometrial cancers are suggestive of defects in pathways governing genome integrity. We sought to assess the prevalence of homologous recombination deficiency (HRD) in endometrial cancers and its association with histopathologic and molecular characteristics.
Ten awards, 1575 nominations, 436 semi-finalists: BMJ’s search for the stars of South Asian healthcare continues
Authors: Jeetha D’Silva
Journal: BMJ (2018)

More entries to BMJ’s annual search for outstanding contributors to clinical care in South Asia have been shortlisted than ever before, discovers <b>Jeetha D’Silva</b>. Winners will be announced at Chennai’s Hilton Hotel on 1 December
Which Patients with Clinically Node-positive Prostate Cancer Should Be Considered for Radical Prostatectomy as Part of Multimodal Treatment? The Impact of Nodal Burden on Long-term Outcomes
Authors: Giorgio Gandaglia, Matteo Soligo, Antonino Battaglia, Tim Muilwijk, Daniele Robesti, Elio Mazzone, Francesco Barletta, Nicola Fossati, Marco Moschini, Marco Bandini, Steven Joniau, R. Jeffrey Karnes, Francesco Montorsi, Alberto Briganti
Journal: European Urology (2018)
Intestinal Immune Dysregulation Driven by Dysbiosis Promotes Barrier Disruption and Bacterial Translocation in Rats With Cirrhosis
Authors: Leticia Muñoz, María‐José Borrero, María Úbeda, Elisa Conde, Rosa del Campo, Macarena Rodríguez‐Serrano, Margaret Lario, Ana‐María Sánchez‐Díaz, Oscar Pastor, David Díaz, Laura García‐Bermejo, Jorge Monserrat, Melchor Álvarez‐Mon, Agustín Albillos
Journal: Hepatology (2018)

In cirrhosis, intestinal dysbiosis, intestinal barrier impairment, and systemic immune system abnormalities lead to gut bacterial translocation (GBT) and bacterial infection. However, intestinal immune system dysfunction and its contribution to barrier damage are poorly understood. This study correlates immune system dysregulation in the intestines of rats at different stages of CCl 4 ‐induced cirrhosis with barrier function and pathogenic microbiota. The following variables were addressed in the small intestine: intraepithelial lymphocyte (IEL) and lamina propria lymphocyte (LPL) activation status and cytokine production (flow cytometry), cytokine mRNA and protein expression (quantitative real‐time PCR and immunofluorescence), microbiota composition of ileum content (16S recombinant DNA massive sequencing), permeability (fecal albumin loss), and epithelial junctions (immunohistochemistry and immunofluorescence). The intestinal mucosa in rats with cirrhosis showed a proinflammatory pattern of immune dysregulation in IELs and LPLs, which featured the expansion of activated lymphocytes, switch to a T helper 1 (Th1) regulatory pattern, and Th17 reduction. In rats with cirrhosis with ascites, this state was associated with epithelial junction protein disruption, fecal albumin loss, and GBT. Direct correlations ( P &lt; 0.01) were observed between elevated interferon gamma (IFNγ)‐expressing T cytotoxic LPLs and fecal albumin and between inflammatory taxa abundance and IFNγ‐producing immune cells in the ileum. Bowel decontamination led to redistributed microbiota composition, reduced proinflammatory activation of mucosal immune cells, normalized fecal albumin levels, and diminished GBT; but there were no modifications in Th17 depletion. Conclusion : The intestinal mucosa of rats with cirrhosis acquires a proinflammatory profile of immune dysregulation that parallels the severity of cirrhosis; this impaired intestinal immune response is driven by gut dysbiosis and leads to disrupted barrier function, promoting GBT.
NCMP-26. STROKE-LIKE MIGRAINE ATTACKS AFTER RADIATION THERAPY SYNDROME IN CHILDREN WITH CANCER
Authors: Qurratulain Ahmed, Zsila Sadighi, John Lucas, Raja Khan
Journal: Neuro-Oncology (2018)

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is an infrequently described symptom complex of transient neurologic deficits, headache and abnormal cortical contrast enhancement on brain MRI. Pathophysiology is unclear, but exposure to cranial radiation (RT) is a sine qua non. We completed a single institution retrospective case series composed of five children with a diagnosis of cancer, history of cranial RT, and episodes of transient neurologic deficits. Five children (2 males, 3 females) fulfilled diagnostic criteria. Tumors were in the posterior fossa (3 medulloblastoma, 1 atypical teratoid rhabdoid tumor) and temporal lobe (1 pleomorphic xanthoastrocytoma). Median age at diagnosis was 9.4 years (range 5.1–14.7). All patients had complete resection, followed by adjuvant 54 Gy focal RT (N=1) or 36 Gy CSI followed by a cone-down to 54 Gy (N=4), and chemotherapy. Median body mass index was 17.1 (range 14 to 30). Median time from the end of RT to first transient neurologic deficit was one year (range 0.7–12.1). Presenting symptoms included gradual development of unilateral weakness (N=4), non-fluent dysphasia (N=1), somnolence (N=1), and headaches (N=3). Neurologic deficits resolved within 30 minutes to 10 days. Transient cortical enhancement was confirmed on MRI in two patients, two had a normal brain MRI, and one had no MRI obtained. Two children had a single and three had multiple episodes over the next few months. Topiramate was successfully used in one and failed along with levetiracetam in another. Two children with protracted symptoms responded to high dose intravenous methyl prednisone for three days followed by 2 weeks of oral taper. Symptoms ultimately resolved in all patients. SMART syndrome is a rare disorder characterized by slow development of neurologic deficits with variable occurrence of abnormal cortical contrast enhancement. The use of anti-epileptics and/or steroids may improve symptoms and speed resolution.
INNV-11. THE HONOR PROJECT: A NEURO-ONCOLOGY TEAM ADDRESSES GRIEF
Authors: Rosemary Rossi, Margaretta Page, Marielle Woodall, Karishma Kumar, Tiffany Jones, Susan Chang
Journal: Neuro-Oncology (2018)

Neuro-oncology team members connect with patients through direct patient care, correspondence and the electronic medical record. Hence, relationships develop between patients and various team members. The prognosis for patients diagnosed with a malignant glioma remains grim. Consequently, team members have constant exposure to death. When a patient dies, team members experience loss but often have no formal opportunity to grieve. Rachel Naomi Remen, MD notes “We burn out, not because we don’t care, but because we don’t grieve...because we have allowed our hearts to become so filled with loss that we have no room left to care.” Grief is unavoidable and may affect job satisfaction and productivity if left unaddressed. METHOD: The Honor Project was designed as a meaning-centered team intervention to give voice to grief through ritual. An “altar” is mounted in a staff-only area. When notified of a death, the team member is invited to pause and mindfully write the name on a card and place it on the altar. The team gathers monthly to read the names aloud and share stories, poems, meditations, tears and laughter. Chocolate is gifted to “ease the bitterness of death and remind us of the sweetness of life.” The team listens to a closing song as they take rest before returning to work. Team members were surveyed after six months. 100% of respondents reported being better able to cope with sadness related to patients’ deaths and feeling less alone in their own grief. The Honor Project provided a meaningful experience at work for 100% of respondents who said it made a difference knowing management allows time during work to give voice to their grief. Identifying work-related loss normalizes grief, enhances coping, helps team members honor their own feelings of loss and creates a supportive work community.
Evolving changes in M-protein and hemoglobin as predictors for progression of smoldering multiple myeloma
Authors: Shebli Atrash, Myra Robinson, Daniel Slaughter, Amanda Aneralla, Taylor Brown, Jordan Robinson, Ami Ndiaye, Chelsea Sprouse, Qing Zhang, James T. Symanowski, Reed Friend, Peter M. Voorhees, Saad Z. Usmani, Manisha Bhutani
Journal: Blood Cancer Journal (2018)