tbuckley/cabot-search huggingface dataset:
ANGI-16. EARLY DETECTION OF TUMOR CELL PROLIFERATION IS ASSOCIATED WITH A UNIQUE RADIOMIC BIOMARKER IN PRECLINICAL GLIOBLASTOMA XENOGRAFT AND PATIENTS
Authors: Islam Hassan, Sanjay Singh, Jennifer Mosley, Nabil Elshafeey, Aikaterini Kotrotsou, Frederick Lang, Pascal Zinn, Rivka Colen
Journal: Neuro-Oncology (2018)

PURPOSE: The mainstay imaging technique in brain tumor is Magnetic resonance imaging (MRI). However, early detection of tumor cell proliferation using MRI is limited due to inapparent disruption of normal brain architecture. Radiomics and machine learning techniques can quantitate thousands of imaging features that can depict neoplastic changes in apparently normal brain. Herein, we investigate the potential role radiomics can play in early detection of tumor cell proliferation in apparently normal MRI using a preclinically trained radiomic. Two glioblastoma stem-like cell lines were transformed to stably express luciferase under a constitutive promoter. A stereotactic injection of tumor cells was performed to generate orthotopic mouse models (N=48). Tumor cell engraftment and in-vivo proliferation were assessed using bio-luminescence imaging (BLI) along with a weekly MRI (Bruker 7T). Images were analyzed, and ROIs were placed using 3D slicer software and radiomic features were extracted using Matlab. ROIs (0.75 mm) were placed on tumor injection sites and normal appearing contralateral brain. Radiomic features were compared for their significant alterations over time using comparative marker selection (CMS). Genomics and Histopathology of tumors were performed ex-vivo. Validation was performed in a cohort of brain cancer patients. Three stages of post-implantation tumor cell presence and proliferation were identified: 1. Immediate post implantation lag/engraftment phase. 2. Linear cellular proliferation phase (normal on conventional MRI). 3. Exponential cellular proliferation phase (apparent tumor on conventional MRI). Our data showed that 43% of extracted radiomic features were significantly changing (P Conclusion: Radiomic texture analysis and machine learning detects tumor cell presence and proliferation in normal-appearing brain prior to tumor development on conventional imaging. CLINICAL RELEVANCE: Radiomics and machine learning algorithms are predictive of tumor presence in seemingly normal MRIs. Early detection of tumors can allow earlier intervention, more extensive radiation planning and appropriately dose chemotherapeutic regimens.
QOLP-28. FEAR OF DYING IN ADULT PRIMARY BRAIN TUMOR PATIENTS: AGE AND GENDER EFFECTS
Authors: Ashlee Loughan, Audrey Villanueva, Sarah Braun, Roxanne Sholevar
Journal: Neuro-Oncology (2018)

Given the lack of curative treatment options, brain tumor patients may have increased vulnerability to death anxiety, yet the literature to date remains sparse. Two consistent findings associated with death anxiety are age and gender effects, with younger adult women reporting higher rates. Furthermore, death anxiety is often underreported and therefore goes untreated, which can negatively impact quality of life and functioning. The purpose of the present study was to address these gaps in the literature by preliminarily investigating prevalence of and associations with death anxiety in brain tumor patients. Eighty-six (51% male, age range 19–81 years) patients diagnosed with primary brain tumors (PBT; grades I-IV) participated in routine neuropsychological evaluations including emotional questionnaires. A single-item question from the Beck Anxiety Inventory (BAI) assessed fear of dying. Descriptive analyses, t-tests, and Pearson correlations were conducted to explore age and gender effects on patients’ fear of death. Thirty percent (n=26) of patients reported fear of dying at the time of evaluation. Women endorsed higher fear severity than men (0.71 vs 0.33; p = .048). There was no relationship between fear severity and age. However, when examining the two effects together, there was a significant difference between men and women aged 30–39 years (0.00 vs. 1.17; p = .035). All descriptive statistics, comparisons, and relationships will be presented. CONCLUSIONS: Results suggest that a significant portion of PBT patients experience a fear of death, and this appears to be more severe in female compared to male patients. Age did not have an independent effect, but young women reported increased fear of death when compared to young men. These results support literature on death anxiety in other populations. Findings could inform intervention development. Importantly, future research should focus on methods to improve early identification of death anxiety in PBT.
Abstract 15211: Circulating FABP4 Concentration Predicts the Progression of Carotid Atherosclerosis in a General Population Without Medication
Authors: Masato Furuhashi, Satoshi Yuda, Atsuko Muranaka, Mina Kawamukai, Megumi Matsumoto, Marenao Tanaka, Norihito Moniwa, Hirofumi Ohnishi, Shigeyuki Saitoh, Kazuaki Shimamoto, Tetsuji Miura
Journal: Circulation (2017)

Introduction: Fatty acid-binding protein 4 (FABP4) is expressed in both adipocytes and macrophages, and adipocytes secrete FABP4. Recent studies have shown significant roles of FABP4 in the development of insulin resistance and atherosclerosis. Hypothesis: Serum FABP4 level predicts the progression of carotid atherosclerosis. Methods: Subjects who participated in the Tanno-Sobetsu Study, a study with a prospective population-based cohort design, in the year 2010 and/or 2013 were enrolled, and subjects on medications were excluded. Serum FABP4 concentration was measured using a commercially available enzyme-linked immunosorbent assay kit. Carotid intima-media thickness (CIMT) was assessed using carotid ultrasonography. Results: In total of 281 subjects (male/female: 109/172), CIMT was significantly correlated with age, adiposity, blood pressure, renal dysfunction and levels of cholesterol, triglycerides, fasting glucose, HbA1c and FABP4 (r = 0.331, P < 0.001). Multiple regression analysis demonstrated that...
TMOD-35. CAN RARE SOX9-POSITIVE CELLS INCITE MYC-DRIVEN MEDULLOBLASTOMA RECURRENCE?
Authors: Sara Bolin, Vasil Savov, Anna Borgenvik, Alexandra Garancher, Gabriela Rosén, Aldwin Rahmanto, Sonja Hutter, Jessica Rusert, Livia Garzia, Grammatiki Fotaki, Rebecca M Hill, Adrian M Dubuc, Marc Remke, Matko aner, Vijay Ramaswamy, Steve Clifford, Olle Sangfelt, Ulrich Schüller, Michael Taylor, Robert Wechsler-Reya, Holger Weishaupt, Fredrik Swartling
Journal: Neuro-Oncology (2018)

Tumor recurrence is the main cause of death among children with medulloblastoma, the most frequent type of malignant pediatric brain tumors. The medulloblastoma subgroup Group 3 has the poorest survival of all four subgroups, and is associated with a high rate of tumor recurrence in children. Mechanisms behind medulloblastoma recurrence are not yet well understood. We found that the transcription factor SOX9 marks quiescent brain tumor stem cells and is suppressed by MYC overexpression in aggressive Group 3 tumors. By using our inducible Tet-OFF transgenic (GTML) mouse model for malignant MYCN-driven Group 3 tumors and human Group 3 MYC-driven patient-derived xenograft (PDX) models we identified rare SOX9-positive, slow-cycling brain tumor cells that are more resistant to standard chemotherapy. Dox treatment normally cures GTML transgenic animals that developed aggressive medulloblastoma by turning MYCN off. However, when crossing the Tet-OFF GTML model with a Tet-ON rtTA-Sox9 model we can redirect MYCN expression to the control of the Sox9 promoter - ultimately driving brain tumor recurrence from rare SOX9-positive cells with 100% penetrance. These recurrent tumors were actively disseminating from the hindbrain into the forebrain. Expression profiling shows that recurring tumors have increased levels of SOX9, are more inflammatory and have elevated levels of MGMT methyltransferase, compared to the primary tumors. Overexpressing SOX9 into Group 3 MB cells directly inhibited MYC, and decreased cell proliferation while promoting metastasis. Paired primary and recurrent human Group 3 and Group 4 tumor biopsies also showed significantly higher levels of SOX9 at recurrence. PDX models of Group 3 tumors further showed increased levels of SOX9 positivity in metastatic compartments. Our data unveils complex mechanisms by which dormant medulloblastoma cells fail to respond to standard therapy and generate tumor relapses.
Signaling Events Downstream of AHR Activation That Contribute to Toxic Responses: The Functional Role of an AHR-Dependent Long Noncoding RNA ( <i>slincR</i> ) Using the Zebrafish Model
Authors: Gloria R. Garcia, Prarthana Shankar, Cheryl L. Dunham, Abraham Garcia, Jane K. La Du, Lisa Truong, Susan C. Tilton, Robert L. Tanguay
Journal: Environmental Health Perspectives (2018)

A structurally diverse group of chemicals, including dioxins [e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)] and polycyclic aromatic hydrocarbons (PAHs), can xenobiotically activate the aryl hydrocarbon receptor (AHR) and contribute to adverse health effects in humans and wildlife. In the zebrafish model, repression of sox9b has a causal role in several AHR-mediated toxic responses, including craniofacial cartilage malformations; however, the mechanism of sox9b repression remains unknown. We previously identified a long noncoding RNA, sox9b long intergenic noncoding RNA (slincR), which is increased (in an AHR-dependent manner) by multiple AHR ligands and is required for the AHR-activated repression of sox9b.Using the zebrafish model, we aimed to enhance our understanding of the signaling events downstream of AHR activation that contribute to toxic responses by identifying: a) whether slincR is enriched on the sox9b locus, b) slincR's functional contributions to TCDD-induced toxicity, c) PAHs that increase slincR expression, and d) mammalian orthologs of slincR.We used capture hybridization analysis of RNA targets (CHART), qRT-PCR, RNA sequencing, morphometric analysis of cartilage structures, and hemorrhaging screens.The slincR transcript was enriched at the 5' untranslated region (UTR) of the sox9b locus. Transcriptome profiling and human ortholog analyses identified processes related to skeletal and cartilage development unique to TCDD-exposed controls, and angiogenesis and vasculature development unique to TCDD-exposed zebrafish that were injected with a splice-blocking morpholino targeting slincR. In comparison to TCDD exposed control morphants, slincR morphants exposed to TCDD resulted in abnormal cartilage structures and a smaller percentage of animals displaying the hemorrhaging phenotype. In addition, slincR expression was significantly increased in six out of the sixteen PAHs we screened.Our study establishes that in zebrafish, slincR is recruited to the sox9b 5' UTR to repress transcription, can regulate cartilage development, has a causal role in the TCDD-induced hemorrhaging phenotype, and is up-regulated by multiple environmentally relevant PAHs. These findings have important implications for understanding the ligand-specific mechanisms of AHR-mediated toxicity. https://doi.org/10.1289/EHP3281.
Abstract 11571: Beneficial Effect of Early Infusion of Landiolol; A Very Short Acting Beta1 Adrenergic Receptor Blocker, on Reperfusion Status in Acute Myocardial Infarction
Authors: Masayoshi Kiyokuni, Tabito Kino, Minako Kagimoto, Nao Yamada, Kiwamu Iwata, Naoki Nakayama, Keiko Takano, Naohiro Komura, Manabu Nitta, Teruyasu Sugano, Tsutomu Endo, Tomoaki Ishigami, Toshiyuki Ishikawa, Kazuo Kimura
Journal: Circulation (2016)

Introduction: Landiolol is the beta-1 selective receptor blocker and its half-life elimination is 4 minutes. The safety and efficacy of landiolol started before coronary reperfusion in patients with ST-segment elevation acute myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) remains unclear. We assessed the hypothesis that very early use of landiolol promotes optimal reperfusion without increasing adverse events for those patients. Methods: We conducted a prospective, single-group trial of landiolol during the pPCI for a STEMI. Landiolol was started intravenously just before the pPCI with 3 μg/kg/min. The reperfusion status and clinical outcomes in 55 treated patients were compared with those in 60 historical control patients treated without landiolol. The optimal reperfusion was assessed by an ST-segment resolution (STR), coronary flow, myocardial brush grade (MBG) and peak creatine kinase (CK) after reperfusion. Result: Time from admission to starting landiolol was 35±23min in landiolol group. Age, sex, coronary risk factors, culprit lesion, SYNTAX score and reperfusion time did not differ between landiolol group and control group (all NS). Those in the landiolol group achieved a higher rate of an STR (64% vs. 42%, p =0.023) and MBG 2/3 (64% vs. 45%, p =0.045), whereas coronary flow and peak CK were comparable between the two groups. A multivariate analysis showed that landiolol use was an independent predictor of an STR (OR 2.99, 95% CI 1.25-7.16, p =0.014). The incidence of non-sustained ventricular tachycardia (27% vs. 50%, p =0.014), hypotension (15% vs. 32%, p =0.046) and progression to Killip class grade III or IV (0% vs. 10%, p =0.028) during admission were lower in the landiolol group. Within 12 months after the admission, the rate of worsening heart failure (0vs7%, p=0.07) tended to be lower in landiolol group. Left ventricular ejection fraction and end-diastolic volume index in 12 months after the admission did not differ between the two groups (landiolol group vs control group: 59±11%vs56±15%, p=0.23; 60±14vs63±30ml/m 2 , p=0.62). Conclusion: In patients with STEMI, intra-procedural landiolol in pPCI may attenuate myocardial reperfusion injury and reduce adverse events.
Abstract 19600: Patients With Cardiovascular Risk Factors Were More Likely to Have Lower Life Satisfaction
Authors: Michèle Baumann, Anastase Tchicaya
Journal: Circulation (2015)

Introduction: Five years after coronary angiography, life satisfaction (LS) among patients may be related to incidents of cardiovascular diseases, risk factors and unhealthy behaviours and socioeconomic conditions but their respective influence remains unclear. Our aim is to analyze LS and its relationships with those factors. Methods: Among the 4,391 patients initially contacted, 547 deaths were reported and 209 had an invalid address. 3,635 patients who underwent coronary angiography in 2008-2009 at the National Institute of Cardiac Surgery and Cardiological Intervention (INCCI) in Luxembourg completed a self-questionnaire assessing LS [1-10] and other covariates. Data were analysed via multiple regression models adjusted initially on age, sex and income, and for a second time with the addition of all CVRF. Results: LS of 1,289 volunteers (69.2 years) was 7.3/10. Most were men, Luxembourgish, employees and manual workers, had secondary education and an income of 36,000 euros or more per year. LS was lowest in female patients, those with a low to middle income. Patients who live in couple had the best LS. Patients with a history in the previous 5 years of physical inactivity (regression coefficient: - 0.903), angina pectoris (rc -0.843), obesity (rc -0.512), diabetes, or hypercholesterolemia, were more likely to have lower LS. The previous associations were mostly maintained on the second analysis, with the exceptions of diabetes and obesity. In addition, patients who stopped smoking because of peer pressure (rc -0.011) had a lower LS. Conclusions: Profiles of patients are linked with least LS: ‘inclined abstainers’ who intended to modify their behaviours, but could not do it, and ‘disinclined abstainers’ who had no intention of changing and were insufficiently concerned to do so. Patients who stopped smoking and perceived it as unpleasant also had the lowest LS. ‘Declined actors’ were those patients who had to adjust their lifestyles, but were ambivalent about their intentions and the behaviour, which they continued. Health promotion programs would benefit from targeting factors that moderate the unfavourable intention-behaviour relationship and can help enhance LS.
EXTH-26. MOLECULAR DETERMINANT OF CLINICAL RESPONSE TO ONC201, AN INHIBITOR OF DOPAMINE RECEPTOR 2 (DRD2) SIGNALING, IN GLIOBLASTOMA PATIENT
Authors: Jie Li, Jun Ma, Yuyu He, Varun Vijay Prabhu, Joshua Allen, Clark Chen
Journal: Neuro-Oncology (2018)

ONC201 is a highly selective antagonist of dopamine receptor D2 (DRD2) that is in phase II clinical trial as treatment for recurrent glioblastoma. Here we examine the molecular determinants of therapeutic response that are associated with long-term survivors. Immuno-histochemical (IHC) analysis/pathway-based transcriptomal analysis of clinical glioblastoma specimens, in vitro- and in vivo-studies of dopamine antagonist inhibition, analysis of glioblastoma specimens in patients treated with the dopamine receptor antagonist, ONC201. In IHC of clinical glioblastoma samples, we found that the expression of dopamine receptor 2 (DRD2) coincides with EGFR over-expression in mesenchymal and classical glioblastomas. In contrast, DRD2 over-expression was found in proneural and neural glioblastomas in the absence EGFR over-expression. These patterns of expression were recapitulated in The Cancer Genome Atlas (TCGA) as well patient derived glioblastoma (PDX) lines. In vitro and in vivo, mesenchymal glioblastoma PDX lines with high expression of EGFR and DRD2 were refractory to DRD2 or EGFR inhibition; simultaneous EGFR and DRD2 inhibition were required to arrest the growth of these mesenchymal glioblastomas. In contrast, proneural glioblastoma lines with high DRD2 expression (and low EGFR expression) were exquisitely sensitive to dopamine antagonists in vitro and in vivo (in subcutaneous and intracranial models). Importantly, proneural glioblastoma lines with high DRD2 expression secrete high levels of dopamine, creating autocrine mitogenic signaling that drive glioblastoma growth. In clinical samples derived from a Phase 2 clinical trial where recurrent glioblastoma patients were treated with the DRD2 antagonist, ONC201, long-terms survival (>2 years survival after glioblastoma recurrence) was observed only in patients afflicted with glioblastomas characterized by low EGFR and high DRD2 expression. Our data suggest that DRD2 signaling is essential in glioblastomas that are not mitogenically driven by EGFR signaling. These tumors appear exquisitely sensitive to ONC201 mediated DRD2 inhibition.
Retrograde single-balloon enteroscopy for the removal of a mollusc shell retained in the ileum of a patient with active Crohn’s disease
Authors: Helena Martínez Lozano, Oscar Nogales Rincon, Cristina Navarrete Marín, Andres Conthe Alonso, Javier García Lledó, Luis Menchén Viso, Ignacio Marín-Jiménez
Journal: Endoscopy (2018)

A 33-year-old man with ileal Crohn's disease (Montreal classification A2, L1, B1) under adalimumab therapy presented to the emergency room with mesogastric abdominal pain, diarrhea, and vomiting during the previous 4 weeks. Physical examination showed no abdominal masses or peritoneal signs. Initial blood tests demonstrated leukocytosis and an increase of C-reactive protein. Abdominal computed tomography (CT) revealed a long segment of distal ileum, containing inflammatory stricturing disease and a radiopaque calcium-density foreign body, compatible with a mollusc shell ([Fig. 1]).
EXTH-31. TARGETING THE FORMIN-DIRECTED CYTOSKELETON WITH SMALL MOLECULE AGONISTS BLOCKS GLIOBLASTOMA PATIENT-DERIVED NEUROSPHERE INVASION
Authors: Kathryn Eisenmann, Jason Schroeder, Krista Pettee, Kathryn Becker, Christine Sattler
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults and aggressive treatment only extends survival by months. While metastasis outside the CNS is rare, GBM is highly invasive. Failure of current GBM therapies to target invasive cells partly explains why these treatments confer only minimal survival advantages: invasive tumors lack easily-defined margins, making complete surgical resection impossible, and invasive GBM cells are inherently more chemo- and radioresistant. Therefore, anti-invasive therapies may effectively sensitize GBM cells to conventional therapies and improve survival. Anti-invasive treatments are thus greatly needed, and cellular mechanisms governing GBM invasion represent understudied therapeutic targets. Much work has centered upon how Rho GTPases mediate GBM invasion, yet the roles of downstream Rho effector proteins are poorly understood and represent potential novel therapeutic targets. A role for the mammalian Diaphanous (mDia)-related formin family of Rho GTPase effector proteins has emerged in metastatic disease. mDias are nanomachines generating linear actin filaments to drive protrusive cytoskeletal structures underlying tumor cell invasion. Using novel small molecule mDia agonists (IMMs, orn intramimics) that induce endogenous mDia functional activities, including F-actin polymerization, we demonstrated roles for mDia in driving polarized GBM cell migration. mDia agonism halted GBM spheroid invasion in three-dimensional (3D) in vitro and ex vivo rat brain slice models. Here, we evaluate if GBM patient cell lines are sensitive to formin agonism to halt invasion. Four patient-derived GBM cell lines were isolated as single cell suspensions, and spontaneously formed non-adherent neurospheres. Neurospheres were embedded in 3D-matrices and allowed to invade +/- IMMs. IMMs dramatically inhibited GBM patient neurosphere invasion, significantly impacting both distance single cells migrated from neurosphere edges and lengths of actin-enriched cellular extensions into matrices. Thus, mDia agonism effectively disrupted multiple aspects of patient-derived GBM neurosphere invasion in vitro, warranting further investigation in patient-derived xenografts.