tbuckley/cabot-search huggingface dataset:
ACTR-27. PHASE 2 STUDY OF DIANHYDROGALACTITOL (VAL-083) IN PATIENTS WITH MGMT-UNMETHYLATED, BEVACIZUMAB-NAÏVE RECURRENT GLIOBLASTOMA
Authors: Barbara O’Brien, John de Groot, Carlos Kamiya-Matsuoka, Shiao-Pei Weathers, Jeffrey Bacha, Dennis Brown, Anne Steino, John Langlands, Richard Schwartz, Sarath Kanekal, Lorena Lopez, Marta Penas-Prado
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) and maintenance TMZ. Almost all GBM patients experience recurrent/progressive disease, and median survival after recurrence is 3–9 months. Effective therapies for recurrent GBM (rGBM) are lacking, representing a significant unmet medical need. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with a poor prognosis. Second-line treatment with the anti-angiogenic agent bevacizumab (BEV) has not improved survival, and 5-year survival is less than 3%. VAL-083 is a bi-functional DNA-targeting agent rapidly inducing interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083s cytotoxicity is independent of MGMT status, and VAL-083 overcomes TMZ-resistance in GBM cell lines, GBM cancer stem cells, and in vivo GBM models. We completed a 3 + 3 dose-escalation trial of VAL-083 in TMZ- and BEV-refractory rGBM. 40mg/m2/day given on days 1,2,3 of a 21-day cycle was generally well-tolerated, and this dose was selected for further clinical evaluation in Phase 2 trials. The trial described here is an ongoing single-arm, biomarker-driven Phase 2 trial in MGMT-unmethylated BEV-naïve adult rGBM. In this trial, 48 patients will receive VAL-083 40mg/m2/day on days 1,2,3 of a 21-day cycle. Tumor response will be assessed by MRI approximately every 42 days, per RANO criteria. The primary objective of this study is to determine if VAL-083 improves median overall survival (mOS) for MGMT-unmethylated rGBM patients compared to a historical mOS of 7.1 months for such patients treated with lomustine (EORTC26101). Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and quality-of-life (QOL) evaluation using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool. Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT02717962.
Abstract 18405: Low Clinical Event Rates in Real-World Patients with Bifurcation Lesions Receiving XIENCE V® Everolimus-Eluting Stents: One-Year Results from the XIENCE V USA Study
Authors: James Hermiller, Mitchell Krucoff, Vivian Mao, Weiying Zhao, Qing Zheng, Olivia Wilburn, David Rutledge, Krishnankutty Sudhir
Journal: Circulation (2010)

Objectives: The safety and efficacy of the XIENCE V® everolimus-eluting stent (XIENCE V) have been demonstrated by low clinical outcome rates in the SPIRIT trials. However, only limited data exists...
Abstract 18390: Effects of a Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) Inhibitor, Alirocumab, on Lipid and Lipoprotein Metabolism in Healthy Subjects
Authors: Gissette Reyes-Soffer, Marianna Pavlyha, Colleen Ngai, Tiffany Thomas, Stephen Holleran, Sekhar Ramakrishnan, Wahida Karmally, Daniel Donovan, Lisa Cowan, William Sasiela, Howard Surks, Jacques Rey, Frank Poitiers, Henry Ginsberg
Journal: Circulation (2015)

Background: Alirocumab is a monoclonal antibody that inhibits binding of PCSK9 to LDL receptors, decreasing their lysosomal degradation and increasing their numbers on cell surfaces. In Phase 2/3 studies, alirocumab 150 mg lowered LDL-cholesterol (C) ~61%, apoB 53%, and fasting triglycerides (TG) 16%. The mechanisms that increased LDL removal or the effects on postprandial (PP) TG levels after alirocumab therapy have not been reported. Method: 18 (10F, 8 M), healthy volunteers completed a Phase 1, placebo-controlled, single-blind, single-sequence study. Subjects received 2 placebo doses followed by 5 alirocumab doses, 150 mg SC every 2 wks. At the end of each treatment period, we measured fasting lipids and lipoproteins and subjects received a high fat meal with PP TG and apoB48 levels measured over 8hrs. Stable isotope studies were performed 3-5 days later to measure apoB turnover in very low density (VLDL), intermediate density (IDL) and LDL. Results: In 18 subjects, Alirocumab significantly reduced plasma total-C by 35% (172±32 to 111±24 mg/dL), LDL-C by 60% (104±23 to 44±21 mg/dL) and, apoB by 45% (90±21 to 45±12 mg/dL). Plasma TG levels decreased by 13% (99±44 to 86±40mg/dL). LDL-C, LDL-TG, and LDL-apoB isolated from plasma by ultracentrifugation fell by 50±15%, 5±2%, and 41±16%, respectively, on alirocumab. Preliminary Kinetic results on N=10, show that the reductions in LDL-apoB were due to an increase in the fractional clearance rate (FCR) of LDL-apoB from 0.50±0.18 on placebo to 1.02±0.35 pools/day on alirocumab (p&lt;0.001). IDL-C, IDL-TG and IDL-apoB were also reduced significantly, with a trend toward an increase in IDL-apoB FCR on alirocumab (placebo: 9.2±4 vs alirocumab: 10.8±3 pools/day; p=0.06). Alirocumab had no effects VLDL-C, VLDL-TG, or VLDL-apoB, nor did alirocumab change VLDL FCR or PR. The area under the curve for PP TG and PP apoB48 did not change from placebo to alirocumab. No serious adverse event or treatment discontinuation occurred. Results for all 18 subjects will be available for presentation. Summary: Alirocumab treatment significantly reduced levels of IDL and LDL-apoB by increasing the FCRs of these lipoproteins, particularly LDL. Alirocumab did not alter the metabolism of VLDL-apoB or PP TG-rich lipoproteins.
Recombination and Large Structural Variations Shape Interspecific Edible Bananas Genomes
Authors: Franc-Christophe Baurens, Guillaume Martin, Catherine Hervouet, Frédéric Salmon, David Yohomé, Sébastien Ricci, Mathieu Rouard, Remy Habas, Arnaud Lemainque, Nabila Yahiaoui, Angélique D’Hont
Journal: Molecular Biology and Evolution (2018)

Admixture and polyploidization are major recognized eukaryotic genome evolutionary processes. Their impacts on genome dynamics vary among systems and are still partially deciphered. Many banana cultivars are triploid (sometimes diploid) interspecific hybrids between Musa acuminata (A genome) and M. balbisiana (B genome). They have no or very low fertility, are vegetatively propagated and have been classified as "AB," "AAB," or "ABB" based on morphological characters. We used NGS sequence data to characterize the A versus B chromosome composition of nine diploid and triploid interspecific cultivars, to compare the chromosome structures of A and B genomes and analyze A/B chromosome segregations in a polyploid context. We showed that interspecific recombination occurred frequently between A and B chromosomes. We identified two large structural variations between A and B genomes, a reciprocal translocation and an inversion that locally affected recombination and led to segregation distortion and aneuploidy in a triploid progeny. Interspecific recombination and large structural variations explained the mosaic genomes observed in edible bananas. The unprecedented resolution in deciphering their genome structure allowed us to start revisiting the origins of banana cultivars and provided new information to gain insight into the impact of interspecificity on genome evolution. It will also facilitate much more effective assessment of breeding strategies.
Exosomes play a role in multiple myeloma bone disease and tumor development by targeting osteoclasts and osteoblasts
Authors: Sylvia Faict, Joséphine Muller, Kim De Veirman, Elke De Bruyne, Ken Maes, Louise Vrancken, Roy Heusschen, Hendrik De Raeve, Rik Schots, Karin Vanderkerken, Jo Caers, Eline Menu
Journal: Blood Cancer Journal (2018)

Abstract Progression of multiple myeloma (MM) is largely dependent on the bone marrow (BM) microenvironment wherein communication through different factors including extracellular vesicles takes place. This cross-talk not only leads to drug resistance but also to the development of osteolysis. Targeting vesicle secretion could therefore simultaneously ameliorate drug response and bone disease. In this paper, we examined the effects of MM exosomes on different aspects of osteolysis using the 5TGM1 murine model. We found that 5TGM1 sEVs, or ‘exosomes’, not only enhanced osteoclast activity, they also blocked osteoblast differentiation and functionality in vitro. Mechanistically, we could demonstrate that transfer of DKK-1 led to a reduction in Runx2, Osterix, and Collagen 1A1 in osteoblasts. In vivo, we uncovered that 5TGM1 exosomes could induce osteolysis in a similar pattern as the MM cells themselves. Blocking exosome secretion using the sphingomyelinase inhibitor GW4869 not only increased cortical bone volume, but also it sensitized the myeloma cells to bortezomib, leading to a strong anti-tumor response when GW4869 and bortezomib were combined. Altogether, our results indicate an important role for exosomes in the BM microenvironment and suggest a novel therapeutic target for anti-myeloma therapy.
Assessment of Intensive Care Unit Laboratory Values That Differ From Reference Ranges and Association With Patient Mortality and Length of Stay
Authors: Patrick D. Tyler, Hao Du, Mengling Feng, Ran Bai, Zenglin Xu, Gary L. Horowitz, David J. Stone, Leo Anthony Celi
Journal: JAMA Network Open (2018)

Laboratory data are frequently collected throughout the care of critically ill patients. Currently, these data are interpreted by comparison with values from healthy outpatient volunteers. Whether this is the most useful comparison has yet to be demonstrated.To understand how the distribution of intensive care unit (ICU) laboratory values differs from the reference range, and how these distributions are related to patient outcomes.Cross-sectional study of a large critical care database, the Medical Information Mart for Intensive Care database, from January 1, 2001, to October 31, 2012. The database is collected from ICU data from a large tertiary medical center in Boston, Massachusetts. The data are collected from medical, cardiac, neurologic, and surgical ICUs. All patients in the database from all ICUs for 2001 to 2012 were included. Common laboratory measurements over the time window of interest were sampled. The analysis was conducted from March to June 2017.The overlapping coefficient and Cohen standardized mean difference between distributions were calculated, and kernel density estimate visualizations for the association between laboratory values and the probability of death or quartile of ICU length of stay were created.Among 38 605 patients in the ICU (21 852 [56.6%] male; mean [SD] age, 74.5 [55.1] years), 8878 (23%) had the best outcome (ICU survival, shortest quartile length of stay) and 3090 (8%) had the worst outcome (ICU nonsurvival). Distribution curves based on ICU data differed significantly from the hospital standard range (mean [SD] overlapping coefficient, 0.51 [0.32-0.69]). All laboratory values for the best outcome group differed significantly from those in the worst outcome group. Both the best and worst outcome group curves revealed little overlap with and marked divergence from the reference range.The standard reference ranges obtained from healthy volunteers differ from the analogous range generated from data from patients in intensive care. Laboratory data interpretation may benefit from greater consideration of clinically contextual and outcomes-related factors.
CADD-26. SMALL MOLECULE EPIGENETIC TARGETING OF METHYL-CPG BINDING PROTEIN 2 (MBD2) FOR MEDULLOBLASTOMA THERAPY
Authors: Erwin Van Meir, Jeffrey Olson, Dan Zhu, Satoru Osuka, Zhaobin Zhang
Journal: Neuro-Oncology (2018)

Adhesion G-protein coupled receptors (ADGRs) are transmembrane proteins involved in cell-cell/matrix interactions. We found that the ADGRB1 gene, which encodes Brain-specific angiogenesis inhibitor 1 (BAI1), is epigenetically silenced in human medulloblastomas through a methyl-CpG binding protein 2 (MBD2)-dependent mechanism. We revealed that BAI1 acts as a tumor suppressor by preventing Mdm2-mediated p53 polyubiquitination, and its loss substantially reduces p53 levels. We found BAI1 directly binds to mdm2 and sequesters it from p53. Reactivation of BAI1/p53 signaling axis by targeting the MBD2 pathway with a new brain-permeable MBD2 inhibitor suppressed human medulloblastoma growth in orthotopic xenograft models. Our findings highlight the importance of BAI1 loss in medulloblastoma and demonstrate that epigenetic restoration of its expression has therapeutic potential. Disruption of the BAI1/mdm2/p53 signaling axis through BAI1 silencing reveals a vulnerability in cancer, and offers an opportunity for therapeutic exploitation through epigenetic reactivation. We provide proof-of-principle that this can be achieved with a chemical scaffold targeting MBD2, and this lead molecule is actionable for translation into a first-in-class therapeutic intervention against medulloblastoma, and possibly other cancers (Zhu D et al, Cancer Cell, in press).
RARE-17. LENALIDOMIDE AS TREATMENT FOR RELAPSED OR REFRACTORY PRIMARY CNS LYMPHOMA: A SINGLE INSTITUTIONAL EXPERIENCE
Authors: Donna Molaie, Jethro Hu, Jeremy Rudnick
Journal: Neuro-Oncology (2018)

Primary CNS Lymphoma (PCNSL) is an aggressive form of diffuse large B-cell lymphoma (DLBCL). Lenalidomide is an immunomodulatory agent which has shown activity in relapsed or refractory CNS and non-CNS DLBCL. The ideal dosing, timing as consolidation therapy, and role in maintenance therapy remain unclear. We describe 3 elderly patients with R/R PCNSL who were treated with lenalidomide. All patients had a pathological diagnosis of PCNSL, immunocompetent status, failed at least 2 previous therapies including methotrexate and rituximab. One patient had also failed autologous stem cell transplant. Lenalidomide was administered orally, 25mg/day on days 1–21 of a 28-day cycle. Median age was 68 (range 65–71). Median KPS was 70 (range 60–70). Patient 1 achieved complete response (CR) after cycle 4, 2 additional maintenance cycles (20mg; reduced for Grade 3–4 Thrombocytopenia), and is in remission after 11 months. Patient 2 achieved partial response (PR) after cycle 1, CR after cycle 8, and 2 additional maintenance cycles; dose reduced at cycle 6 (20mg) for Grade 3–4 Neutropenia, and is in remission after 14 months. Patient 3 achieved PR after cycle 1, mixed response after cycle 2, and died 15 weeks after start of treatment; of note, patient was also on rituximab. Molecular and immunologic correlates are pending and will be presented with the abstract. CONCLUSIONS: This case series shows lenalidomide has single agent activity in heavily pre-treated R/R PCNSL. All the patients had clinical and radiographic response to treatment. Hematologic toxicities occurred at higher dose, however even at reduced dose, lenalidomide was effective in maintaining remission. In elderly patients, using lenalidomide at relapse and deferring neurotoxic treatment options may have a role in preserving good performance status. Further prospective studies are warranted to determine the efficacy and optimal dose of lenalidomide in patients with newly diagnosed and R/R PCNSL.
Abstract 14463: GlycA and Not High-sensitive C-Reactive Protein is Associated With Epicardial Fat. The ELSA-Brasil Baseline
Authors: Debora C Azevedo, Adriana Oliveira, Marcio S Bittencourt, Murilo Foppa, Bruce B Duncan, sabela M Bensenor, Paulo A Lotufo
Journal: Circulation (2017)

Introduction: Epicardial adipose tissue is a visceral fat depot that can locally affect coronary arteries through secretion of proinflammatory molecules. GlycA is a novel proton nuclear magnetic re...
Transcriptional profiling of human amniotic fluid-derived stem cells reaching senescence
Authors: Hyun-Jung Kim, Su-Mi Bae, Jeong Eun Park, Jong-chul Shin, Heung-Jae Chun, Hyun-Young Ahn, Jong-Won Rhie, Jiyoung Kim, Haekwon Kim, Woong Shick Ahn
Journal: Cancer Research (2008)

5425  To maintain the homeostasis of stem cells and prevent tumorigenesis of the stem cells, it is very important to either prevent or accelerate stem cell senescence. In order to identify gene expression changes during stem cell senescence, we compared the gene expression profiles of human amniotic fluid (HAF)-derived stem cells over several passages (1st, 2nd, 4th, 6th, 8th, and 10th) using the Sentrix Human Ref-8 illumina microarray chip. Among 25,804 genes in this chip, there was an over 2-fold change in 1,970 genes relative to the control (1st passage); in all of the groups evaluated genes were selected that were serially upregulated or downregulated over time. Quantitative real-time PCR validated the microarray data for selected genes: the markedly increased genes were CXCL12, cadherin 6 (CDH6) and folate receptor 3 (FOLR3) and the downregulated genes were cyclin D2, keratin 8, insulin-like growth factor 2 (IGF2), natriuretic peptide precursor B (NPPB), and cellular retinoic acid binding protein 2 (CRABP2). The expression patterns of the selected genes were consistent with the microarray data except for CXCL12 and IGF2. Interestingly, the expression of NPPB was dramatically downregulated over time and was almost unidentifiable at the 10th passage compared with the control (1st passage). By contrast, FOLR3 mRNA expression was dramatically increased as the number of passages increased. Taken together, although the function of NPPB and FOLR3 in stem cell senescence is not known, these results strongly suggest that NPPB and FOLR3 play a significant role in the regulation of stem cell senescence.
Clinical utility of tumor genomic profiling in patients with high plasma circulating tumor DNA burden or metabolically active tumors
Authors: Cathy Zhou, Zilong Yuan, Weijie Ma, Lihong Qi, Angelique Mahavongtrakul, Ying Li, Hong Li, Jay Gong, Reggie R. Fan, Jin Li, Michael Molmen, Travis A. Clark, Dean Pavlick, Garrett M. Frampton, Brady Forcier, Elizabeth H. Moore, David K. Shelton, Matthew Cooke, Siraj M. Ali, Vincent A. Miller, Jeffrey P. Gregg, Philip J. Stephens, Tianhong Li
Journal: Journal of Hematology & Oncology (2018)

This retrospective study was undertaken to determine if the plasma circulating tumor DNA (ctDNA) level and tumor biological features in patients with advanced solid tumors affected the detection of genomic alterations (GAs) by a plasma ctDNA assay. Cell-free DNA (cfDNA) extracted from frozen plasma (N = 35) or fresh whole blood (N = 90) samples were subjected to a 62-gene hybrid capture-based next-generation sequencing assay FoundationACT. Concordance was analyzed for 51 matched FoundationACT and FoundationOne (tissue) cases. The maximum somatic allele frequency (MSAF) was used to estimate the amount of tumor fraction of cfDNA in each sample. The detection of GAs was correlated with the amount of cfDNA, MSAF, total tumor anatomic burden (dimensional sum), and total tumor metabolic burden (SUVmax sum) of the largest ten tumor lesions on PET/CT scans. FoundationACT detected GAs in 69 of 81 (85%) cases with MSAF > 0. Forty-two of 51 (82%) cases had ≥ 1 concordance GAs matched with FoundationOne, and 22 (52%) matched to the National Comprehensive Cancer Network (NCCN)-recommended molecular targets. FoundationACT also detected 8 unique molecular targets, which changed the therapy in 7 (88%) patients who did not have tumor rebiopsy or sufficient tumor DNA for genomic profiling assay. In all samples (N = 81), GAs were detected in plasma cfDNA from cancer patients with high MSAF quantity (P = 0.0006) or high tumor metabolic burden (P = 0.0006) regardless of cfDNA quantity (P = 0.2362). This study supports the utility of using plasma-based genomic assays in cancer patients with high plasma MSAF level or high tumor metabolic burden.
Physical activity on prescription in accordance with the Swedish model increases physical activity: a systematic review
Authors: Aron Onerup, Daniel Arvidsson, Åse Blomqvist, Eva-Lotte Daxberg, Lennart Jivegård, Ingibjörg H Jonsdottir, Stefan Lundqvist, Anders Mellén, Josefine Persson, Petteri Sjögren, Therese Svanberg, Mats Borjesson
Journal: British Journal of Sports Medicine (2018)

Objectives This study investigates the effects of the core elements of the Swedish model for physical activity on prescription (PAP) by evaluating studies that compared adults who received PAP with adults who did not receive PAP. All participants were adults identified by a healthcare professional as in need of increased physical activity. Primary outcome was level of physical activity. Design Systematic review. Eligibility criteria (1) Published 1999. (2) Systematic review, randomised controlled trial (RCT), non-RCT or case series (for adverse events). (3) ≥12 weeks’ follow-up. (4) Performed in the Nordic countries. (5) Presented in English, Swedish, Norwegian or Danish. Data sources Systematic searches in PubMed, Embase, the Cochrane Library, AMED, CINAHL and SweMed+ in September 2017. Included articles were evaluated using checklists to determine risk of bias. Results Nine relevant articles were included: seven RCTs, one cohort study and one case series. Primary outcome was reported in seven articles from six studies (five RCTs, one cohort study, 642 participants). Positive results were reported from three of the five RCTs and from the cohort study. No study reported any negative results. Swedish PAP probably results in an increased level of physical activity (GRADE⊕⊕⊕Ο). Conclusions Although the number of the reviewed articles was relatively modest, this systematic review shows that PAP in accordance with the Swedish model probably increases the level of physical activity. As a model for exercise prescription, Swedish PAP may be considered as part of regular healthcare to increase physical activity in patients.
STEM-21. DECIPHERING THE RESPONSE OF SUBVENTRICULAR ZONE-NESTED GLIOBLASTOMA CELLS AFTER SURGERY
Authors: Arnaud Lombard, Matthias Dedobbeleer, Estelle Willens, Gilles Reuter, Didier Martin, Bernard Rogister
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most frequent malignant brain tumor in adults, with poor prognosis, subsequent to systematic recurrences, which occur in 80% of cases in the resection margin of initial tumor. We previously demonstrated that, after experimental striatal xenotransplantation, GBM cells, and particularly GBM-initiating cells (GIC), are able to escape the tumor mass and specifically colonize the sub-ventricular zone (SVZ), a well-known neurogenic zone in adult brains. We also demonstrated that this specific oriented migration is driven by a CXCL12-CXCR4 signalization. In this study, we address the potential implication of SVZ-nested tumor cells in local GBM relapses. MATERIALS AND We engrafted in the right striatum of nude mice GBM cells (GB138) from a human primary culture, which are previously transfected with a lentiviral construction in order to express the RFP spontaneously, while they conditionally express eGFP, only in presence of Cre-recombinase. As the GB138 cells reach the SVZ, we injected in the lateral ventricle an Adeno-Associated Viral vector expressing Cre-recombinase, which is able to infect nearby the SVZ cells, including the GB138 cells that have reached this region. Finally, we compared 3 mice that were not operated (control group) with 3 mice that underwent tumor resection (surgery group) and quantify green spots in the tumor mass (TM) and/or resection cavity (RC) every 20 microns thanks to Lightsheet microscope after tissue clarification. We found that the median of green spots for the 3 mice of the control group was respectively 1, 0 and 0 in TM, while the median for the surgery group was 7, 8 and 47 in RC. The Standard Deviation (SD) for the control group was respectively 1.1, 0.4 and 0.6, while SD for the surgery group was respectively 1.5, 1.7 and 16. SVZ-nested GBM cells seem to be recruited for tumor relapse after surgery.