tbuckley/cabot-search huggingface dataset:
Abstract 9776: Association of Early Stress Testing With Outcomes for Emergency Department Evaluation of Suspected Acute Coronary Syndrome
Authors: Benjamin Sun, Amber Laurie, Rongwei Fu, Maros Ferencik, Michael Shapiro, Christopher Lindsell, Deborah Diercks, James Hoekstra, Judd Hollander, J. Douglas Kirk, W.Frank Peacock, W.Brian Gibler, Venkataraman Anantharaman, Charles Pollack
Journal: Circulation (2015)

Introduction: The emergency department (ED) evaluation of suspected acute coronary syndrome (ACS) is a common, challenging, and costly task with high clinical stakes. Professional society guidelines recommend early stress testing (within 72 hours of ED visit); however, there are no data to demonstrate improved outcomes with this approach. Hypotheses: 1.) Early stress testing improves outcomes, and 2.) The association between early stress testing and outcomes is modified by pre-test ACS risk. Methods: We analyzed prospectively collected registry data from 9 emergency departments on patients with suspected ACS. The primary outcome was 30-day major adverse cardiovascular events (MACE), including all-cause death, acute myocardial infarction, and urgent revascularization. The exposure variable of interest was early stress testing. We used the HEART score to determine pre-test ACS risk (low, intermediate, high). To mitigate potential confounding by indication, patients with and without early stress testing were matched in a 1:2 ratio using propensity score methods. The propensity score model included over 40 demographic, clinical, biomarker, and ECG covariates. Results: The analytic cohort included 946 patients with early stress testing and 1,892 without early stress testing. There were no significant baseline imbalances after propensity score matching (p&gt;0.1 for all covariates). There was no association between early stress testing and 30-day MACE in the overall cohort (OR 1.3; 95%CI 0.8-2.1). There was evidence of effect modification by pre-test ACS risk strata (low: OR 1.2, 95%CI 0.2-5.3; intermediate: 2.1, 95%CI 1.1-4.1; high: 0.4, 95%CI 0.1-1.4). In intermediate risk patients, early stress testing is associated with increased rates of revascularization (OR 2.8, 95%CI 1.3-6.0), but not with death/ acute myocardial infarction (OR 0.9, 95%CI 0.1-4.6). Conclusions: Early stress testing does not reduce 30-day MACE in the ED evaluation of suspected ACS. In intermediate-risk patients, early stress testing may result in increased revascularization rates without reduction in the objective outcomes of death or myocardial infarction. These findings challenge existing care guidelines and require confirmation by randomized trials.
Author Correction: STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis
Authors: Neibla Priego, Lucía Zhu, Cátia Monteiro, Manon Mulders, David Wasilewski, Wendy Bindeman, Laura Doglio, Liliana Martínez, Elena Martínez-Saez, Santiago Ramón y Cajal, Diego Megías, Elena Hernández-Encinas, Carmen Blanco-Aparicio, Lola Martínez, Eduardo Zarzuela, Javier Muñoz, Coral Fustero-Torre, Elena Piñeiro-Yáñez, Aurelio Hernández-Laín, Luca Bertero, Valeria Poli, Melchor Sanchez-Martinez, Javier A. Menendez, Riccardo Soffietti, Joaquim Bosch-Barrera, Manuel Valiente
Journal: Nature Medicine (2018)
Abstract 15515: Mechanism of Fever-Induced QT Prolongation in Patients With KCNH2 Mutations in the S5-Pore Region: Evidence From Genotypic and Functional Analyses
Authors: Kenshi Hayashi, Tadashi Nakajima, Yasutaka Kurata, Shoichi Tange, Noboru Fujino, Kenji Sakata, Tetsuo Konno, Toyonobu Tsuda, Yoji Nagata, Ryota Teramoto, Yoshihiro Tanaka, Takekatsu Saito, Masa-aki Kawashiri, Yoshiaki Kaneko, Kunio Ohta, Masahiko Kurabayashi, Masakazu Yamagishi
Journal: Circulation (2016)

Introduction: Previous studies demonstrated that patients with type-2 long QT syndrome (LQT2) caused by a mutation in the Kv11.1 S5-pore region have an increased risk of arrhythmia during fever. Ho...
A phase I study of intravenous artesunate (IV AS) in patients with solid tumors.
Authors: John F. Deeken, Hongkun Wang, Brandon George Smaglo, Jimmy J. Hwang, Aiwu Ruth He, Louis M. Weiner, John Marshall, Giuseppe Giaccone, Stephen V. Liu, Jim Luecht, Christina Urso, Jay Y Spiegel, Amrita Cheema, Michael J. Pishvaian
Journal: Journal of Clinical Oncology (2015)

2535 Background: Although the artemisinin class of anti-malarial drugs has shown significant anti-cancer activity in preclinical models, no prospective clinical trials have so far been performed. Proposed anticancer mechanisms include: DNA damage, inhibition of angiogenesis, TRAIL-mediated apoptosis, and inhibition of several signaling pathways. We performed a phase I clinical study to determine the maximum tolerated dose (MTD), and the dose limiting toxicities (DLTs) of IV AS. Methods: Patients (Pts) with refractory solid tumors were enrolled in this accelerated titration dose escalation study with planned dose levels of 8, 12, 18, 25, 34 and 45 mg/kg given on days 1 and 8 of a 21 day cycle. One patient would be treated at each dose level until a ≥ level 2 toxicity occurred during cycle 1, then a traditional 3+3 dose escalation rule would apply until 2 of 6 patients experienced DLTs on a dose level. Intensive PK was performed. Archived tumor blocks were obtained for correlative studies. Results: Between 01/2013 and 04/2014, 19 pts were enrolled, 17 of whom were evaluable for toxicity; 16 were evaluable for efficacy. The median age was 59, 12 (63%) were female, and 10 (52%) were Caucasian. The first pt on 8mg/kg had a Gr 3 non-DLT toxicity, so 3+3 dose escalation was then initiated. DLTs were seen at dosages of 12 (1 of 6 patients), 18 (1 of 6) and 25mg/kg (2 of 2), and were neutropenic fever (Gr 4), hypersensitivity reaction (Gr 3), AST elevation (Gr 4), and nausea/vomiting (Gr 3), respectively. The MTD was determined to be 18mg/kg. Grade 3/4 AEs seen in 2 pts each (12%) were: LFT abnormalities, anemia, neutropenia, and febrile neutropenia. One pt died on study related to disease progression and was deemed to not be drug related. No responses were observed; 3 patients had prolonged stable disease for 8, 10, and 11 cycles with ampullary, renal, and ovarian cancer, respectively, for a disease control rate of 19%. Tumor expression of transferrin and ABCB6 did not correlate with disease control. PK results will be presented. Conclusions: The MTD of IV AS is 18mg/kg on this schedule. Treatment was well tolerated at that dose level. Modest clinical activity was seen.
DEV-02. CLINICAL FEATURES OF 1027 TUMORS OF CENTRAL NERVOUS SYSTEM IN CHILDREN: SINGLE INSTITUTIONAL REPORT FROM SHANGHAI XINHUA HOSPITAL, THE FOUNDING MEMBER OF CNOG
Authors: Yipeng Han, Yang Zhao, Feng Jiang, Qifeng Li, Baocheng Wang, Chenran Zhang, Jie Ma
Journal: Neuro-Oncology (2018)

Central nervous system (CNS) tumor is the most common solid neoplasm in children. Here we report clinical features of children with CNS tumor treated in our institute during recent 10 years. Retrospective study was conducted in children with CNS tumor treated in Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, during 2006 to 2016. Clinical data were collected. Statistical calculation was conduct for characteristic analyses. 1027 cases of CNS tumor in children were collected, with 611 males and 336 females. Age ranges were 10.22% in infants (< 1 y/o), 27.07% in toddler (1 - 3 y/o), 35.15% in preschool children (3 - 7 y/o), 26.78% in school-age children (7 - 15 y/o) and 0.78% in adolescence (> 15 y/o). 423 cases were diagnosed with WHO I-II grades and 367 cases were with WHO III-IV grades. There were 538 supratentorial tumors and 424 subtentorial tumors. The most common tumor type was pilocytic astrocytoma (n=141, 13.80%), followed by medulloblastoma (n=132, 12.92%). The gender ratios in different age ranges were stable, with high incidence in male than in female. In total, low grade tumors were more common than high grade tumors. Pilocytic astrocytoma was most common tumor, followed by medulloblastoma.
MBRS-34. MOLECULAR CHARACTERIZATION OF RECURRENT MEDULLOBLASTOMA REVEALS AN UNEXPECTEDLY HIGH INCIDENCE OF SECONDARY MALIGNANCY
Authors: Rahul Kumar, Maximilian Deng, Vasilisa A Rudneva, Giles W Robinson, Girish Dhall, Laure J Klesse, Daniel C Bowers, Murali Chintagumpala, Sarah Leary, Brent A Orr, Stefan M Pfister, Amar Gajjar, David T W Jones, Paul A Northcott
Journal: Neuro-Oncology (2018)

Despite an overall 5-year progression free survival of approximately 80% for primary medulloblastomas (MBs), recurrent disease confers an abysmal prognosis with less than 10% 5-year survival. Subgroup affiliation at recurrence has been reported as stable though divergent clonal selection may explain treatment failure upon relapse. The confirmation of histopathologic diagnosis at recurrence thus represents a key task to facilitate selection of efficacious therapy and to gain deeper understanding of the biology driving recurrent disease. DNA methylation-based classification of pediatric brain tumors has emerged as a robust methodology for refining histopathologic diagnosis and defining disease-specific subgroups. We leveraged Illumina Infinium BeadChip arrays to characterize a series of >50 patient-matched, histopathologically diagnosed, primary/relapse MB pairs. Entity and subgroups were assigned by comparison with a database consisting of >2800 reference methylation profiles (https://www.molecularneuropathology.org/mnp). Genome-wide copy-number aberrations were inferred from the BeadChip arrays, and mutational analysis (whole exome sequencing) was performed on the majority of samples. Molecular classification was performed on n=59 primary/relapse MB pairs, inferring the following subgroup representation amongst our cohort: WNT (n=1, 2%), SHH (n=17, 30%), Group 3 (n=15, 25%), Group 4 (n=25, 42%). MB subgroup status was highly conserved across the series (90%), consistent with prior reports. Notably, we determined that 6/59 (10%) of histopathologically diagnosed MB ‘relapses’ molecularly classified as non-MB, including multiple glioblastomas (3/6). Pairwise copy-number and mutational analyses are ongoing to determine the degree of conservation and/or divergence amongst somatic alterations between primary/relapse MB pairs and to identify molecular patterns associated with secondary malignancy.
HGCSG 1301: A Multicenter, Double-Blind, Randomized control phase II trial comparing Hange-shashin-to versus placebo to prevent diarrhea in patients with metastatic colorectal cancer under IRIS/Bev second-line treatment
Authors: M. Nakamura, Y. Komatsu, T. Muranaka, M. Yagisawa, Y. Kawamoto, H. Nakatsumi, S. Yuki, T. Saiki, A. Ishiguro, M. Tateyama, Y. Kobayashi, T. Miyagishima, T. Takahata, A. Sato, M. Dazai, H. Okuda, K. Fujikawa, K. Eto, S. Muto, K. Hatanaka, T. Amano, Y. Sakata
Journal: Annals of Oncology (2018)

Introduction: S-1 plus irinotecan (IRIS) showed non-inferiority to fluorouracil and folinic acid plus irinotecan (FOLFIRI) by FIRIS study. Therefore, IRIS is widely used with bevacizumab (IRIS/Bev) as the second-line chemotherapy in patients with colorectal cancer. The most frequent non-hematological adverse event shown at the study was diarrhea. Baicalin contained within Hange-shashin-to is a potent competitive inhibitor of beta-glucuronidase which cleaves conjugated SN-38-glucuronide to SN-38 which causes cytotoxic diarrhea as an active metabolite from irinotecan. We conducted to evaluate the usefulness of prophylactic administration of Hange-shashin-to to prevent diarrhea in patients receiving IRIS/Bev. Methods: This trial was designed as a multicenter, randomized, double-blind, placebo-controlled study. We administrated Hange-shashin-to 2.5g or placebo PO t.i.d. until 3 months from the first treatment cycle of IRIS/Bev. The primary endpoint is proportion of Grade 3 or worse diarrhea assessed by CTCAE v4.0. This study is registered with UMIN-CTR, number UMIN000012276. Results: Between Jan 1, 2014 and Mar 31, 2017, 59 patients with colorectal cancer in need of second-line chemotherapy from 11 institutes in japan were randomly assigned to receive Hange-shashin-to (n = 28, Group H) or placebo (n = 29, Group P). The patients' characteristics were well-balanced. The median relative dose intensities of S-1, irinotecan and bevacizumab were 0.89 vs 0.89, 0.89 vs 0.89 and 0.89 vs 0.86 in group H vs group P. The proportions of Grade 3 or worse diarrhea were 10.7% (3 of 28) in Group H and 13.8% (4 of 29) in Group P (p = 1.00). Those of any grade diarrhea were 64.3% (18 of 28) in Group H and 72.4% (21 of 29) in Group P (p = 0.58). The other major adverse events (grade 3 or worse) were fatigue (3.6% vs 10.3%), anorexia (14.3% vs 10.3%), nausea (0.0% vs 3.4%) in Group H vs Group P. The overall response rate in group H vs group P was 13.6% vs 7.7% (p = 0.65), and the disease control rate was 86.4% vs 80.8% (p = 0.71), respectively. Conclusion: Our study to examine the diarrhea control effect by Hange-shashin-to induced by IRIS/Bev did not show any significant difference between two groups.
Preventing Diabetes Distress in Adolescents With Type 1 Diabetes: Results 1 Year After Participation in the STePS Program
Authors: Korey K. Hood, Esti Iturralde, Joseph Rausch, Jill Weissberg-Benchell
Journal: Diabetes Care (2018)

OBJECTIVE The aim is to report 1-year outcomes of the Supporting Teens Problem Solving (STePS) study, a randomized controlled trial comparing a distress and depression prevention program with a diabetes education program for adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS With 264 adolescents in two locations (Chicago and San Francisco Bay Area), a randomized controlled trial was conducted comparing the Penn Resilience Program for type 1 diabetes (PRP T1D) to Advanced Diabetes Education. Interventions lasted 4.5 months, and assessments were conducted at baseline, and 4.5, 8, 12, and 16 months. Outcomes of interest were diabetes distress (DD), depressive symptoms, resilience, diabetes self-management, and glycemic control. Latent growth curve modeling was used to test between-group differences over time. RESULTS Results indicate that there was acceptable randomization and exposure to interventions, and that exposure to PRP T1D was associated with substantial reductions in DD. In addition, stable glycemic control, resilience characteristics, and depressive symptoms were observed 1 year post-treatment. Diabetes management deteriorated in both groups. CONCLUSIONS Intervening before symptoms of psychological distress start can prevent the development of the DD commonly seen in adolescents with type 1 diabetes. The STePS program represents a promising prevention program, and future reports on 2- and 3-year outcomes will explore benefits over longer periods of time.
LGG-27. A CASE FOR EARLY DABRAFENIB USE IN PATIENTS WITH LOW-GRADE GLIOMAS
Authors: Krupesh Patel, Derek Hanson
Journal: Neuro-Oncology (2018)

BRAF kinase mutations and duplications are among the most common genetic alterations seen in pediatric low-grade gliomas. The BRAF V600E mutation is a missense mutation involving an amino acid substitution at position 600 in BRAF, from valine to glutamic acid, leading to constitutive activation of the MAPK pathway. Dabrafenib, a selective BRAF inhibitor, has demonstrated clinical efficacy in BRAF V600E-positive low-grade gliomas in early phase testing. While dabrafenib is typically used as a second-line agent in low-grade glioma, its efficacy, minimal toxicity, and ease of administration make the drug an attractive candidate for first-line use. We present two patients with BRAF V600E-postitive low-grade gliomas who received respective late and early dabrafenib therapy. The first is a patient with a glioneuronal tumor involving the brain and spine. Over nine years, her symptoms progressed to include paraplegia despite surgical resection, multiple chemotherapy regimens, and radiotherapy. Following her most recent progression, her tumor was re-examined and found to express the BRAF V600E mutation. She received dabrafenib with subsequent resolution of her brain lesion and significant improvement in her spine disease. The second patient presented with left-sided weakness and a visual field deficit and underwent a partial resection of a right thalamic BRAF V600E-positive ganglioglioma. She began first-line therapy with dabrafenib with subsequent neurologic improvement and a decrease in T2 hyperintensity and resolution of tumor enhancement on MRI. These contrasting cases highlight the need to consider early dabrafenib therapy in patients with high-risk BRAF V600E-positive tumors as a means to prevent further neurologic injury.
ATRT-38. TAK228 COMBINES WITH NAVITOCLAX TO ENHANCE PLATINUM-INDUCED CYTOTOXICITY IN AT/RT
Authors: Jeffrey Rubens, Sabrina Wang, Shreya Sharma, Smit Shah, Kathy Warren, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2018)

Survival in atypical teratoid rhabdoid tumors (AT/RT) is plagued by drug resistance to platinum-intensive therapies. We have previously shown the dual mTORC1/2 inhibitor TAK228 (aka MLN0128) extends survival in orthotopic mouse models of AT/RT by enhancing cisplatin-induced apoptosis. TAK228 decreases expression of the anti-apoptotic protein MCL-1 but leads to a reflexive increase in anti-apoptotic proteins BCL-2 and BCL-XL. We hypothesize that combining TAK228 with the BH3 mimetic, navitoclax will enhance platinum-induced cytotoxicity, reduce drug resistance, and extend survival in AT/RT. TAK228 combined with navitoclax decreases expression of MCL-1, BCL-2, and BCL-XL; shifting toward a pro-apoptotic balance of BCL-2 family proteins. Navitoclax combines synergistically with TAK228 to slow AT/RT cell growth (MTS assay, p<0.01 t-test; MUSE viability assay, p<0.01 ANOVA) and enhances carboplatin-induced cytotoxicity (MUSE Annexin-V, p<0.01 by ANOVA; western for c-PARP). Clinical trials identify 30mg TAK228 weekly as the maximum tolerated dose in adults, which converts to 6mg/kg in mice. This dose penetrates AT/RT orthotopic xenograft tumors within 1 hour of oral administration, inhibits mTORC1/2 activation, and decreases MCL-1 expression until 48 hours after administration. Clinical trials of navitoclax reveal a similar rapid onset of activity with pre-clinical evidence of CNS penetration. Our pilot experiments find combinations of TAK228, navitoclax, and carboplatin are well tolerated in mice. Long term survival studies are ongoing. We are currently developing a phase I clinical trial testing TAK228 combined with carboplatin to treat relapsed pediatric brain tumors with plans for follow-up studies adding navitoclax to enhance the efficacy of this drug combination.
DIPG-41. IDENTIFICATION OF BIRC5 AS A NOVEL THERAPEUTIC TARGET FOR DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Meng Li, Jiajia Wang, Yi Sui, Tiantian Li, Fang Liu, Lei Zhang, Wenyan Jiang, Jie Ma, Michelle Monje, Yujie Tang
Journal: Neuro-Oncology (2018)

Diffuse Intrinsic Pontine Glioma (DIPG) remains to be a lethal type of pediatric brain tumor to date, indicating an urgent need of finding novel therapeutic strategy. Through screening of a collection of anti-tumor agents against a patient-derived DIPG primary tumor cell line, we identified a few novel therapeutic candidates for treating DIPG, among which BIRC5 inhibitor YM155 was the top potent agent. Next, we confirmed that YM155 could selectively inhibit multiple DIPG primary cell lines with IC50 less than 10nM. Moreover, our gene expression analyses showed that BIRC5 was significantly upregulated in DIPG primary tumor tissues and paired normal cortex tissues from the same patient. Genetically targeting of BIRC5 with CRISPR-Cas9 or RNAi approach could also effectively disrupt the growth of multiple DIPG cell lines, confirming BIRC5 as a valid therapeutic target for treating DIPG. Mechanistically, BIRC5 inhibition could cause cell cycle arrest, shut off proliferation and induce massive apoptosis. Furthermore, we tested the combinatory inhibitory effects of YM155 plus chemotherapy or targeted therapy drugs with proven anti-DIPG activity, including THZ1, JQ1, Gemcitabine, Panobinostat, GSK-J4 and et al. The preliminary results demonstrated YM155 could work synergistically with a few of above-mentioned drugs in vitro. We are also testing the in vivo inhibitory effects of targeting BIRC5 against DIPG preclinical PDX models. Together, our study identified BIRC5 inhibition as a novel therapeutic strategy against DIPG.
A20 and ABIN-1 synergistically preserve intestinal epithelial cell survival
Authors: Michael G. Kattah, Ling Shao, Yenny Y. Rosli, Hiromichi Shimizu, Michael I. Whang, Rommel Advincula, Philip Achacoso, Sanjana Shah, Bao H. Duong, Michio Onizawa, Priscilia Tanbun, Barbara A. Malynn, Averil Ma
Journal: The Journal of Experimental Medicine (2018)

A20 (TNFAIP3) and ABIN-1 (TNIP1) are candidate susceptibility genes for inflammatory bowel disease and other autoimmune or inflammatory diseases, but it is unclear how these proteins interact in vivo to prevent disease. Here we show that intestinal epithelial cell (IEC)-specific deletion of either A20 or ABIN-1 alone leads to negligible IEC loss, whereas simultaneous deletion of both A20 and ABIN-1 leads to rapid IEC death and mouse lethality. Deletion of both A20 and ABIN-1 from enteroids causes spontaneous cell death in the absence of microbes or hematopoietic cells. Studies with enteroids reveal that A20 and ABIN-1 synergistically restrict death by inhibiting TNF-induced caspase 8 activation and RIPK1 kinase activity. Inhibition of RIPK1 kinase activity alone, or caspase inhibition combined with RIPK3 deletion, abrogates IEC death by blocking both apoptosis and necroptosis in A20 and ABIN-1 double-deficient cells. These data show that the disease susceptibility proteins A20 and ABIN-1 synergistically prevent intestinal inflammation by restricting IEC death and preserving tissue integrity.
Metabolic changes in hypertrophic cardiomyopathies: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology
Authors: Jolanda van der Velden, Carlo G Tocchetti, Gilda Varricchi, Anna Bianco, Vasco Sequeira, Denise Hilfiker-Kleiner, Nazha Hamdani, Adelino F Leite-Moreira, Manuel Mayr, Ines Falcão-Pires, Thomas Thum, Dana K Dawson, Jean-Luc Balligand, Stephane Heymans
Journal: Cardiovascular Research (2018)

Disturbed metabolism as a consequence of obesity and diabetes may cause cardiac diseases (recently highlighted in the cardiovascular research spotlight issue on metabolic cardiomyopathies).1 In turn, the metabolism of the heart may also be disturbed in genetic and acquired forms of hypertrophic cardiac disease. Herein, we provide an overview of recent insights on metabolic changes in genetic hypertrophic cardiomyopathy and discuss several therapies, which may be explored to target disturbed metabolism and prevent onset of cardiac hypertrophy. This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.