tbuckley/cabot-search huggingface dataset:
GENE-10. H3K27ME3-MEDIATED SILENCING TUMOR SUPPRESSORS SUPPORTS THE PROLIFERATION OF PEDIATRIC BRAIN TUMOR CELLS HARBORING THE H3.3K27M MUTATION
Authors: Dong Fang, Haiyun Gan, Liang Cheng, Jeong-Heon Lee, Hui Zhou, Jann Sarkaria, David Daniels, Zhiguo Zhang
Journal: Neuro-Oncology (2017)

Recent genetic studies have shown that the lysine 27 to methionine of histone H3.3 (H3.3K27M) mutant proteins expressed in over 75% of diffuse intrinsic pontine glioma (DIPG) cases inhibit H3K27 methyltransferase PRC2, resulting in a global loss of tri-methylation of H3K27 (H3K27me3). In addition, H3K27me3 is also retained at hundreds of gene loci. However, it is not known how and why H3K27me3 is retained in DIPG cells. Here we show that H3K27me3 is enriched on chromatic loci where the levels of H3.3K27M mutant proteins are low. Furthermore, H3K27me3-mediated silencing of tumor suppressor genes supports the proliferation of DIPG cells. Together, these studies reveal mechanisms whereby H3K27me3 is retained in the environmental of global loss of this mark and the functional significance of retention of this mark in tumorigenesis.
The categorical role of structurally iconic signs
Authors: Brent Strickland, Valentina Aristodemo, Jeremy Kuhn, Carlo Geraci
Journal: Behavioral and Brain Sciences (2017)

Abstract Goldin-Meadow &amp; Brentari (G-M&amp;B) argue that, for sign language users, gesture – in contrast to linguistic sign – is iconic, highly variable, and similar to spoken language co-speech gesture. We discuss two examples (telicity and absolute gradable adjectives) that challenge the use of these criteria for distinguishing sign from gesture.
Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation
Authors: Shawn Yost, Bas de Wolf, Sandra Hanks, Anna Zachariou, Chiara Marcozzi, Matthew Clarke, Richarda M de Voer, Banafsheh Etemad, Esther Uijttewaal, Emma Ramsay, Harriet Wylie, Anna Elliott, Susan Picton, Audrey Smith, Sarah Smithson, Sheila Seal, Elise Ruark, Gunnar Houge, Jonathon Pines, Geert J P L Kops, Nazneen Rahman
Journal: Nature Genetics (2017)
LGG-12. THE RATE OF GROWTH OF UNTREATED PEDIATRIC BRAIN TUMORS – A CASE SERIES
Authors: Ariel Gilbert, Usiakimi Igbaseimokumo
Journal: Neuro-Oncology (2017)

INTRODUCTION: Radiological imaging (MRI or CT scan) provides the first line for diagnosis of brain tumors. Given the uniform fatality of malignant brain tumors, no ethical studies of rate of tumor growth without treatment are possible. Therefore, only observations from natural events can provide a clue to the rate of growth of untreated tumors. A case series of children with earlier brain scans who subsequently developed brain tumors is therefore being presented to gain an understanding of the natural evolution of these tumors. METHOD: Institutional Review Board approval was obtained. About 435 tumors treated between January 2005 and December 2015 were screened. All children with previous normal or abnormal brain imaging prior to the “diagnostic scan” were included in the study. Seven patients met the inclusion criteria and their demographic data, histology, and date of previous and diagnostic scan, clinical data including date of surgery were abstracted on to a spread sheet and analyzed for this study. The radiological evolution was reviewed with two attending radiologists. RESULTS: There were 6 males and 1 female. The mean age was 5.95 years (range 6 months to 17 years). Two patients (29%) had gangliogliomas and five patients (71%) had malignant tumors (3 medulloblastomas, one glioblastoma multiforme and one pineoblastoma). The median time from the normal scan to the diagnostic scan was 7 months for the malignant tumors and 64.75 months for the benign tumors (p = 0.37). It was observed that the gangliogliomas also started as diffuse non-enhancing lesions that evolved into the discretely enhancing tumors. CONCLUSION: The time for the evolution of malignant brain tumors is short and WHO I tumors like gangliogliomas are more diffuse than the MRI appearances may suggest.
Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample
Authors: Shuji Ogino
Journal: Cancer Research (2007)

1790  Background: The CpG island methylator phenotype (CIMP or CIMP-high) with extensive promoter methylation is a distinct phenotype in colorectal cancer. However, a choice of markers for CIMP has been controversial. A recent extensive investigation has selected five methylation markers (CACNA1G, IGF2,NEUROG1, RUNX3 and SOCS1) as surrogate markers for epigenomic aberrations in tumor. The use of these markers as a CIMP-specific panel needs to be validated by a large independent dataset.  Design: We collected 920 colorectal cancers from two large prospective cohort studies. Utilizing MethyLight assays, we quantified DNA methylation in eight CIMP-specific markers {CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, plus CDKN2A (p16), CRABP1 and MLH1}. We determined microsatellite instability (MSI) status and sequenced KRAS and BRAF.  Results: A CIMP-high cutoff was set at ≥6/8 or ≥5/8 methylated promoters, based on BRAF and KRAS mutation frequency spectra in MSI-high and microsatellite stable (MSS) tumors. Table shows sensitivity, specificity and concordance rates of a single marker-based CIMP diagnosis against the 8-marker CIMP panel. All but two very specific markers [MLH1 (98% specific) and SOCS1 (93% specific)] demonstrated ≥87% sensitivities and ≥80% specificities. Based on the data, the eight markers were ranked in order as: RUNX3, CACNA1G, IGF2, MLH1, NEUROG1, CRABP1, SOCS1 and CDKN2A. A panel of markers including at least RUNX3, CACNA1G, IGF2 and MLH1 could serve as a sensitive and specific marker panel for CIMP-high.  Conclusion: Our results indicate overall good concordance in methylation patterns and good performance of all of the 8 markers.  Table. Sensitivity & Specificity of Each Marker for Diagnosis of CIMP-High in 920 Colorectal Cancers  Sensitivity = “(the number of CIMP-high cases positive for a given marker) / (the number of all CIMP-high cases)”. Specificity = “(the number of CIMP-low/0 cases negative for a given marker) / (the number of all CIMP-low/0 cases)”.
Abstract 16567: Mitochondrial Ca 2+ Influx Contributes to Early After Depolarizations in Nonischemic Cardiomyopathic Mice
Authors: An Xie, Hong Liu, Anyu Zhou, Guangbin Shi, Man Liu, Cody Rutledge, Euy-Myoung Jeong, Samuel C Dudley
Journal: Circulation (2016)

Introduction:  Heart failure (HF) is associated with increased arrhythmic risk and triggered activity. Abnormal Ca 2+  handling is thought to underlie triggered activity, and mitochondria participate in Ca 2+  homeostasis.   Hypothesis:  Therefore, we tested whether mitochondrial Ca 2+  flux contributed to early afterdepolarizations (EADs) in HF.   Methods:  A model of nonischemic HF (NI-HF) was induced in C57BL/6 mice by hypertension. Tail-cuff plethysmography, echocardiography, ECG telemetry, patch-clamp, cytoplasmic (and mitochondrial) Ca 2+  transient measurement, real-time PCR and Western blotting techniques were used.   Results:  The left ventricular end-diastolic volume was significantly enlarged and the ejection fraction was substantially reduced in cardiomyopathic mice. Meanwhile, NI-HF mice developed a significant augmentation of both systolic and diastolic blood pressure. Isoproterenol-induced premature ventricular contractions and ventricular fibrillation were more prevalent in NI-HF mice than sham controls. Isolated myopathic myocytes showed a substantial decreased cytoplasmic Ca 2+  transients, a prominent increased mitochondrial Ca 2+  transients and a significant increase in the action potential duration at 90% repolarization (APD90). The alteration of APD90 was consistent with  in vivo  QTc elongation and could be explained by augmented L-type Ca 2+  currents, increased Na + -Ca 2+  exchange currents (NCX) and decreased total K +  currents. Sixty-six percent of myopathic ventricular myocytes showed EADs compared with 17% of sham myocytes ( p &lt0.05). Intracellular application of 1 μM Ru360, a mitochondrial Ca 2+  uniporter (MCU) specific antagonist, could reduce mitochondrial Ca 2+  transients, decrease APD90 and ameliorate EADs. Furthermore, knock down MCU could inhibit mitochondrial Ca 2+  uptake, reduce NCX, decrease APD90 and depress EADs in NI-HF mice ventricular cells which led to less ventricular fibrillation in NI-HF mice, implicating mitochondrial Ca 2+  handling in modulating the arrhythmic risk through NCX induced EADs.   Conclusions:  Mitochondrial Ca 2+  handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a novel therapeutic target to reduce arrhythmic risk in this condition.
Association between initial post-concussion presentation and persistent symptoms at 1–month post-concussion
Authors: Johna Register-Mihalik, Mackenzie Herzog, O Josh Bloom, Janna Fonseca, Kristen Phillips, Valerie De Maio
Journal: British Journal of Sports Medicine (2017)

Objective To examine associations between acute post-concussion measures and 1-month persistent symptom presence among paediatric concussion patients. Design Prospective cohort. Setting Three family medicine clinics, from the same practice, in an urban/suburban area of the USA. Subjects Paediatric concussion patients (n=179); ages 8-18 years (median age=15; IQR: 13-16) presenting within three days of injury. Intervention Participants completed a systematic evaluation during their initial visit and a 4-6 week follow-up survey (80% follow-up; n=144). The initial visit variables included age, gender, previous head injury, total symptom severity, Immediate Postconcussion Assessment and Cognitive Test (ImPACTTM) composite scores, and near point convergence (NPC). Outcome measures The primary outcome was 1-month follow-up persistent symptom presence, determined using the Rivermead Postconcussion Symptoms Questionnaire. We assessed univariate relationships for each variable with persistent symptoms. Variables significant in univariable analyses (p&lt;0.10) were included in a multivariable logistic regression model. Results Persistent symptoms were reported for 27.1% (n=39) of participants. Females were more likely to have persistent symptoms (OR=1.9; 95% CI: 0.9, 4.0; p=0.086). Initial visit total symptom severity (Z=4.2; p&lt;0.001) was higher in those with persistent symptoms. Initial visit verbal memory (Z=−1.7; p=0.083), processing speed (Z=−1.7; p=0.093), and reaction time (Z=2.8; p=0.001) were worse in those with persistent symptoms. Total symptom severity was the only factor significant in the multivariable model (OR=1.04; 95% CI=1.02–1.07). Conclusions Gender, acute symptom burden and post-concussion neurocognitive deficits have significant relationships with persistent symptom presence. Clinicians should be mindful of these factors when considering treatment. Competing interests The current study was funded in part by the National Operating Committee on Standards for Athletic Equipment. Dr. Bloom is employed at the study setting. Ms. Fonseca is employed at the study setting. Ms. Phillips is employed at the study setting.
How could improvement in the management of T-cell acute lymphoblastic leukemia be achieved? Experience of Princess Nourah Oncology Center, National Guard Hospital, Jeddah, Saudi Arabia
Authors: T. M. Khattab, W. A. Jastaniah, S. K. Felimban, N. Elemam, K. Abdullah, B. Ahmed
Journal: Journal of Clinical Oncology (2009)

10048 Background: T-cell acute lymphoblastic leukemia (T-ALL) is representing 10–15% of pediatric ALL. The use of more intensive treatments and risk adapted therapy have significantly improved the outcome of patients with T-ALL and event-free survival rate of 60–70% are now reported in children. Our published data showed that T-ALL phenotype patients fared poorly with 5 year survival of 27% versus 83% for precursor B-ALL (Recent Advances Research Update: 2006, 7; 1, P 51–56). Objectives: We reviewed all patients diagnosed with T-ALL to assess risk classification according to NCI criteria, type of therapy received, overall survival and causes of mortality. Methods: Retrospective review of all patients files diagnosed with T-ALL from 1989 until now with data collection including; sex, age, white cell count (WBCs), CNS disease, type of protocol used, length of survival, overall survival, cause of death (toxic, disease). Results: Over the last 20 years, T-ALL cases registered were 52/460 (11%) of all ALL cases, Male:Female ratio 42:10 (4.2:1), median age 7 year (range: 1.5–12 yrs). Median WBCs 50,000/Cmm (range: 1.500–619,000/Cmm) and positive CNS at diagnosis 10/52 (20%). NCI risk classification criteria showed SR 24/52 (46%) and HR 28/52 (54%). Protocols used were UKALL ( n = 21; 3 UKALL X-B, 4 UKALL X-D, 10 UKALL XI and 4 MRC-97 ). BFM (n = 8); and CCG 1961 (n = 23). Overall survival 27/52 (52%) and 25 pts. died (48%); 15 secondary to disease recurrence (9 on UKALL, 4 BFM, 2 CCG 1961); 4 during induction, 1 fulminant hepatic failure, 1 tumor lysis syndrome, and 4 due to toxicities (mucormycosis, staphylococcal toxic shock syndrome, CMV pneumonia, pseudomonas sepsis). Survival for different regimen; UKALL: 5/21=31%, BFM: 4/8=50%, CCG: 18/23=78%, while overall cohort survival 52%. Mean length of survivors 4 year (range 4–140 month) and mean length for non-survivors 1 year (range 0.1–40 months). Conclusions: This review showed the improvement of T-ALL survival from 27% to 56%. Using augmented therapy based on CCG1961 was associated with better outcome. Further risk and response stratification in addition to intensification of therapy for T-cell ALL in our center may prove to be beneficial. Therapy remains an important prognostic factor. No significant financial relationships to disclose.
HGG-10. COMBINATION OF BEVACIZUMAB AND TEMOZOLOMIDE IN CHILDREN WITH PRIMARY HIGH-GRADE GLIOMAS
Authors: Boris Kholodov, Andge Valiakhmetova, Ekaterina Tarasova, Sergey Gorelishev, Marina Ryzhova, Yuri Trunin, Sergey Roumyantsev, Kaspot Matuev
Journal: Neuro-Oncology (2017)

PURPOSE: The survival rate of children with primary high grade CNS-gliomas remains low. There are no effective chemotherapeutic regimens for pediatric HGG. Recent studies have shown the effectiveness of Bevacizumab & Temozolomide combination in adults. The aim of our study was to evaluate the effect of this approach in increasing overall survival (OS) in children with CNS-HGGs. PATIENTS AND METHODS: In a prospective study, from January 2009 to December 2016, we observed the group of 25 children aged 2 - 17 years (males - 16, females - 9) with ana-plastic astrocytoma (n=11) and glioblastoma (n=14) of CNS. After surgery all patients received local radiotherapy (RT) in dose 55–60 Gy combined with Temozolomide 75 mg/m2 daily from the first day of RT. Following RT patients received 6–12 cycles of combined therapy which consisted of Te-mozolomide 150 mg/m2 orally, on days 1–5 and Bevacizumab 5 mg/kg intravenously, on days 1 and 15, repeated every 28-days. Follow up therapy included Bevacizumab in dose (5 mg/kg) every 21 days during 12 months. The primary end point was progression-free survival; secondary end points were overall survival and safety. RESULTS: Response assessment showed that 6/25 (24%) achieved complete response (PR), 8/25 (32%) - partial response (PR) and 11/25 (44%) - stable disease (SD). The median PFS was 19,5 months. The -12, 24, -36 and 48-month PFS were 65 ± 14%, 44 ± 16%, 32 ± 12% and 28 ± 10%, respectively. The median OS was 24,5 months. The -12, 24, 36 and 48-month OS were 73 ± 13%, 46 ± 15%, 39 ± 12% and 34 ± 10%, respectively. The therapy was well tolerated with low toxicity. Grade 3 thrombocytopenia related to Temozolomide was noted in 10 patients, grade 2 proteinuria - in 2, and intratumoral hemorrage - in 1. CONCLUSION: Combination of Bevacizumab and Temozolomide in children with primary HGGs, resulted in increased PFS and OS and better tolerance compared to historical data.
Clinical Characteristics, Histopathological Features, and Clinical Outcome of Methamphetamine-Associated Cardiomyopathy
Authors: Stephan Schürer, Karin Klingel, Marcus Sandri, Nicolas Majunke, Christian Besler, Reinhard Kandolf, Philipp Lurz, Michael Luck, Pia Hertel, Gerhard Schuler, Axel Linke, Norman Mangner
Journal: JACC Heart Failure (2017)
Abstract P065: Hypercholesterolemia Induced Atherosclerosis via the Mechanism of Autophagy Pathway
Authors: Chunjiang Tan, Wenlie Chen, Yanbin Wu, Ruhui Lin, Jiumao Lin
Journal: Circulation Research (2011)

Objectives: To investigate the mechanism of hypercholesterolemia in the pathogenesis of atherosclerosis (AS). Background: As the main risk factor of AS, the mechanism of hypercholesterolemia (HC) in the pathogenesis of AS remains unclear. Methods: White New Zealand male rabbits were fed a high cholesterol diet (H) for 14 weeks to induce AS with normal diet fed rabbits as a control(N). In vitro, human aortic vascular endothelia (HAVED) and smooth muscle cells (HSMC) were incubated with different concentrations of HC in the comparison with the cells that the specific gene of Beclin1 or LC3-I/II were knocked down by siRNA transfection. Blood lipids, and vascular histologic structure, mRNA and protein expressions of Becline1, microtubule-associated protein 1 light chain 3(LC3-I/II) and autophagosomes were determined in the rabbit abdominal aorta or in the cultured cells. Results: Serum levels of total cholesterol,triglyceride and low density lipoprotein cholesterol were significantly increased in H than those in N ( P &lt;0.05). Histologic structure of abdominal aorta showed more aggravated in wall thickness, lumen narrowness and atheroma in H than those in N ( P &lt;0.05). The expressions of Becline1, LC3-I/II in mRNA or proteins were strongly increased in H than those in N ( P &lt;0.05), which was consistent with the expressions of autophagosomes in the two groups.At the cap or the shoulder of atheromas, the expressions of Becline1, LC3-I/II and autophagosomes were far more enhanced than those in non-atheromatous areas in the same sample of H group ( P &lt;0.05). In vitro, HAVED or HSMC that preincubated with HC revealed more expressions of Becline1, LC3-I/II and autophagosomes, which were relevant to the concentrations and the preincubation time of HC, compared to the cells that incubated with N serum. Further, the autophagosomes in the cultured cells were correlated with the number of survive cells. Compared to the intact cells, the expressions of autophagosomes in the cells that the gene of Beclin1 or LC3-I/II was knocked down were greatly suppressed, and the number of survive cells was relatively increased, even they were exposed to HC incubation. Conclusions: The current experiments suggested that HC mediated the pathogenesis of AS partially via the pathway of autophagy.
IMMU-07. CHECKPOINT MOLECULE B7-H3 IS HIGHLY EXPRESSED ON MEDULLOBLASTOMA AND PROVES TO BE A PROMISING CANDIDATE FOR CAR T CELL IMMUNOTHERAPY
Authors: Johanna Theruvath, Sabine Heitzeneder, Robbie Majzner, Claus Moritz Graef, Karen Cui, Anandani Nellan, Samuel H Cheshier, Crystal Mackall, Siddhartha Mitra
Journal: Neuro-Oncology (2017)

BACKGROUND: B7-H3 (CD276) is a member of the B7 family of molecules involved in immune regulation and is over-expressed on a wide variety of solid tumor types. For this study we used a second-generation chimeric antigen receptor (CAR) T-cell targeting B7-H3 with the 41BB using a binder based on antibody MGA271. This CAR was previously created by the Mackall group and showed strong efficacy against an osteosarcoma model. The goal of this study was to test the anti-tumor function of the B7-H3 CAR in a myc-amplified highly aggressive medulloblastoma xenograft model. METHODS: We screened several medulloblastoma cell lines for B7-H3 expression and tested cytokine release (IL-2, TNF-α, INF-g) in vitro. Immunodeficient mouse xenograft models of a human Group 3, myc-amplified medulloblastoma cancer cell-line (D425) was used for in vivo efficacy studies. RESULTS: High expression of B7-H3 antigen was observed on various medulloblastoma cell lines (D425, MED8A, SU_MB002, D283, D341) and a freshly resected primary tumor sample classified as group 2 SHH subgroup. 24hr co-incubation of B7-H3 CAR T-cells and tumor cells resulted in a high cytokine release of IL-2, TNF-α, INF-g. Administration of a single intratumoral infusion of 1 x 106 B7-H3 CAR T-cells into the posterior fossa was able to eradicate tumor burden. Furthermore, intravenous administered single infusion of 10x 106 B7-H3 CAR T-cells succeeded in crossing the blood-brain barrier and lead to prolonged survival (p= 0,007). CONCLUSIONS: We show B7-H3 overexpression on various medulloblastoma and primary patient sample. CAR T-cell targeting B7-H3 is efficacious in eradicating medulloblastoma.
Long-Term Excessive Body Weight and Adult Left Ventricular Hypertrophy Are Linked Through Later-Life Body Size and Blood Pressure
Authors: Huijie Zhang, Tao Zhang, Shengxu Li, Yajun Guo, Wei Shen, Camilo Fernandez, Emily Harville, Lydia A. Bazzano, Elaine M. Urbina, Jiang He, Wei Chen
Journal: Circulation Research (2017)

Childhood adiposity is associated with cardiac structure in later life, but little is known regarding to what extent childhood body weight affects adult left ventricular geometric patterns through adult body size and blood pressure (BP).Determine quantitatively the mediation effect of adult body weight and BP on the association of childhood body mass index (BMI) with adult left ventricular (LV) hypertrophy.This longitudinal study consisted of 710 adults, aged 26 to 48 years, who had been examined for BMI and BP measured ≥4× during childhood and ≥2× during adulthood, with a mean follow-up period of 28.0 years. After adjusting for age, race, and sex, adult BMI had a significant mediation effect (76.4%; P<0.01) on the childhood BMI-adult LV mass index association. The mediation effects of adult systolic BP (15.2%), long-term burden (12.1%), and increasing trends of systolic BP (7.9%) were all significant (P<0.01). Furthermore, these mediators also had significant mediation effects on the association of childhood BMI with adult LV hypertrophy, eccentric hypertrophy, and concentric hypertrophy. Importantly, the mediation effects of adult BMI were all significantly stronger than those of adult systolic BP on LV mass index, LV hypertrophy, and LV remodeling patterns (P<0.01). Additionally, the mediation effect of systolic BP on concentric hypertrophy was significantly stronger than that on eccentric hypertrophy (P<0.01).These findings suggest that increased childhood BMI has long-term adverse impact on subclinical changes in adult cardiac structure, and early life excessive body weight and adult LV hypertrophy are linked through later life excessive body weight and elevated BP.