tbuckley/cabot-search huggingface dataset:
Abstract 113: <i>Klf5</i> and <i>Ppara</i> Expression is Increased at the Early Stage and Reduced at the Late Stage of Myocardial Ischemia/Reperfusion in Mice
Authors: Christine J Pol, Mesele-Christina Valenti, Sarah M Schumacher, Ancai Yuan, Erhe Gao, Ira J Goldberg, Walter J Koch, Konstantinos Drosatos
Journal: Circulation Research (2015)

Inhibition of cardiac fatty acid oxidation (FAO) is considered beneficial after ischemia reperfusion (I/R). Krüppel-like factors (KLF) have an important role in metabolism. In a model of cardiac energetic deficiency (LPS-treated mice), in silico promoter analysis and whole genome array analysis indicated cardiac KLF5 as important regulator of Ppara . Gene expression analysis in human ventricular myocytes (AC16) treated with Ad-Klf5 followed by ChIP analysis confirmed that KLF5 is a positive transcriptional regulator of Ppara . Mice with cardiomyocyte-specific Klf5 ablation (αMHC-Klf5 -/- ) that we made had reduced cardiac Ppara expression and other FAO-related genes. The role of PPARα activation in I/R injury is unclear as both beneficial and detrimental effects have been reported. We aimed to gain insight in the effects of KLF5 and PPARα on acute I/R injury. To mimic I/R in vitro , AC16 cells were subjected to hypoxia (9.5 h) followed by short (1h) or prolonged (14h) normoxia. Ppara expression was initially (1h) increased (p&lt;0.05) and then (14 h) decreased (p&lt;0.05). Klf5 expression pattern showed a trend of similar changes . Infarction was performed by 30 min of left coronary artery occlusion followed by 2 or 24 hours of reperfusion in wild type mice. I/R resulted in a trend for an initial increase in Klf5 (2-fold, p=0.05), Ppara (3-fold, p=0.08), and Pdk4 (8-fold, p&lt;0.01) mRNA at 2h post-surgery. Klf5 (2-fold; p&lt;0.01) and Ppara (9-fold; p&lt;0.05) expression were decreased 24h post-surgery. Consistent with Ppara changes, there was a 2-fold decrease of Cpt1 (p&lt;0.01) and Vlcad (p&lt;0.01) and a trend for decreased Aox (2-fold), Lcad (2-fold), and Pdk4 (6-fold) compared to sham. Echocardiography indicated normal cardiac function after 24h post-surgery. Despite reduced FAO, αMHC-Klf5 -/- mice subjected to I/R had a marked increase in mortality; 40% (4 of 10) of αMHC-Klf5 -/- mice died within the first 24h of reperfusion while no mortality was observed in wild type mice that underwent I/R. In conclusion, I/R is associated with an increase in Klf5 and Ppara in the first hours of reperfusion followed by a decrease in Klf5 and Ppara . Increased mortality for αMHC-Klf5 -/- mice with I/R injury suggests that the initial increase may be an adaptive response that is critical for survival.
DIPG-19. MESENCHYMAL STEM CELLS TARGET DIFFUSE INTRINSIC PONTINE GLIOMA IN MICE AFTER INTRANASAL DELIVERY
Authors: Michael Chastkofsky, Daniele Procissi, Cynthia Yang, Stewart Goldman, Maciej Lesniak, Rintaro Hashizume, Irina Balyasnikova
Journal: Neuro-Oncology (2017)

Diffuse Intrinsic Pontine Glioma (DIPG) is a high-grade pediatric brainstem glioma afflicting children 7–9 years old. The anatomic and diffuse characteristics of DIPG prevent surgical removal, and the blood-brain barrier impedes chemotherapy, while radiation, the current standard treatment, does not improve survival. Intranasal delivery (IND) of mesenchymal stem cells (MSC) can potentially overcome these obstacles and transport therapeutics directly to DIPG. We utilized a patient-derived xenograft model of DIPG implanted in the brainstem of nude mice to assess the viability of IND of MSCs for targeting DIPG. Magnetic resonance imaging (MRI) was used for tumor detection and longitudinal tracing and quantification of superparamagnetic iron nanoparticle-labeled MSCs. Whole brain scans were acquired using a T2-weighted MR sequence in 3 dimensions with isotropic spatial resolution (150-micron), and were performed before and at multiple time-points after (1h, 24h, 48h, and 120h) IND of MSCs. All images were realigned for accurate comparison between time-points. Concentrated hypointense signals, indicative of iron-labelled MSCs, were observed in the brainstem 2 days post-IND, which became more diffuse 5 days post-IND. Prussian Blue (PB) staining confirmed the presence of iron nanoparticles in the brainstem. Immunocytochemistry (ICC), using antibodies against MSC marker CD105, and DIPG-specific mutation H3-K27M, identified MSCs surrounding the tumor at 5 days post-IND. Additionally, PB staining detected iron nanoparticles in the trigeminal nerve, confirming the route of MSC migration to the brain. Fractionated brain irradiation (0.5 Gy delivered 3 times/week for 2 weeks), significantly improved MSC migration and targeting of DIPG, as determined by MRI, PB, and ICC. Cytokine array analysis of irradiated DIPG tumors revealed a significant upregulation of MIP-3-beta and TRAIL R4, potentially promoting MSC migration to irradiated DIPG tumors. Our findings demonstrate the potential for stem cell-based therapeutics to target DIPG and warrants further investigation. Supported by the Robert H. Lurie Comprehensive Cancer Center.
EPND-02. GENOMIC COPY NUMBER ALTERATIONS IN EPENDYOMOMA
Authors: Smadar Avigad, Yulia Margolin Miller, Suzana Fichman-Horn, Meora Feinmesser, Shalom Michowitz, Hendrik Witt, Stefan M. Pfister, Marcel Kool, Kristian Pajtler, Isaac Yaniv, Helen Toledano
Journal: Neuro-Oncology (2017)

Ependymoma is the third most common malignant pediatric tumor of the central nervous system. Poor outcome and unpredictable behavior of this tumor in children along with insufficient therapeutic approaches have created the need to better understand the biology of ependymoma. DNA copy number alterations (CNAs) are a hallmark of cancer that can drive the expression of oncogenes or delete tumor suppressor genes. CNAs were analysed in 34 primary ependymoma primary tumor samples and in 10 paired primary-relapse samples. Copy number alterations were identified in eighteen primary tumor samples (53%). The average number of CNAs was 3.9 alterations per tumor. The most common CNAs identified were: 1q gain (28%), 8 gain (33%) and 10p loss (28%). Progression Free Survival (PFS) of patients harboring chromosome 8 gain was 0% versus 31% for those with normal copy number (p=0.016). Using the cut off of under or equal/above 5 alterations per tumor, could identify a group of patients with an increased risk of 4.8 fold to progress (p=0.005). PFS of patients with ≥ 5CNA was 10% versus 32% for those with less than 5 CNA’s (p=0.026). According to correlation between CNAs and clinical parameters, high number of CNAs is more common in high grade tumors (p=0.015) and in patients over 3 years old (p=0.017).In the paired primary-relapse samples, number of CNAs in relapse tumor samples was higher than in primary tumors (6.5 vs. 3.9 alterations, respectively). Of the ten paired samples analyzed: three had no CNAs and were identical, two harbored the identical CNA changes between primary and relapse samples and in the remaining 5 clonal evolution was apparent. In two out of the five, the original clone acquired additional changes and in three, the relapse clone was completely different. We suggest CNAs as a new independent prognostic factor for relapse.
LGG-16. LOCATION AND HISTOLOGY DICTATE THE LIKELIHOOD OF MOLECULAR EVENTS IN PEDIATRIC LOW-GRADE GLIOMA
Authors: Scott Ryall, Michal Zapotocky, Anthony Arnoldo, Matthew Mistry, Ana Guerreiro Stucklin, Alvaro Lassaletta, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2017)

Over the last decade, a plethora of genetic information in pediatric low-grade gliomas (pLGG) has been uncovered. Clinically, many of these molecular markers have been implicated in aiding in patient diagnosis, predicting prognosis, and stratifying the most effective therapeutic strategy. However, there has yet to be a consensus on what molecular markers to test for, how to test for them, or their incidence across tumour locations and histologies. We compiled a cohort of low-grade gliomas treated at the Hospital for Sick Children. MRI and pathology reviews confirmed tumour location and diagnosis. Molecular testing was conducted using a combination of the QX200 Bio-Rad Droplet-Digital PCR, NanoString nCounter, FISH, and RNA-seq depending on the alteration being tested for and the available material. Our cohort consisted of 480 patients with complete clinical and molecular data. The most frequent alteration in our cohort was KIAA1549-BRAF fusions (37%), followed by BRAF_V600E (20%). BRAF fusion events were most commonly seen in pilocytic and pilomyxoid astrocytoma (67% and 69%, respectively), whereas BRAF_V600E was primarily observed in ganglioglioma and PXA (52% and 85%, respectively). Interestingly, both low grade glioma, NOS and diffuse astrocytoma showed a wide array of molecular events, including BRAF_V600E, BRAF fusions, MYBL1 alterations and H3F3A_K27M. With respect to tumour location, the cerebellum showed significant enrichment for BRAF fusions (80%). In the hemispheres, diencephalon, brainstem and spinal cord, more mutational diversity was seen, with BRAF fusion and BRAF_V600E appearing most frequently, while additional events such as H3F3A_K27M, MYBL1 alterations, and FGFR1 fusions are also present. The work here shows the utility of targeted non-NGS techniques by which hotspot mutations and fusion events can be detected. Further, we show in which histological grades and locations specific events tend to cluster, providing a stepwise procedure by which the most likely molecular marks can be tested for.
Abstract 9778: Establishing Inter Rater Reliability of the National Early Warning Score (NEWS)
Authors: Donna M Miller
Journal: Circulation (2015)

A change in patient condition is a dynamic process which can go unrecognized and result in a failure to rescue. Changes in patients’ vital signs can precede adverse events many hours before critical events such as cardiac arrest or emergent transfer to the Intensive Care Unit occurs. Quantitative assessment tools are used to predict risk and need for additional resources at the bedside. These tools are referred to as Early Warning Scoring Systems. The Royal College of Physicians developed a standardized tool called the National Early Warning Score (NEWS, 2012) that uses a variety of physiologic parameters to assess risk and establish a trigger threshold for summoning additional resources. Purpose: Early warning scoring tools have been found to be reliable and accurate in predicting patient decompensation. However, data from instruments are only as reliable and accurate as the caregiver who obtains and documents the parameters. The purpose of this study was to establish inter rater reliability between the RN and PCA using NEWS. Design, Sample, Setting, Procedures: This study was conducted on the clinical units of a 104 bed Long Term Acute Care Hospital (LTCH) system. These units accept patients directly from Intensive Care Units who require intense services to maintain their trajectory toward recovery. The NEWS provides a way for early detection of patient decompensation which can prevent readmission to acute care and the subsequent financial implications The convenience sample consisted of 22 RNs and 6 PCAs. Consented subjects reviewed an unfolding case study that portrayed a typical patient on the LTCH unit. Subjects were asked to circle the parameter ranges on the NEWS tool that corresponded to physiologic values in the scenario. Findings: Krippendorff’s alpha was utilized to determine the level of agreement among the raters examining the three scenarios. An alpha value of 0.94 was obtained indicating a high level of agreement among the raters. Conclusion: The NEWS can serve as a reliable adjunct to the provision of safe patient care. While it is not the sole source for determining
Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study
Authors: K. Reich, A. Pinter, J.P. Lacour, C. Ferrandiz, G. Micali, L.E. French, M. Lomaga, Y. Dutronc, C. Henneges, S. Wilhelm, S. Hartz, C. Paul
Journal: British Journal of Dermatology (2017)

It has been shown that the interleukin (IL)‐23/IL‐17 axis is critical in the pathogenesis of psoriasis. To present the primary end point (week 12) and safety and efficacy data up to week 24 from a head‐to‐head trial (IXORA‐S) of the IL‐17A inhibitor ixekizumab (IXE) vs. the IL‐12/23 inhibitor ustekinumab (UST). Randomized patients received IXE (160‐mg starting dose, then 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks, n = 136) or UST (45 mg or 90 mg weight‐based dosing per label, n = 166). The primary end point was the proportion of patients reaching ≥ 90% Psoriasis Area and Severity Index improvement (PASI 90). Hommel‐adjusted key secondary end points at week 12 included PASI 75, PASI 100, static Physician's Global Assessment (sPGA) score of 0 or 1, sPGA score of 0, Dermatology Life Quality Index (DLQI) score of 0 or 1, ≥ 4‐point reduction on the itch numerical rating scale (NRS) and changes in itch NRS and skin pain visual analogue scale. At week 12, IXE (n = 99, 72·8%) was superior to UST (n = 70, 42·2%) in PASI 90 response (response difference 32·1%, 97·5% confidence interval 19·8−44·5%, P < 0·001). Response rates for PASI 75, PASI 100 and sPGA (0,1) were significantly higher for IXE than for UST (adjusted P < 0·05). At week 24, IXE‐treated patients had significantly higher response rates than UST‐treated patients for PASI, sPGA and DLQI (unadjusted P < 0·05). No deaths were reported, and the treatments did not differ with regard to overall incidences of adverse events (P = 0·299). The superior efficacy of IXE demonstrated at week 12 persisted up to week 24. The safety profiles were consistent with those previously reported for both treatments.
Abstract 366: Disease Phenotype Assessment Across a Library of iPSC-Derived Cardiomyocytes From Patient Cohorts Carrying Distinct Mutations for Familial Hypertrophic Cardiomyopathy
Authors: Jason Tsai, Jason Lam, Veronica Sanchez-Freire, Rishali Gadkari, Maya Agarwal, Jing Bian, Guanyi Huang, Ashita Magal, Feng Lan, Andrew S Lee
Journal: Circulation Research (2015)

Familial hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in the young, and is the most common inherited heart defect affecting 1 in 500 individuals worldwide. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have been demonstrated to model aspects of HCM, but only one iPSC model has been reported for a single HCM mutation in one gene. Here we compare disease phenotypes across a library of patient-specific HCM iPSC-CMs carrying distinct mutations to assess the range of phenotypes that may present in iPSC-CMs derived from different patient cohorts. iPSCs were generated from three patient cohorts carrying known hereditary mutations for HCM in TNNI3, TNNT2, and MYH7 and family-matched controls. Disease phenotypes in patient-specific iPSC-CMs were modeled using immunostaining, Ca2+ imaging, multielectrode array, and video analysis of contractile motion. HCM iPSC-CMs displayed a range of disease phenotypes as assessed by cell size, Ca2+ homeostasis, electrophysiology, and contractile arrhythmia. Different HCM mutations resulted in distinct disease phenotype presentation. Importantly, identical mutations demonstrated similar readouts across multiple lines and clones whereas distinct mutations exhibited differential disease phenotypes. These findings indicate disease-specific iPSC-CMs present with a range of phenotypes for HCM that vary by specific mutation and that iPSC libraries are important for cellular characterization of diseases such as HCM. Figure 1. Derivation and disease phenotype modeling of iPSC-CMs generated from patients carrying distinct familial HCM mutations and family-matched controls.
Erratum: Corrigendum: A study of allelic diversity underlying flowering-time adaptation in maize landraces
Authors: J Alberto Romero Navarro, Martha Wilcox, Juan Burgueño, Cinta Romay, Kelly Swarts, Samuel Trachsel, Ernesto Preciado, Arturo Terron, Humberto Vallejo Delgado, Victor Vidal, Alejandro Ortega, Armando Espinoza Banda, Noel Orlando Gómez Montiel, Ivan Ortiz-Monasterio, Félix San Vicente, Armando Guadarrama Espinoza, Gary Atlin, Peter Wenzl, Sarah Hearne, Edward S Buckler
Journal: Nature Genetics (2017)
Young people with injuries from alcohol, drugs, or violence show increased suicide risk
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

Adolescents who are admitted to hospital for alcohol, drug, or violence related injuries have a similar risk of suicide in the next 10 years as people who have self harmed and should be offered the same support from mental health professionals, a study has found.

The study,1 funded by the Department of Health, looked at data from around one million adolescents aged 10-19 who were admitted to a UK hospital emergency department from 1997 to 2012 with injuries from self harm, drug, alcohol, violence, or an accident.

The results, reported in the Lancet , showed that a small number of adolescents (0.5%) died within 10 years of being admitted. Overall, the risk …
Test-retest reliability of the kinarm end-point robot for assessment of sensory, motor and neurocognitive function in athletes
Authors: Brian W Benson, Madeline Cosh, Cameron S Mang, Stephen H Scott, Chantel Debert, Sean Dukelow
Journal: British Journal of Sports Medicine (2017)

Objective To determine the reliability of the KINARM robot in assessing sensorimotor and neurocognitive function in athletes. Design Test-retest reliability. Setting Sport Medicine Clinic. Participants Thirty-nine randomly selected athletes (mean age: 18±3 years) over 2011–2012 and 2014–2015 seasons. Outcome measures Sixty-three parameters from five robotic tasks (Visually Guided Reaching, Position Matching, Object Hit, Object Hit and Avoid, and Trail Making B) characterising sensorimotor and neurocognitive function. Each athlete was tested three times, with an average of 43±27 days between baseline (BL) and first retest (R1), and 306±32 days between R1 and second retest (R2). Reliability was assessed by intra-class correlation coefficients (ICCs) between BL and R1, and R1 and R2. Change in task performance between assessments was also evaluated with multivariate analysis of variance (MANOVA) and post-hoc comparisons within specific task parameters. Main results ICCs ranged from −0.03 to 0.94 and −0.52 to 0.93 for BL to R1 and R1 to R2, respectively. ICCs were moderate to high (≥0.5) for 46 of 63 parameters (68%) from BL to R1, and 48 of 63 parameters (76%) from R1 to R2. MANOVAs and post-hoc comparisons indicated improvements in performance on 12/63 parameters (19%) between BL and R1, and changes in performance on 11/63 parameters (17%) between BL and R2. No significant changes were revealed in parameter performance between R1 and R2 sessions. Conclusions Overall, results suggest moderate to good test-retest reliability for the majority of KINARM robot task parameters in measuring baseline sensorimotor and neurocognitive function in athletes. Competing interests Brian W Benson In the future may receive a small royalty from BKIN Technologies Ltd. in consideration for assisting with development and validation of the KINARM end-point robotic device for use in acute sport concussion assessment and management. None. Stephen H Scott Co-founder and CSO of BKIN Technologies that commercialises the KINARM robot.
Abstract 178: Volume Overload Induced by Mitral Regurgitation Alters Spatial Regulation of Nitric Oxide/Reactive Nitrogen Species Signaling
Authors: Yuchuan Liu, Abdelkarim Sabri, Louis Dell'Italia, Victor Rizzo, Emily J Tsai
Journal: Circulation Research (2012)

Volume-overload (VO), as seen in regurgitant valvular disease, large myocardial infarction, and severe cardiac systolic dysfunction, triggers eccentric hypertrophy. Given that nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) modulate cardiomyocyte hypertrophy, apoptosis, and cardioprotection, differential regulation of these signals may distinguish eccentric from the more commonly studied concentric hypertrophy. We recently showed that pressure-overload (PO) induces relocalization and oxidation of the NO receptor soluble guanylyl cyclase (sGC), thereby diminishing cyclase activity and cGMP cardioprotection. The effects of volume-overload on NO and cGMP signaling are unknown. We tested the hypothesis that VO induces relocalization but not oxidation of sGC, thereby disrupting spatial regulation of NO-cGMP signaling without depressing cyclase activity. Volume-overload was established by chordal rupture-induced mitral regurgitation in dogs. We compared intracellular localization and activity of sGC in VO and control LVs (N=5 per group). Both sGC subunits were detected within and outside of caveolae-enriched lipid raft microdomains (Cav3+LR). In VO hearts, sGCβ1 fell in expression by nearly 50% and relocalized away from Cav3+LR to non-lipid raft microdomains (NLR). Despite VO-induced sGCβ1 changes, overall NO-stimulated sGC activity was preserved. An enhanced response to heme/NO-independent sGC activator BAY 60-2770 suggested that a subset of sGC was heme-oxidized in VO hearts, though to a much lesser degree than in PO hearts. As in PO hearts, Cav3+LR appear to protect sGC from heme-oxidation in VO hearts. Initial study of downstream reactive nitrogen species (RNS) and cGMP signaling supported our theory that VO altered spatial regulation of NO-cGMP signaling. Also, a trend towards increased overall tyrosine-nitration, predominantly within NLR, was observed in VO hearts. Volume-overload shifted cardiac NO-cGMP signaling from Cav3+LR to NLR microdomains without depressing NO/heme-dependent sGC activation. These findings suggest that differential spatial regulation of NO/RNS signaling, rather than simply increased RNS signaling, might drive the distinct molecular pathophysiology of eccentric hypertrophy.
Sofosbuvir and ribavirin in adolescents 12‐17 years old with hepatitis C virus genotype 2 or 3 infection
Authors: Stefan Wirth, Philip Rosenthal, Regino P. Gonzalez‐Peralta, Maureen M. Jonas, William F. Balistreri, Chuan‐Hao Lin, Winita Hardikar, Kathryn Kersey, Benedetta Massetto, Bittoo Kanwar, Diana M. Brainard, Jiang Shao, Evguenia Svarovskaia, Brian Kirby, Ronen Arnon, Karen F. Murray, Kathleen B. Schwarz
Journal: Hepatology (2017)

Children with chronic hepatitis C virus infection have limited treatment options. We evaluated the all-oral combination of sofosbuvir and ribavirin in adolescents aged 12-17 with hepatitis C virus genotype 2 or 3 (ClinicalTrials.gov NCT02175758). Fifty-two patients received sofosbuvir 400 mg once daily and weight-based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS-331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12). The median age of patients was 15 years, and 75% had genotype 3. Eighty-three percent of patients were treatment-naive, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% confidence interval, 90%-100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for those with genotype 3. The single patient who did not achieve SVR12 was lost to follow-up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in phase 2 and 3 sofosbuvir studies, the area under the curve and maximum concentration for sofosbuvir and GS-331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%-200%.Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic hepatitis C virus genotype 2 or 3 infection. (Hepatology 2017;66:1102-1110).