tbuckley/cabot-search huggingface dataset:
Abstract 293: Tcf7l2 Expression And Isoform Switching In Mouse Hearts
Authors: LU XIAO, Haiqing Bai, James Boyer, Bo Ye, Ning Hou, Haodong Xu, Faqian Li
Journal: Circulation Research (2013)

Lu Xiao, Haiqing Bai, James Boyer, Bo Ye, Ning Hou, Haodong Xu, and Faqian Li Department of Pathology and Laboratory Medicine and Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, NY, USA Backgrounds: Canonical Wnt signaling appears to have multiphasic and often antagonistic roles in cardiac development. The molecular mechanism for these opposing actions is not clear. We hypothesized that alternative splicing of TCF7L2, a nuclear interaction partner of beta-catenin is involved in the specificity of canonical Wnt signaling. Methods: RT-PCR were performed on embryonic (E16.5) and neonatal (day 8) hearts with primers spanning the end of first exon and the beginning of last exon and the products were cloned and sequenced. Result: There are totally 18 exons identified so far in TCF7L2. We sequenced 56 clones and 53 clones (29 from day 8) and (24 from E16.5) contained TCF7L2 sequences. No exon 6 or exon 17 was found in TCF7L2 transcripts of mouse hearts. Most clones (more than 80%) from E16.5 and day 8 hearts excluded exon 4. Both E16.5 and day 8 hearts had one clone with exon 9 deletion which does not change reading frame and another with alterations in exon 3 that lead to reading frame shift and premature stop codon. As reported in other organs, there were extensive alternative splicing in the C-terminal exons 14, 15 and 16. The inclusion of exon 14 was more frequently in day 8 (18 of 29, 62%) than in E16.5 (8 of 24, 33%) hearts. The peptide encoded by exon 14 has conserved functional motif. Additionally, this alternative exon usage can change the C-terminus of TCF7L2 to include or exclude the so-called E tail with two binding motifs for C-terminal binding protein. Conclusion: The isoform switch of TCF7L2 occurs in neonatal mouse hearts and may have a role in the terminal differentiation of cardiac myocytes during this period.
MEDU-36. MERIVA® AND A NOVEL CHEMICALLY-MODIFIED CURCUMIN FOR THE TREATMENT OF MEDULLOBLASTOMA
Authors: Avery Wright, Benjamin Stuart, Rosamaria Ruggieri, Shamik Chakraborty, Kevin Kelley, Robert Wechsler-Reya, Francis Johnson, Lorne Golub, Joseph Scaduto, Marc Symons
Journal: Neuro-Oncology (2017)

Medulloblastoma is the most common pediatric central nervous system cancer, and despite an overall favorable prognosis with intensive multimodal treatment, children are especially at risk for significant negative effects of these treatments. There is a need for treatments that are less toxic with fewer negative long-term sequelae. Curcumin, the active component of the dietary spice turmeric, has shown promising anti-cancer effects in vitro and in preclinical models of many types of cancer, including medulloblastoma. Along with its potent anti-cancer effects, low toxicity and a wide therapeutic window make curcumin an ideal candidate as a novel therapeutic for pediatric cancer. A major barrier to achieving curcumin’s potential is poor bioavailability. To address this challenge we are focusing on two approaches: Meriva and TRB-N0224. Meriva is a curcumin-phosphatidylcholine complex shown to have 18-fold higher absorption than unformulated curcumin, while TRB-N0224 is a chemically modified curcumin. Our objective is to demonstrate therapeutic efficacy in an animal model of medulloblastoma. In vitro studies were conducted using the primary cell lines IMB226 sonic hedgehog-type cells (SHH) and D425MED group 3 medulloblastoma cells. Animal studies were performed using 2 models: a D425MED orthotopic xenograft model in immunocompromised mice and an orthotopic transplant model of group 3 medulloblastoma (Myc + DN-p53) in syngeneic C57BL/6 mice. We have demonstrated in vitro efficacy of both Meriva and TRB-N0224 against SHH and group 3 medulloblastoma cells. The D425MED animal model revealed negligible efficacy of Meriva using either oral or intraperitoneal administration. A pilot study with the Myc + DN-p53 model revealed a dose-dependent trend toward therapeutic efficacy of both Meriva and TRB-N0224 which point to a possible immunomodulatory role of curcumin in the control of tumor growth. Experiments with larger cohorts are in progress.
Abstract 69: Reduction of Diastolic Dysfunction by Treatment of a Combination of Agonists of Adenosine Receptor in Spontaneously Hypertensive Rats Submitted to Myocardial Infarction
Authors: Gisele Zapata-Sudo, Tais N Frazão, Jaqueline S da Silva, Eliezer J Barreiro, Carlos A Fraga, Roberto T Sudo
Journal: Circulation Research (2015)

Introduction: This work investigated the cardioprotective actions of the combination of a positive inotropic agent (LASSBio-294 ) and a potent vasodilator (LASSBio-897) in spontaneously hypertensive rats (SHR) submitted to myocardial infarction (MI). Methods: Twenty four SHR (180-200 g) were randomly divided in sham-operated (SO) and infarcted groups (MI) and each group subdivided in two: treatment with vehicle (DMSO) or with LASSBio-294 + LASSBio-897 (5mg/kg each, p.o.) during 8 weeks. After treatment period, the animals were submitted to echocardiography to determine the anterior wall thickness (AWT), ejection fraction (EF), fractional shortening (FS) and the ratio of early and late transmitral filling velocity (E/A). In addition, the following hemodynamic parameters were evaluated: mean blood pressure (MBP), left ventricular end diastolic pressure (LVEDP), left ventricular end-systolic pressure (LVESP) and LV contractility and relaxation (dp/dt max ). Hypertrophy was measured using the relation between heart weight to body weight (HW/BW). The volume fraction of collagen (%) was determined by measuring the area of H&amp;E stained tissue within a given field. Results: MI induced in SHR promoted a decrease in AWT; EF; FS and E/A from 2.0 ± 0.4 to 1.6 ± 0.9 mm; from 53.1 ± 7.5 to 25.3 ± 6.4 %; from 40.0 ± 0.9 to 25.3 ± 11.0 %; and from 1.4 ± 0.1 to 0.9 ± 0.1, respectively. Treatment with the combination of drugs, increased AWT to 2.5 ± 0.6 mm; EF to 73.2 ± 1.0 %; FS to 43.5 ± 6.6%; and E/A to 1.3 ± 0.1. Increase of LVEDP from 4.6 ± 0.3 to 30.0 ± 3.6 mmHg and duplicated oxygen consumption were observed in MI-SHR. The negative dP/dt was reduced from 6152 ± 1015 to 3957 ± 1225 mm Hg/s. After treatment, all hemodynamic parameters were restored to values similar to SO group. Mean blood pressure which was increased after MI from 168. 2 ± 18.6 to 197.7 ± 10.7 returned to 137.0 ± 19.3 mm Hg after treatment. Increased deposition of colagen from 15.1 ± 3.9 to 24.0 ± 0.9 % induced by MI was prevented with treatment with the combination of drugs (12.9 ± 3.8 %). Conclusion: Oral administration of the combination of LASSBio-294 and LASSBio-897 could be considered promising in preventing cardiac dysfunction in SHR submitted to MI.
Effect of a rule change on concussions and other injuries in professional baseball
Authors: Green Gary, John D’Angelo, Jon Coyles, Alex Valadka
Journal: British Journal of Sports Medicine (2017)

Objective To evaluate the hypothesis that a rule change can lower the incidence of concussions and other injuries in professional baseball. Design Retrospective review of professional baseball’s electronic medical record system. All Minor (MiLB) and Major League Baseball (MLB) teams are required to use this system. Setting Five full MiLB and MLB seasons in the United States and Canada. Participants All players in MiLB and MLB were included. The 30 MLB clubs have 750 active players and play 162 games per season. MiLB has approximately 7500 active players on 200 teams that play 56-144 games annually. Intervention Before the 2014 season, MLB instituted a rule limiting home plate collisions between base runners and catchers. Outcome measures All concussions and other injuries at home plate from 2011 to 2015 were analysed by mechanism and player position. Main results From 2011-2013, an annual average of 117 injuries occurred at home plate in both MiLB and MLB, with an average of 4823 days lost annually. An average of 13 concussions occurred annually in both MiLB and MLB. Following the rule change, in 2014-2015 there was an annual average of 60 home plate injuries with 1592 days lost. There were 6 MiLB home plate concussions in 2014 and none in 2015. There were no home plate concussions in MLB in 2014-2015 (p=0.07). MiLB and MLB combined for approximately 660,000 athlete exposures per season. Conclusions This rule change was associated with a strong trend toward reduced concussions and other injuries at home plate. Competing interests Mr. D’Angelo and Mr. Coyles are employed by Major League Baseball. Dr. Green receives payment from Major League Baseball for his role as Medical Director. Dr. Valadka is a paid consultant to Major League Baseball. The authors have no other disclosures to report.
Towards the Potential Use of In Vitro Expanded Regulatory T-Cells (Tregs) in Aplastic Anemia (AA): Opportunities for Therapy
Authors: Benedetta Costantini, Shahram Kordasti, Marc Martinez-Llordella, Giovanni Povoleri, Judith C. W. Marsh, Frederic Toulza, Ghulam J. Mufti
Journal: Blood (2016)
Gene Expression Profiling in <i>BRAF</i>-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib
Authors: Matthew J. Wongchenko, Grant A. McArthur, Brigitte Dréno, James Larkin, Paolo A. Ascierto, Jeffrey Sosman, Luc Andries, Mark Kockx, Stephen D. Hurst, Ivor Caro, Isabelle Rooney, Priti S. Hegde, Luciana Molinero, Huibin Yue, Ilsung Chang, Lukas Amler, Yibing Yan, Antoni Ribas
Journal: Clinical Cancer Research (2017)

Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated.Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P < 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures.Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3-2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95% CI, 1.0-2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR, 1.1; 95% CI, 0.7-1.8; P = 0.66).Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature. Clin Cancer Res; 23(17); 5238-45. ©2017 AACR.
Genes for Asthma? An Analysis of the European Community Respiratory Health Survey
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Besides environmental triggers, a family history of asthma is a strong risk factor for the development of asthma in offspring. The pooled data from 13,963 interviews of randomly selected, 20 to 48 yr-old participants from the 30 centers of the European Community Respiratory Health Survey (ECRHS) were analyzed with conventional logistic regression and a Class A regressive model adapted for the segregation of various transmission modes in families. The asthma prevalence in the interviewed index generation was 6.9% (95% confidence interval [CI]: 6.5 to 7.3), and in the parent generation was 6.1% (5.8 to 6.4). As with asthma prevalence, the risk of a subject having asthma if a parent had asthma also had a large geographic variation across the survey centers. The mean risk if a father had asthma was 2.9 (2.4 to 3.5), and If the mother had asthma was 3.2 (2.6 to 3.9). The risk increased to 7.0 (3.9 to 12.7) if both parents were affected. For developing extrinsic asthma, extrinsic asthma in any parent was a greater risk factor (4.9 [3.9 to 6.0]) than intrinsic asthma of the parent (1.5 [0.8 to 2.6]), and the risk for women was slightly higher than that for men (4.3 [3.3 to 5.5] versus 3.6 [2.6 to 5.0]). Applying different segregation models, only a model for a two-allele gene with a codominant inheritance could not be rejected, assuming a major gene with a population frequency of 24.2%. Further results make a multilocus/threshold model likely. In conclusion, a history of asthma in parents is a strong risk factor for asthma in the offspring. Under the assumptions of the applied segregation analysis, at least one major gene exists which could be a gene involved also in allergy. However, asthma is not fully described by a single-gene model. The risk for asthma varies within the European countries, and should be seen in the context of a complex genetic and environmental pathophysiology.
Medical Assistance in Dying — Implementing a Hospital-Based Program in Canada
Authors: Madeline Li, Sarah Watt, Marnie Escaf, Michael Gardam, Ann Heesters, Gerald O’Leary, Gary Rodin
Journal: New England Journal of Medicine (2017)

After Canada legalized medical assistance in dying (MAiD), the University Health Network in Toronto implemented a hospital-based MAiD program. UHN offers a framework for assessing patients for and providing MAiD while respecting the rights of patients and staff.
New Definition of Treatment Response in Adult Acute Lymphoblastic Leukemia (ALL): Use of Molecular Markers for Minimal Residual Disease (MRD).
Authors: Nicola Goekbuget, Monika Brueggemann, Renate Arnold, Claus-Rainer Bartram, Rainer Fietkau, Mathias Freund, Arnold Ganser, Michael Kneba, Thomas Lipp, Wolf-Dieter Ludwig, Georg Maschmeyer, Dorle Messerer, Thorsten Raff, Harald Rieder, Eckhard Thiel, Dieter Hoelzer
Journal: Blood (2009)
Change to collecting data makes counting GPs impossible, says royal college
Authors: Matthew Limb
Journal: BMJ (2017)

GP numbers in England fell from September 2016 to March 2017 despite a multibillion pound rescue plan to ease shortages in general practice, figures from NHS Digital show.1 The Royal College of GPs said that a depleted GP workforce was unacceptable when the workload was “soaring.”

Provisional estimates (figures exclude locums) showed 33 423 full time equivalent (FTE) GPs at 31 March this year—down 381 from September 2016 (33 804). In the most recent quarter to March 2017, however, a small rise of 36 GPs was recorded, up from 33 387 FTEs at 31 December 2016.

In April 2016 NHS England announced extra annual investment, rising to an …
Cerebrospinal Fluid Cytokines Correlate With Aseptic Meningitis and Blood–Brain Barrier Function in Neonatal‐Onset Multisystem Inflammatory Disease: Central Nervous System Biomarkers in Neonatal‐Onset Multisystem Inflammatory Disease Correlate With Central Nervous System Inflammation
Authors: Jackeline Rodriguez‐Smith, Yen‐Chih Lin, Wanxia Li Tsai, Hanna Kim, Gina Montealegre‐Sanchez, Dawn Chapelle, Yan Huang, Cailin H. Sibley, Massimo Gadina, Robert Wesley, Bibiana Bielekova, Raphaela Goldbach‐Mansky
Journal: Arthritis & Rheumatology (2017)

Objective To evaluate proinflammatory cytokines and leukocyte subpopulations in the cerebrospinal fluid (CSF) and blood of patients with neonatal‐onset multisystem inflammatory disease (NOMID) after treatment, and to compare inflammatory cytokines in the CSF and blood in 6 patients treated with 2 interleukin‐1 (IL‐1) blockers—anakinra and canakinumab. Methods During routine follow‐up visits between December 2011 and October 2013, we immunophenotyped the CSF of 17 pediatric NOMID patients who were treated with anakinra, and analyzed CSF cytokine levels in samples obtained at baseline and at 3–5‐year follow‐up visits and compared them to samples from healthy controls. Results CSF levels of IL‐6, interferon‐γ–inducible 10‐kd protein (IP‐10/CXCL10), and IL‐18 and monocyte and granulocyte counts significantly decreased with anakinra treatment but did not normalize to levels in the controls, even in patients fulfilling criteria for clinical remission. CSF IL‐6 and IL‐18 levels significantly correlated with measures of blood–brain barrier function, specifically CSF protein (r = 0.75 and r = 0.81, respectively) and albumin quotient (r = 0.79 and r = 0.68, respectively). When patients were treated with canakinumab versus anakinra, median CSF white blood cell counts and IL‐6 levels were significantly higher with canakinumab treatment (10.2 cells/mm 3 versus 3.7 cells/mm 3 and 150.7 pg/ml versus 28.5 pg/ml, respectively) despite similar serum cytokine levels. Conclusion CSF leukocyte subpopulations and cytokine levels significantly improve with optimized IL‐1 blocking treatment, but do not normalize. The correlation of CSF IL‐6, IP‐10/CXCL10, and IL‐18 levels with clinical laboratory measures of inflammation and blood–brain barrier function suggests that they may have a role as biomarkers in central nervous system (CNS) inflammation. The difference in inhibition of CSF biomarkers between 2 IL‐1 blocking agents, anakinra and canakinumab, suggests differences in efficacy in the intrathecal compartment, with anakinra being more effective. Our data indicate that intrathecal immune responses shape CNS inflammation and should be assessed in addition to blood markers.
Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction
Authors: Takuma Tsuda, Mikito Takefuji, Nina Wettschureck, Kazuhiko Kotani, Ryota Morimoto, Takahiro Okumura, Harmandeep Kaur, Shunsuke Eguchi, Teruhiro Sakaguchi, Sohta Ishihama, Ryosuke Kikuchi, Kazumasa Unno, Kunihiro Matsushita, Shizukiyo Ishikawa, Stefan Offermanns, Toyoaki Murohara
Journal: The Journal of Experimental Medicine (2017)

Heart failure occurs when the heart is unable to effectively pump blood and maintain tissue perfusion. Despite numerous therapeutic advancements over previous decades, the prognosis of patients with chronic heart failure remains poor, emphasizing the need to identify additional pathophysiological factors. Here, we show that corticotropin releasing hormone receptor 2 (Crhr2) is a G protein-coupled receptor highly expressed in cardiomyocytes and continuous infusion of the Crhr2 agonist, urocortin 2 (Ucn2), reduced left ventricular ejection fraction in mice. Moreover, plasma Ucn2 levels were 7.5-fold higher in patients with heart failure compared to those in healthy controls. Additionally, cardiomyocyte-specific deletion of Crhr2 protected mice from pressure overload-induced cardiac dysfunction. Mice treated with a Crhr2 antagonist lost maladaptive 3'-5'-cyclic adenosine monophosphate (cAMP)-dependent signaling and did not develop heart failure in response to overload. Collectively, our results indicate that constitutive Crhr2 activation causes cardiac dysfunction and suggests that Crhr2 blockade is a promising therapeutic strategy for patients with chronic heart failure.
Asthma Is Associated with a Lower Risk of Sepsis and Sepsis-related Mortality
Authors: Joe G. Zein, Thomas E. Love, Serpil C. Erzurum
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

To the Editor:The immunopathology of asthma is complex.Although classic type 2 helper T-cell (Th2) immune responses are one major mechanism underlying asthma, other contributing mechanisms include activation of IL-17-mediated neutrophilic inflammation and innate Toll-like receptor responses to pathogens.These pathways are important to normal host response to pathogens and may potentially benefit patients with asthma.Greater mast cell degranulation and release of mediators, such as tumor necrosis factor-a and IL-6, may benefit outcomes of infections through enhanced neutrophil influx and killing of bacteria (1).Parasitic worms, which drive Th2 polarization, enhance clearance of Klebsiella in a septic peritonitis murine model and improve survival (2).In humans, circulating Th2 levels are higher among survivors as compared with matched patients who died after Staphylococcus aureus infection in a case-control study (3).Non-Th2 pathways also likely benefit patients with asthma.Toll-like receptors are linked to asthma and are primary sensors of invading pathogens (4-6).Heightened innate responses would enable faster pathogen clearance.Cecal puncture-induced sepsis in mice deficient in IL-17 receptor leads to less neutrophil recruitment into the peritoneal cavity, greater spread of infection, greater inflammatory response, and increased mortality as compared with wild-type mice (7).We hypothesized that individuals with asthma, characterized by activation of proinflammatory pathways, have a lower incidence of sepsis and/or sepsis-related mortality.We investigated this using the 2012 Healthcare Cost and Utilization Project-National Inpatient Sample (NIS), and validated results with additional data sources : 2007, 2008, and 2011 NIS and Cleveland Clinic Health System (CCHS) admissions between 2010 and 2014 for patients hospitalized with pneumonia, urinary tract infection (UTI), or skin and soft tissue infection (SSTI).The NIS is the largest all-payer inpatient database available in the United States and an important component of the Healthcare Cost and Utilization Project.In accordance with data use agreement, we analyzed a 20% weighted sample of U.S. hospital discharges, constituting more than 7 million discharges in each year.Deidentified data of patients hospitalized at the Cleveland Clinic from 2010
Abstract 17626: Sildenafil Prevents Progressive Hypertrophy and Normalizes the Enhanced Slow Force Response in Dystrophic Myocardium
Authors: Peter P Rainer, Kinya Seo, Dong I Lee, Scarlett Hao, Djahida Bedja, David A Kass
Journal: Circulation (2012)

Background Duchenne Muscular Dystrophy (DMD) is a frequent and devastating disease that affects both skeletal muscle and the heart, resulting in cardiomyopathy in virtually all patients. Key features include nNOS-dysregulation and excessive Ca2+ entry upon mechanical stress. A possible source of increased Ca2+ entry are mechano-sensitive TRPC channels. As TRPC3/6 channels can be suppressed by PKG phosphorylation, we hypothesized that augmentation of PKG stimulation ameliorates invivo function coupled to blunting of stretch-activated Ca2+ entry and the slow force response (SFR).  Methods Mdx, utrophin+/- mice were treated with sildenafil 200mg/kg/d for 2 months and followed-up by echocardiography; gene expression was assessed by qRT-PCR and PDE5 activity by fluorescence polarization. The SFR and Ca2+ transients were assessed in single cardiomyocytes attached to carbon fibers and papillary muscle preparations when exposed to stretch.  Results Mdx, utrophin+/- mice demonstrated marked hypertrophy when compared to WT or mdx-only mice, with up-regulation of fetal gene expression markers (ANP 4.5±0.8-fold, BNP 2.5±0.4-fold, bMHC 2.8±0.4-fold, p  Conclusion PDE5 inhibition is effective in preventing progressive hypertrophy and normalizing molecular markers of heart failure in dystrophic hearts. The SFR is enhanced in dystrophic cardiomyocytes and can be normalized by PDE5 inhibition or acute TRPC antagonism. These data support the involvement of TRPC channels in excessive Ca2+ entry and the enhanced SFR, offering a rationale for modifying TRPC Ca2+ entry, either by direct antagonism or by PKG phosphorylation of TRPC channels.
Efficacy and Safety of Azacitidine (AZA) Versus Conventional Care Regimens (CCR) in Patients Aged ≥75 Years with Acute Myeloid Leukemia (AML) in the Phase 3 AZA-AML-001 Study
Authors: John F. Seymour, Rena Buckstein, Valeria Santini, Hartmut Döhner, Richard M. Stone, Mark D. Minden, Ching-Yuan Kuo, Dina Ben-Yehuda, Joan Bargay, Stephen Songer, Jerry Weaver, C.L. Beach, Hervé Dombret
Journal: Blood (2016)