tbuckley/cabot-search huggingface dataset:
RNA-Seq Identifies Circulating miR-125a-5p, miR-125b-5p, and miR-143-3p as Potential Biomarkers for Acute Ischemic Stroke
Authors: Steffen Tiedt, Matthias Prestel, Rainer Malik, Nicola Schieferdecker, Marco Duering, Veronika Kautzky, Ivelina Stoycheva, Julia Böck, Bernd H. Northoff, Matthias Klein, Franziska Dorn, Knut Krohn, Daniel Teupser, Arthur Liesz, Nikolaus Plesnila, Lesca Miriam Holdt, Martin Dichgans
Journal: Circulation Research (2017)

Currently, there are no blood-based biomarkers with clinical utility for acute ischemic stroke (IS). MicroRNAs show promise as disease markers because of their cell type-specific expression patterns and stability in peripheral blood.To identify circulating microRNAs associated with acute IS, determine their temporal course up to 90 days post-stroke, and explore their utility as an early diagnostic marker.We used RNA sequencing to study expression changes of circulating microRNAs in a discovery sample of 20 patients with IS and 20 matched healthy control subjects. We further applied quantitative real-time polymerase chain reaction in independent samples for validation (40 patients with IS and 40 matched controls), replication (200 patients with IS, 100 healthy control subjects), and in 72 patients with transient ischemic attacks. Sampling of patient plasma was done immediately upon hospital arrival. We identified, validated, and replicated 3 differentially expressed microRNAs, which were upregulated in patients with IS compared with both healthy control subjects (miR-125a-5p [1.8-fold; P=1.5×10-6], miR-125b-5p [2.5-fold; P=5.6×10-6], and miR-143-3p [4.8-fold; P=7.8×10-9]) and patients with transient ischemic attack (miR-125a-5p: P=0.003; miR-125b-5p: P=0.003; miR-143-3p: P=0.005). Longitudinal analysis of expression levels up to 90 days after stroke revealed a normalization to control levels for miR-125b-5p and miR-143-3p starting at day 2 while miR-125a-5p remained elevated. Levels of all 3 microRNAs depended on platelet numbers in a platelet spike-in experiment but were unaffected by chemical hypoxia in Neuro2a cells and in experimental stroke models. In a random forest classification, miR-125a-5p, miR-125b-5p, and miR-143-3p differentiated between healthy control subjects and patients with IS with an area under the curve of 0.90 (sensitivity: 85.6%; specificity: 76.3%), which was superior to multimodal cranial computed tomography obtained for routine diagnostics (sensitivity: 72.5%) and previously reported biomarkers of acute IS (neuron-specific enolase: area under the curve=0.69; interleukin 6: area under the curve=0.82).A set of circulating microRNAs (miR-125a-5p, miR-125b-5p, and miR-143-3p) associates with acute IS and might have clinical utility as an early diagnostic marker.
Optical Coherence Tomography Findings in Patients With Coronary Stent Thrombosis
Authors: Tom Adriaenssens, Michael Joner, Thea C. Godschalk, Nikesh Malik, Fernando Alfonso, Erion Xhepa, Dries De Cock, Kenichi Komukai, Tomohisa Tada, Javier Cuesta, Vasile Sirbu, Laurent J. Feldman, Franz-Josef Neumann, Alison H. Goodall, Ton Heestermans, Ian Buysschaert, Ota Hlinomaz, Ann Belmans, Walter Desmet, Jurrien M. ten Berg, Anthony H. Gershlick, Steffen Massberg, Adnan Kastrati, Giulio Guagliumi, Robert A. Byrne
Journal: Circulation (2017)

Stent thrombosis (ST) is a serious complication following coronary stenting. Intravascular optical coherence tomography (OCT) may provide insights into mechanistic processes leading to ST. We performed a prospective, multicenter study to evaluate OCT findings in patients with ST.Consecutive patients presenting with ST were prospectively enrolled in a registry by using a centralized telephone registration system. After angiographic confirmation of ST, OCT imaging of the culprit vessel was performed with frequency domain OCT. Clinical data were collected according to a standardized protocol. OCT acquisitions were analyzed at a core laboratory. Dominant and contributing findings were adjudicated by an imaging adjudication committee.Two hundred thirty-one patients presenting with ST underwent OCT imaging; 14 (6.1%) had image quality precluding further analysis. Of the remaining patients, 62 (28.6%) and 155 (71.4%) presented with early and late/very late ST, respectively. The underlying stent type was a new-generation drug-eluting stent in 50.3%. Mean reference vessel diameter was 2.9±0.6 mm and mean reference vessel area was 6.8±2.6 mm2. Stent underexpansion (stent expansion index <0.8) was observed in 44.4% of patients. The predicted average probability (95% confidence interval) that any frame had uncovered (or thrombus-covered) struts was 99.3% (96.1-99.9), 96.6% (92.4-98.5), 34.3% (15.0-60.7), and 9.6% (6.2-14.5) and malapposed struts was 21.8% (8.4-45.6), 8.5% (4.6-15.3), 6.7% (2.5-16.3), and 2.0% (1.2-3.3) for acute, subacute, late, and very late ST, respectively. The most common dominant finding adjudicated for acute ST was uncovered struts (66.7% of cases); for subacute ST, the most common dominant finding was uncovered struts (61.7%) and underexpansion (25.5%); for late ST, the most common dominant finding was uncovered struts (33.3%) and severe restenosis (19.1%); and for very late ST, the most common dominant finding was neoatherosclerosis (31.3%) and uncovered struts (20.2%). In patients presenting very late ST, uncovered stent struts were a common dominant finding in drug-eluting stents, and neoatherosclerosis was a common dominant finding in bare metal stents.In patients with ST, uncovered and malapposed struts were frequently observed with the incidence of both decreasing with longer time intervals between stent implantation and presentation. The most frequent dominant observation varied according to time intervals from index stenting: uncovered struts and underexpansion in acute/subacute ST and neoatherosclerosis and uncovered struts in late/very late ST.
A phase 1 dose escalation study of eFT508, an inhibitor of mitogen-activated protein kinase-interacting serine/threonine kinase-1 (MNK-1) and MNK-2 in patients with advanced solid tumors.
Authors: Gerald Steven Falchook, Jeffrey R. Infante, Funda Meric-Bernstam, Langdon L. Miller, Karen Morison, Debra Vallner, Sam Sperry, Vikas Goel, Gary Gene Chiang, Kevin Webster, Jeremy Barton, Manish R. Patel
Journal: Journal of Clinical Oncology (2017)

2579 Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of multiple solid tumors. eFT508, a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, and thereby selectively regulates translation of a small set of mRNAs. In addition to direct antitumor activity, eFT508 triggers an anti- tumor immune response and enhances responses to checkpoint inhibitors in preclinical models. Methods: Using a 3+3 dose escalation schema, cohorts of solid tumor patients (pts) were treated with eFT508 administered orally once daily at doses ranging from 50 mg to 600 mg. Results: 28 pts were treated, and the most common tumor types were colorectal cancer (8), prostate cancer (3), and soft tissue sarcoma (3). Median number of prior therapies was 4. The most common observed adverse events (AEs) included nausea (47%), vomiting (47%), dyspepsia (23%), fatigue (20%), and constipation (20%). Two pts treated at 600 mg experienced Gr 3 related AEs, including one pt with Gr3 nausea and vomiting (met criteria for dose limiting toxicity) and one pt with reversible Gr3 AST/ALT elevation. 6 pts achieved stable disease with duration ranging from 82 to 196 days. Pharmacokinetic analysis revealed that eFT508 is bioavailable and rapidly absorbed, with median T max of 2 hours and a mean T 1/2 of 12 hours. Minimal accumulation was observed between Days 1 and 14/15, with mean accumulation factor of 1.2-fold. Analysis of eIF4E phosphorylation in peripheral blood cells suggested that doses ≥ 300 mg achieved engagement sufficient for maximal efficacy as predicted by preclinical models. Conclusions: Preliminary results suggest that eFT508 is well tolerated, and dose escalation continues with a cohort of pts providing pretreatment and on treatment biopsies for evaluation of target engagement and immunomodulatory effects. After determination of the recommended phase 2 dose, further evaluation will include monotherapy cohorts in specific tumor types as well as cohorts to evaluate efficacy and tolerability in combination with checkpoint inhibitors. Clinical trial information: NCT02605083.
Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium
Authors: Atsushi Tachibana, Michelle R. Santoso, Morteza Mahmoudi, Praveen Shukla, Lei Wang, Mihoko Bennett, Andrew B. Goldstone, Mouer Wang, Masahiro Fukushi, Antje D. Ebert, Y. Joseph Woo, Eric Rulifson, Phillip C. Yang
Journal: Circulation Research (2017)

Cardiac myocytes derived from pluripotent stem cells have demonstrated the potential to mitigate damage of the infarcted myocardium and improve left ventricular ejection fraction. However, the mechanism underlying the functional benefit is unclear.To evaluate whether the transplantation of cardiac-lineage differentiated derivatives enhance myocardial viability and restore left ventricular ejection fraction more effectively than undifferentiated pluripotent stem cells after a myocardial injury. Herein, we utilize novel multimodality evaluation of human embryonic stem cells (hESCs), hESC-derived cardiac myocytes (hCMs), human induced pluripotent stem cells (iPSCs), and iPSC-derived cardiac myocytes (iCMs) in a murine myocardial injury model.Permanent ligation of the left anterior descending coronary artery was induced in immunosuppressed mice. Intramyocardial injection was performed with (1) hESCs (n=9), (2) iPSCs (n=8), (3) hCMs (n=9), (4) iCMs (n=14), and (5) PBS control (n=10). Left ventricular ejection fraction and myocardial viability, measured by cardiac magnetic resonance imaging and manganese-enhanced magnetic resonance imaging, respectively, was significantly improved in hCM- and iCM-treated mice compared with pluripotent stem cell- or control-treated mice. Bioluminescence imaging revealed limited cell engraftment in all treated groups, suggesting that the cell secretions may underlie the repair mechanism. To determine the paracrine effects of the transplanted cells, cytokines from supernatants from all groups were assessed in vitro. Gene expression and immunohistochemistry analyses of the murine myocardium demonstrated significant upregulation of the promigratory, proangiogenic, and antiapoptotic targets in groups treated with cardiac lineage cells compared with pluripotent stem cell and control groups.This study demonstrates that the cardiac phenotype of hCMs and iCMs salvages the injured myocardium effectively than undifferentiated stem cells through their differential paracrine effects.
Sequencing the gut metagenome as a noninvasive diagnosis for advanced nonalcoholic steatohepatitis
Authors: Lixin Zhu, Robert D. Baker, Ruixin Zhu, Susan S. Baker
Journal: Hepatology (2017)

Zhu, Lixin Ph.D.; Baker, Robert D. M.D., Ph.D.; Zhu, Ruixin Ph.D.; Baker, Susan S. M.D., Ph.D. Author Information
Abstract 129: Human Mesenchymal Stem Cells Augment Contractile Function of Human Engineered Cardiac Tissues
Authors: Timothy Cashman, Irene C Turnbull, Ioannis Karakikes, Jose Da Silva, Joshua M Hare, Roger J Hajjar, Kevin D Costa
Journal: Circulation Research (2013)

Mesenchymal stem cells (MSC) have demonstrated efficacy for improving cardiomyocyte (CM) function in vitro, in vivo and in clinical trials, but the mechanism of this enhancement remains elusive. The objective of this study was to test the hypothesis that human engineered cardiac tissues (hECT) offer a viable model system to investigate the effects of human MSC on CM contractile function. Human CM (hCM) were produced from embryonic stem cells (hESC, H7 line) using a small-molecule based differentiation approach. Blebbistatin and BMP4 were added to hESC suspended in StemPro34 differentiation media for 24 h, followed by BMP4 and Activin A to day 4.5, followed by addition of IWR-1 Wnt inhibitor for at least 4 days. To create hECT, approximately 1 million hCM were mixed with 2.0 mg/ml bovine type I collagen and 0.9 mg/ml Matrigel, and pipetted into a mold fabricated from polydimethylsiloxane with integrated cantilever end-posts. To model hMSC cell therapy, two types of hECT were created: hCM-only control hECT, and hMSC-CM hybrid hECT containing hCM mixed with 5-10% of human bone marrow-derived MSC. Over several days in culture, the hECT self-assembled and started beating; end-post deflection was tracked in real time to compute twitch force using beam theory. Human CMs were produced with high efficiency (&gt;70% cTnT+) with a predominantly ventricular phenotype (MLC2v+). Resulting hECTs exhibited spontaneous beating (1.3±0.4 Hz), cellular alignment, registered sarcomeres, and expression of cardiac specific genes cTnT, α-MHC, β-MHC and SERCA2a. After 11±2 days in culture, developed stress (force/area) was over 10-fold higher in hMSC-CM hybrid tissues (0.27±0.048 mN/mm 2 ) compared to hCM-only controls (0.02±0.006 mN/mm 2 ; p=0.04, n=5 per group). This reflected significantly greater twitch force (0.11±0.004 mN vs 0.033±0.016 mN, p=0.016) and smaller cross-sectional area (0.19±0.12 mm 2 vs 0.49±0.10 mm 2 ; p=0.003) in hMSC-CM hybrid vs hCM-only hECT. In conclusion, human ECT offer a novel system to study MSC-CM interactions. The findings suggest hMSC supplementation improves contractility compared to CM-only hECT. Investigating the mechanisms of hMSC-mediated enhancement of hECT function may yield insights into MSC-based therapies for cardiac regeneration.
Evaluation of Cell Surface Markers and Targets in Leukemic Stem Cells (LSC) Reveals Distinct Expression Profiles, Unique Drug Effects, and Specific Checkpoint Regulation in AML LSC and CML LSC
Authors: Irina Sadovnik, Harald Herrmann, Katharina Blatt, Gregor Eisenwort, Niklas Mueller, Gabriele Stefanzl, Gregor Hoermann, Susanne Herndlhofer, Karin Bauer, Barbara Peter, Rene Gaupmann, Axel Schulenburg, Wolfgang R. Sperr, Peter Valent
Journal: Blood (2016)
Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis Frequently Have Subclinical Inflammation in the Proximal Colon
Authors: Noa Krugliak Cleveland, David T. Rubin, John Hart, Christopher R. Weber, Katherine Meckel, Anthony L. Tran, Arthur S. Aelvoet, Isabella Pan, Alex Gonsalves, John Nick Gaetano, Kelli M. Williams, Kristen Wroblewski, Bana Jabri, Joel Pekow
Journal: Clinical Gastroenterology and Hepatology (2017)
Topotecan compared with no terapy and carboplatin/paclitaxel in patients with ovarian cancer: Multicenter Italian Trials in Ovarian Cancer (MITO-1) randomized study
Authors: Maria Rosaria Valerio, De Placido S, Scambia G, Di Vagno G, Naglieri E, Lombardi A, Biamonte R, Marinaccio M, Carteni G, Manzione L, Febbraro A, De Matteis A, Valerio Mr, Danese S, Perrone F, Lauria R, De Laurentis M, Greggi S, Gallo C, Pignata S
Journal: Journal of Clinical Oncology (2004)
Home spirometry for idiopathic pulmonary fibrosis: ready for prime time?
Authors: Toby M. Maher
Journal: European Respiratory Journal (2017)

The treatment of idiopathic pulmonary fibrosis (IPF) has been transformed with the advent of effective anti-fibrotic therapy [1]. Despite this there remain many challenges confronting those providing day-to-day care to individuals with IPF. Although IPF inevitably progresses over time, the rate at which it does so varies between individuals and is frequently punctuated by life-threatening acute exacerbations or episodes of infection. Additionally, there is currently a lack of measures for determining efficacy of anti-fibrotic treatment for individual patients, which makes decisions to change or persist with therapy difficult. From a clinical trial perspective, the successes of pirfenidone and nintedanib make the development of the next generation of treatments harder. With all future trials expected to be performed on background anti-fibrotic therapy, the rate of decline in FVC seen in trials will be less, thus reducing the window for determining the efficacy of any additional drug [2]. Home spirometry in IPF can be used to shorten clinical trials and may enable patient self-management in the future <http://ow.ly/Jqft30dGiaB> T.M. Maher is supported by an NIHR Clinician Scientist Fellowship (NIHR Ref.: CS-2013-13-017).
Pneumomediastinum and pneumorrhachis from recreational nitrous oxide inhalation: no laughing matter
Authors: Aniket N Tavare, Dana Li, Samanjit S Hare, Dean D Creer
Journal: Thorax (2017)

A 16-year-old girl with no medical history presented to our emergency department with rapid onset and progressive facial and neck swelling, dyspnoea and dysphonia. The previous night she had attended a nightclub, had sniffed ketamine and inhaled nitrous oxide. On examination she had swelling of her face, neck and upper torso with palpable crepitus. Scattered bilateral expiratory wheeze was present on auscultation. She was mildly tachycardic and tachypnoeic but other observations were normal. Neurological examination was normal. A chest radiograph demonstrated extensive subcutaneous emphysema. CT scan of the neck, chest and abdomen without intravenous contrast confirmed the presence of extensive subcutaneous gas within …
Effect of Obstructive Sleep Apnea Treatment on Renal Function in Patients with Cardiovascular Disease
Authors: Kelly A. Loffler, Emma Heeley, Ruth Freed, Craig S. Anderson, Ben Brockway, Alastair Corbett, Catherina L. Chang, James A. Douglas, Katherine Ferrier, Neil Graham, Garun S. Hamilton, Michael Hlavac, Nigel McArdle, John McLachlan, Sutapa Mukherjee, Matthew T. Naughton, Francis Thien, Alan Young, Ronald R. Grunstein, Lyle J. Palmer, Richard J. Woodman, Patrick J. Hanly, R. Doug McEvoy
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Obstructive sleep apnea (OSA) is associated with impaired renal function, but uncertainty exists over whether OSA treatment can influence renal outcomes.Objectives: To determine the effects of continuous positive airway pressure (CPAP) on renal function in subjects with coexisting OSA and cardiovascular disease.Methods: This was a substudy of the international SAVE (Sleep Apnea Cardiovascular Endpoints) trial, in which 2,717 patients with moderate to severe OSA and established coronary or cerebrovascular disease were randomized to receive either CPAP plus usual care or usual care alone. Renal function and adverse renal events were compared between the CPAP (n = 102) and usual care (n = 98) groups. Glomerular filtration rate was estimated at randomization and at the end of follow-up, and the urinary albumin-to-creatinine ratio was measured at study exit.Measurements and Main Results: In 200 substudy participants (mean age, 64 yr; median, 4% oxygen desaturation index; 20 events/h; mean estimated glomerular filtration rate at baseline, 82 ml/min/1.73 m2), the median (interquartile range) changes in estimated glomerular filtration rate (ml/min/1.73 m2/yr) were −1.64 (−3.45 to −0.740) in the CPAP group and −2.30 (−4.53 to −0.71) in the usual care group (P = 0.21) after a median of 4.4 years. There were no between-group differences in end-of-study urinary albumin-to-creatinine ratio or in the occurrence of serious renal or urinary adverse events during the trial. The level of CPAP adherence did not influence the findings.Conclusions: CPAP treatment of OSA in patients with cardiovascular disease does not alter renal function or the occurrence of renal adverse events.Clinical trial registered with www.clinicaltrials.gov (NCT00738179).
Endoscopic submucosal dissection of a huge esophageal atypical lipomatous tumor (well-differentiated liposarcoma) with a 4-year recurrence-free survival
Authors: Ming-Yan Cai, Jia-Xin Xu, Ping-Hong Zhou
Journal: Endoscopy (2017)

A 35-year-old man complained of dull pain after food intake. His medical history and findings from physical examinations and laboratory tests were unremarkable. Standard esophagogastroduodenoscopy revealed a huge mass in the cervical esophagus. On endoscopy, the sausage-like pedunculated tumor protruded into the lumen ([Fig. 1]). Chest computed tomography (CT) scan showed a large mass that was well-circumscribed, intraluminal, and heterogeneous (fatty density in the upper section and parenchymal density in the lower part) ([Fig. 2]). The mass was located between the T1 to T8 levels and connected to the posterior wall of the esophagus.
Abstract 199: Distinctive Roles of Linker Histone H1 Variants in the Hypertrophic Response of Cardiomyocytes
Authors: Michelle S Parvatiyar, Timothy D Lopez, Sarah Franklin, Thomas M Vondriska
Journal: Circulation Research (2013)

Heart failure results when cardiac output is insufficient to meet physiological requirements and is often preceded by development of cardiomyocyte hypertrophy. As cardiac myocytes respond to hypertrophic stresses they re-express developmentally important genes, normally senescent in the adult. The chromatin structural events underlying this “fetal gene program” are unknown. We previously showed by proteomics that histones, components of the chromatin protein functional unit, the nucleosome, are altered during hypertrophic and failing phases of pressure overload in mouse: linker histone variants H1.2 and H1.5 decreased in hypertrophied myocardium while H1.0 increased during the transition to failure. The linker histone H1 family influences higher order chromatin structure and gene expression, although the role of this family in the heart is unknown. To assess the role of linker histones in hypertrophy, neonatal rat ventricular cardiomyocytes (NRVMs) were transfected with siRNAs individually targeting six H1 variants. Loss of H1.3 and H1.4 respectively induced a significant 26.1% (76 of 90) and 13.5% (80 of 94) increase in cell size area (µm2). A role of H1 in the hypertrophic response is evidenced by its influence on myosin heavy chain (MHC) mRNA expression. Knock-down of individual H1 variants significantly altered the MHC isoform ratio: loss of H1.3 increased α-MHC levels 1.5 fold and decreased β-MHC 1.6 fold while H1.5 depletion decreased α-MHC 2.5 fold. Both H1.3 and H1.4 knock-down increased atrial natriuretic factor (ANF) 1.3 fold while H1.5 loss decreased ANF 6.2 fold shown by qRT-PCR. Treatment with hypertrophy-inducing agents Isoproterenol (1μM), Endothelin (2nM) or Phenylephrine (10μM), reduced H1 mRNA levels however with subtle effects on protein abundance. To evaluate whether H1 loss shifted NRVM nuclei from a predominantly heterochromatic toward euchromatic state favoring gene accessibility we examined distinct histone markers of chromatin states. Histone H1.5 knock-down significantly decreased H3K9Me3 levels, a silencing mark associated with heterochromatin, 1.7 fold. Therefore we conclude that variants package distinctive regions of the genome and that H1.3 and H1.4 controls genes involved in the hypertrophic response.
Teenage boys shouldn’t be given HPV vaccine, says joint committee
Authors: Jacqui Wise
Journal: BMJ (2017)

The human papillomavirus (HPV) vaccination programme should not be extended to boys, as it would not be cost effective, the UK Joint Committee on Vaccination and Immunisation has said in an interim ruling.1

Since 2008 girls aged 12 and 13 in the UK have been offered HPV vaccination to protect against the development of cervical cancer in later life. HPV infects males and females, and in boys and men it can progress to cause anal, penile, and oropharyngeal and oral cavity cancers, and anogenital warts.

In 2013 Australia became the first country in the world to fund a national HPV vaccination scheme for boys.2 A pilot scheme to evaluate …