tbuckley/cabot-search huggingface dataset:
Constitutive phosphorylation of Chk1 at serine 317 in a medulloblastoma cell line is sensitive to the inhibition of the phosphatidyalinositol-3-kinase-related kinase (PIKK) pathway
Authors: Bo Cui, Stewart P. Johnson, Francis Ali-Osman, Darell D. Bigner, Henry S. Friedman
Journal: Cancer Research (2006)

4254  Medulloblastoma is the most common malignant brain tumor in children and accounts for approximately one fourth of all childhood brain tumors. The human checkpoint kinase 1 (Chk1) is a major effector of normal S-phase progression and is involved in G2/M-phase checkpoint signaling in response to genotoxic stress. Following DNA damage, Chk1 is phosphorylated in vivo at serine 317 and 345 by its upstream activator, ATR, which is a member of the phosphatidyalinositol-3-kinase-related kinase (PIKK) family that also includes DNA-PKcs and ATM. In the present study, we identified a constitutively phosphorylated form of Chk1 in D341 MED, a permanent cell line established in our laboratory from a cerebellar medulloblastoma. Immunoblotting studies with phospho-specific anti-Chk1 antibodies showed that Chk1 was phosphorylated at serine 317. Phosphorylation of Chk1 at serine 317 was nearly abolished by treatment of D341 MED with 3 mM caffeine, an inhibitor of PIKKs. However, treatment of D341 MED with 30 μM wortmannin, a concentration that has been shown to completely inhibit the activities of DNA-PKcs and ATM, produced only a slight reduction in phosphorylation of Chk1 at serine 317. Furthermore, treatment with the heat shock protein 90 (Hsp90) inhibitor, 17-allylamino, 17-demethoxygeldanamycin (17AAG), a derivative of a natural benzoquinone ansamycin antibiotic geldanamycin (GA) from Streptomyces geldanus, demonstrated a selective dose- and time-dependent reduction in the level of total Chk1 in D341 MED. In contrast, the level of the phosphorylated form of Chk1 remained basically unchanged, suggesting that the phosphorylated Chk1 was resistant to 17AAG-induced degradation. In summary, we have provided evidence of the novel finding of a constitutively phosphorylated form of human Chk1 that is sensitive to the inhibition of the PIKK pathway. Currently, we are targeting ATR with siRNA to determine its role in the constitutive phosphorylation of Chk1 in D341 MED and plan to investigate the functional implication of the phosphorylation of Chk1 at serine 317.
Novel Humanised ROR1 Chimeric Antigen Receptors for the Treatment of Haematological Malignancies
Authors: Satyen Harish Gohil, Marco Della Peruta, Solange R Paredes-Moscosso, Micaela Harrasser, Gordon Weng-Kit Cheung, David M Davies, Martin A Pule, Amit C Nathwani
Journal: Blood (2016)
Lay Health Worker Involvement in Evidence-Based Treatment Delivery: A Conceptual Model to Address Disparities in Care
Authors: Miya L. Barnett, Anna S. Lau, Jeanne Miranda
Journal: Annual Review of Clinical Psychology (2018)

Mobilizing lay health workers (LHWs) to deliver evidence-based treatments (EBTs) is a workforce strategy to address mental health disparities in underserved communities. LHWs can be leveraged to support access to EBTs in a variety of ways, from conducting outreach for EBTs delivered by professional providers to serving as the primary treatment providers. This critical review provides an overview of how LHW-supported or -delivered EBTs have been leveraged in low-, middle-, and high-income countries (HICs). We propose a conceptual model for LHWs to address drivers of service disparities, which relate to the overall supply of the EBTs provided and the demand for these treatments. The review provides illustrative case examples that demonstrate how LHWs have been leveraged globally and domestically to increase access to mental health services. It also discusses challenges and recommendations regarding implementing LHW-supported or -delivered EBTs.
Abstract 15287: Muscle Sympathetic Nerve Activity and Arterial Stiffness in Resistant Hypertensive Patients With Metabolic Syndrome
Authors: C. Tsioufis, K. Dimitriadis, E. Koutra, A. Kasiakogias, A. Kordalis, K. Kintis, G. Georgiopoulos, D. Tousoulis
Journal: Circulation (2015)

Introduction: Resistant hypertension is related to sympathetic overdrive and arterial stiffening, while there are scarce data whether metabolic syndrome further potentiates sympathetic activity and vascular abnormalities in this setting. Hypothesis: The aim of this study was to assess the effect of the metabolic syndrome on muscle sympathetic nerve activity (MSNA) and arterial stiffness in resistant hypertensive patients. Method: We studied 24 patients with resistant hypertension [age: 58±10 years, 15 males, office blood pressure (BP): 178/94±15/12 mmHg, 24-hour BP: 149/84±15/11 mmHg, under 4.2±0.5 drugs] that underwent transthoracic echocardiographic study and blood sampling for assessment of the metabolic profile. Metabolic syndrome was defined according to the Adult Treatment Panel III criteria and arterial stiffness was evaluated on the basis of carotid to femoral pulse wave velocity (PWV). In all participants sympathetic drive was assessed by MSNA estimations based on established methodology (microneurography). Results: Resistant hypertensive patients with metabolic syndrome (n=11) compared to those without (n=13) exhibited higher waist circumference (108.1±5.4 vs 94.6±9.2 cm, p=0.001), fasting glucose (131.8±2.9 vs 94.6±2.1 mg/dl, p&lt;0.05), office systolic BP (186±17 vs 171±15 mmHg, p&lt;0.001) and left ventricular mass index (134.2±18.1 vs 124.6±17.2 g/m2, p=0.001). Moreover, metabolic syndrome patients compared to those without were characterized by greater levels of carotid to femoral PWV (11.7±0.8 vs 9.3±1.1 m/sec, p&lt;0.001) and sympathetic nerve traffic as reflected by MSNA levels (84.2±2.8 vs 75.1±2.2 bursts per 100 heart beats, p&lt;0.001). In all participants MSNA was related to waist circumference (r=0.38, p=0.002) and office systolic BP levels (r=0.35, p&lt;0.05) but there was no association with PWV values (p=NS). Conclusions: In resistant hypertensive patients, metabolic syndrome is associated with high MSNA and PWV levels. These findings support that metabolic syndrome further deteriorates sympathetic activity and arterial stiffening characterizing resistant hypertension.
Islet-reactive CD8 <sup>+</sup> T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors
Authors: Slobodan Culina, Ana Ines Lalanne, Georgia Afonso, Karen Cerosaletti, Sheena Pinto, Guido Sebastiani, Klaudia Kuranda, Laura Nigi, Anne Eugster, Thomas Østerbye, Alicia Maugein, James E. McLaren, Kristin Ladell, Etienne Larger, Jean-Paul Beressi, Anna Lissina, Victor Appay, Howard W. Davidson, Søren Buus, David A. Price, Matthias Kuhn, Ezio Bonifacio, Manuela Battaglia, Sophie Caillat-Zucman, Francesco Dotta, Raphael Scharfmann, Bruno Kyewski, Roberto Mallone, Jean-Claude Carel, Nadia Tubiana-Rufi, Laetitia Martinerie, Amélie Poidvin, Evelyne JacqzAigrain, Laurence Corvez, Véronique Berruer, Jean-François Gautier, Baz Baz, Nassima Haddadi, Fabrizio Andreelli, Chloé Amouyal, Sophie Jaqueminet, Olivier Bourron, Eric Dasque, Agnès Hartemann, Amal Lemoine-Yazigi, Danièle Dubois-Laforgue, Florence Travert, Marilyne Feron, Patrice Rolland, Valérie Vignali, Michel Marre, Philippe Chanson, Claire Briet, Pierre-Jean Guillausseau, Leila Ait-Bachir, Carole Collet, Frédéric Beziaud, Virginie Desforges-Bullet, Gwenaelle Petit-Aubert, Sophie Christin-Maitre, Bruno Fève, Camille Vatier, Nathalie Bourcigaux, Céline Lautridou, Najiba Lahlou, Prissile Bakouboula, Caroline Elie, Hélène Morel, Jean-Marc Treluyer, Marie-Claude Gagnerault, Claire Maillard, Anna Jones
Journal: Science Immunology (2018)

The human leukocyte antigen-A2 (HLA-A2)-restricted zinc transporter 8186-194 (ZnT8186-194) and other islet epitopes elicit interferon-γ secretion by CD8+ T cells preferentially in type 1 diabetes (T1D) patients compared with controls. We show that clonal ZnT8186-194-reactive CD8+ T cells express private T cell receptors and display equivalent functional properties in T1D and healthy individuals. Ex vivo analyses further revealed that CD8+ T cells reactive to ZnT8186-194 and other islet epitopes circulate at similar frequencies and exhibit a predominantly naïve phenotype in age-matched T1D and healthy donors. Higher frequencies of ZnT8186-194-reactive CD8+ T cells with a more antigen-experienced phenotype were detected in children versus adults, irrespective of disease status. Moreover, some ZnT8186-194-reactive CD8+ T cell clonotypes were found to cross-recognize a Bacteroides stercoris mimotope. Whereas ZnT8 was poorly expressed in thymic medullary epithelial cells, variable thymic expression levels of islet antigens did not modulate the peripheral frequency of their cognate CD8+ T cells. In contrast, ZnT8186-194-reactive cells were enriched in the pancreata of T1D patients versus nondiabetic and type 2 diabetic individuals. Thus, islet-reactive CD8+ T cells circulate in most individuals but home to the pancreas preferentially in T1D patients. We conclude that the activation of this common islet-reactive T cell repertoire and progression to T1D likely require defective peripheral immunoregulation and/or a proinflammatory islet microenvironment.
Long-Term Follow-up of Previously Treated Patients Who Received Ibrutinib for Symptomatic Waldenstrom's Macroglobulinemia: Update of Pivotal Clinical Trial
Authors: Steven P Treon, Kirsten Meid, Joshua Gustine, Kurt S. Bantilan, Toni Dubeau, Patricia Severns, Guang Yang, Lian Xu, Christopher Patterson, Irene M Ghobrial, Jacob Laubach, Zachary Hunter, Jorge J. Castillo, Maria L. Palomba, Ranjana H. Advani
Journal: Blood (2017)
Increased Waitlist Mortality and Lower Rate for Liver Transplantation in Hispanic Patients With Primary Biliary Cholangitis
Authors: George Cholankeril, Humberto C. Gonzalez, Sanjaya K. Satapathy, Stevan A. Gonzalez, Menghan Hu, Mohammad Ali Khan, Eric R. Yoo, Andrew A. Li, Donghee Kim, Satheesh Nair, Robert J. Wong, Paul Y. Kwo, Stephen A. Harrison, Zobair M. Younossi, Keith D. Lindor, Aijaz Ahmed
Journal: Clinical Gastroenterology and Hepatology (2018)
An off-target effect of BX795 blocks herpes simplex virus type 1 infection of the eye
Authors: Dinesh Jaishankar, Abraam M. Yakoub, Tejabhiram Yadavalli, Alex Agelidis, Neel Thakkar, Satvik Hadigal, Joshua Ames, Deepak Shukla
Journal: Science Translational Medicine (2018)

A kinase inhibitor shows promise as a topical antiviral against ocular herpes.
Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations
Authors: David Mayhew, Nathalie Devos, Christophe Lambert, James R Brown, Stuart C Clarke, Viktoriya L Kim, Michal Magid-Slav, Bruce E Miller, Kristoffer K Ostridge, Ruchi Patel, Ganesh Sathe, Daniel F Simola, Karl J Staples, Ruby Sung, Ruth Tal-Singer, Andrew C Tuck, Stephanie Van Horn, Vincent Weynants, Nicholas P Williams, Jeanne-Marie Devaster, Tom M A Wilkinson
Journal: Thorax (2018)

Background Alterations in the composition of the lung microbiome associated with adverse clinical outcomes, known as dysbiosis, have been implicated with disease severity and exacerbations in COPD. Objective To characterise longitudinal changes in the lung microbiome in the AERIS study (Acute Exacerbation and Respiratory InfectionS in COPD) and their relationship with associated COPD outcomes. Methods We surveyed 584 sputum samples from 101 patients with COPD to analyse the lung microbiome at both stable and exacerbation time points over 1 year using high-throughput sequencing of the 16S ribosomal RNA gene. We incorporated additional lung microbiology, blood markers and in-depth clinical assessments to classify COPD phenotypes. Results The stability of the lung microbiome over time was more likely to be decreased in exacerbations and within individuals with higher exacerbation frequencies. Analysis of exacerbation phenotypes using a Markov chain model revealed that bacterial and eosinophilic exacerbations were more likely to be repeated in subsequent exacerbations within a subject, whereas viral exacerbations were not more likely to be repeated. We also confirmed the association of bacterial genera, including Haemophilus and Moraxella , with disease severity, exacerbation events and bronchiectasis. Conclusions Subtypes of COPD have distinct bacterial compositions and stabilities over time. Some exacerbation subtypes have non-random probabilities of repeating those subtypes in the future. This study provides insights pertaining to the identification of bacterial targets in the lung and biomarkers to classify COPD subtypes and to determine appropriate treatments for the patient. Trial registration number Results, NCT01360398 .
Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis
Authors: Xinshou Ouyang, Sheng-Na Han, Ji-Yuan Zhang, Evangelos Dioletis, Balazs Tamas Nemeth, Pal Pacher, Dechun Feng, Ramon Bataller, Joaquin Cabezas, Peter Stärkel, Joan Caballeria, Rebecca LePine Pongratz, Shi-Ying Cai, Bernd Schnabl, Rafaz Hoque, Yonglin Chen, Wei-hong Yang, Irma Garcia-Martinez, Fu-Sheng Wang, Bin Gao, Natalie Julia Torok, Richard Glenn Kibbey, Wajahat Zafar Mehal
Journal: Cell Metabolism (2018)
The sea lamprey germline genome provides insights into programmed genome rearrangement and vertebrate evolution
Authors: Jeramiah J. Smith, Nataliya Timoshevskaya, Chengxi Ye, Carson Holt, Melissa C. Keinath, Hugo J. Parker, Malcolm E. Cook, Jon E. Hess, Shawn R. Narum, Francesco Lamanna, Henrik Kaessmann, Vladimir A. Timoshevskiy, Courtney K. M. Waterbury, Cody Saraceno, Leanne M. Wiedemann, Sofia M. C. Robb, Carl Baker, Evan E. Eichler, Dorit Hockman, Tatjana Sauka-Spengler, Mark Yandell, Robb Krumlauf, Greg Elgar, Chris T. Amemiya
Journal: Nature Genetics (2018)

The sea lamprey (Petromyzon marinus) serves as a comparative model for reconstructing vertebrate evolution. To enable more informed analyses, we developed a new assembly of the lamprey germline genome that integrates several complementary data sets. Analysis of this highly contiguous (chromosome-scale) assembly shows that both chromosomal and whole-genome duplications have played significant roles in the evolution of ancestral vertebrate and lamprey genomes, including chromosomes that carry the six lamprey HOX clusters. The assembly also contains several hundred genes that are reproducibly eliminated from somatic cells during early development in lamprey. Comparative analyses show that gnathostome (mouse) homologs of these genes are frequently marked by polycomb repressive complexes (PRCs) in embryonic stem cells, suggesting overlaps in the regulatory logic of somatic DNA elimination and bivalent states that are regulated by early embryonic PRCs. This new assembly will enhance diverse studies that are informed by lampreys' unique biology and evolutionary/comparative perspective.
The Judicial Threat to Public Health Innovation — The Sword of <i>Boreali</i>
Authors: Thomas G. Merrill, Wilfredo Lopez, Sarah B. Perl, Mary T. Bassett
Journal: New England Journal of Medicine (2018)

A 1987 court decision regarding a New York State regulation of tobacco use has been used to strike down various innovative — but "controversial" — public health regulations that would probably have saved lives.
Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies
Authors: Matthew D. F. McInnes, David Moher, Brett D. Thombs, Trevor A. McGrath, Patrick M. Bossuyt, Tammy Clifford, Jérémie F. Cohen, Jonathan J. Deeks, Constantine Gatsonis, Lotty Hooft, Harriet A. Hunt, Christopher J. Hyde, Daniël A. Korevaar, Mariska M. G. Leeflang, Petra Macaskill, Johannes B. Reitsma, Rachel Rodin, Anne W. S. Rutjes, Jean-Paul Salameh, Adrienne Stevens, Yemisi Takwoingi, Marcello Tonelli, Laura Weeks, Penny Whiting, Brian H. Willis
Journal: JAMA (2018)

<h3>Importance</h3> Systematic reviews of diagnostic test accuracy synthesize data from primary diagnostic studies that have evaluated the accuracy of 1 or more index tests against a reference standard, provide estimates of test performance, allow comparisons of the accuracy of different tests, and facilitate the identification of sources of variability in test accuracy. <h3>Objective</h3> To develop the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagnostic test accuracy guideline as a stand-alone extension of the PRISMA statement. Modifications to the PRISMA statement reflect the specific requirements for reporting of systematic reviews and meta-analyses of diagnostic test accuracy studies and the abstracts for these reviews. <h3>Design</h3> Established standards from the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network were followed for the development of the guideline. The original PRISMA statement was used as a framework on which to modify and add items. A group of 24 multidisciplinary experts used a systematic review of articles on existing reporting guidelines and methods, a 3-round Delphi process, a consensus meeting, pilot testing, and iterative refinement to develop the PRISMA diagnostic test accuracy guideline. The final version of the PRISMA diagnostic test accuracy guideline checklist was approved by the group. <h3>Findings</h3> The systematic review (produced 64 items) and the Delphi process (provided feedback on 7 proposed items; 1 item was later split into 2 items) identified 71 potentially relevant items for consideration. The Delphi process reduced these to 60 items that were discussed at the consensus meeting. Following the meeting, pilot testing and iterative feedback were used to generate the 27-item PRISMA diagnostic test accuracy checklist. To reflect specific or optimal contemporary systematic review methods for diagnostic test accuracy, 8 of the 27 original PRISMA items were left unchanged, 17 were modified, 2 were added, and 2 were omitted. <h3>Conclusions and Relevance</h3> The 27-item PRISMA diagnostic test accuracy checklist provides specific guidance for reporting of systematic reviews. The PRISMA diagnostic test accuracy guideline can facilitate the transparent reporting of reviews, and may assist in the evaluation of validity and applicability, enhance replicability of reviews, and make the results from systematic reviews of diagnostic test accuracy studies more useful.
Increased Prevalence of Rare Sucrase-isomaltase Pathogenic Variants in Irritable Bowel Syndrome Patients
Authors: Koldo Garcia-Etxebarria, Tenghao Zheng, Ferdinando Bonfiglio, Luis Bujanda, Aldona Dlugosz, Greger Lindberg, Peter T. Schmidt, Pontus Karling, Bodil Ohlsson, Magnus Simren, Susanna Walter, Gerardo Nardone, Rosario Cuomo, Paolo Usai-Satta, Francesca Galeazzi, Matteo Neri, Piero Portincasa, Massimo Bellini, Giovanni Barbara, Daisy Jonkers, Shanti Eswaran, William D. Chey, Purna Kashyap, Lin Chang, Emeran A. Mayer, Mira M. Wouters, Guy Boeckxstaens, Michael Camilleri, Andre Franke, Mauro D’Amato
Journal: Clinical Gastroenterology and Hepatology (2018)

Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC).
Abstract 17448: Echocardiographic Radial and Circumferential Strain Follow-up Analysis of Neurocardiac Injury in Patients With Subarachnoid Hemorrhage
Authors: Zhi Qi, Masataka Sugahara, Elizabeth A Crago, Yugang Chang, Theodore F Lagattuta, Khalil Yousef, Robert M Friedlander, Marilyn T Hravnak, John Gorcsan
Journal: Circulation (2016)

Introduction:  Neurocardiac injury in aneurysmal subarachnoid hemorrhage (aSAH) has been well described. Most researchers regard aSAH is accompanied by transient cardiac dysfunction, a kind of stress cardiomyopathy.   Hypothesis:  The aim was to discuss the change of patients between early stage after aSAH and shortly later stage using Echocardiography.   Methods:  We prospectively studied patients with aSAHbetween early stage (Day 0 to 5 after SAH) and shortly later stage (Day 5 to 12) in a patient subset (early n=130, later n=68; late study not always obtained due to patient discharge or death). Besides traditional echo parameters, we assessed speckle tracking circumferential and radialstrain (18 segments from 3 left ventricular short axis views). The time-to-peakdifference from earliest to latest activated segment was determined from each view as the radial strain time variation (RST), then calculated the mean of three views (RSTD-Mean). The time-to-peak radial strain difference (APT) between LV anterior septum and posterior wall in left ventricular short axis view at papillary muscle level were calculated.   Results:  Of 66 aSAH patients had baseline and follow-up data, 18 (27%) had highly positive cardiac troponin I (cTnI) (>=0.3 ng/ml) and 48 (73%) had mildly positive or negative cTnI (   Conclusions:  The improvement (later stage vs. early stage) of RSTD-Mean and APT in mildly positive or negative cTnI group were more significant than these in highly positive cTnI group. Both RSTD-Mean and APT are novel strain parameters to indicate LV regional discoordination of patients with aSAH and has promise for clinical utility.