tbuckley/cabot-search huggingface dataset:
Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma
Authors: Domenico Alessandro Silvestris, Ernesto Picardi, Valeriana Cesarini, Bruno Fosso, Nicolò Mangraviti, Luca Massimi, Maurizio Martini, Graziano Pesole, Franco Locatelli, Angela Gallo
Journal: Genome biology (2019)

Adenosine-to-inosine (A-to-I) RNA editing is an essential post-transcriptional mechanism mediated by ADAR enzymes that have been recently associated with cancer. Here, we characterize the inosinome signature in normal brain and de novo glioblastoma (GBM) using new metrics that re-stratify GBM patients according to their editing profiles and indicate this post-transcriptional event as a possible molecular mechanism for sexual dimorphism in GBM. We find that over 85% of de novo GBMs carry a deletion involving the genomic locus of ADAR3, which is specifically expressed in the brain. By analyzing RNA editing and patient outcomes, an intriguing gender-dependent link appears, with high editing of Alus shown to be beneficial only in male patients. We propose an inosinome-based molecular stratification of GBM patients that identifies two different GBM subgroups, INO-1 and INO-2, which can identify novel high-risk gender-specific patient groups for which more aggressive treatments may be necessary. Our data provide a detailed picture of RNA editing landscape in normal brain and GBM, exploring A-to-I RNA editing regulation, disclosing unexpected editing implications for GBM patient stratification and identification of gender-dependent high-risk patients, and suggesting COG3 I/V as an eligible site for future personalized targeted gene therapy.
2019 ARIA Care pathways for allergen immunotherapy
Authors: Jean Bousquet, Oliver Pfaar, Alkis Togias, Holger J. Schünemann, Ignacio Ansotegui, Nikolaos G. Papadopoulos, Ioanna Tsiligianni, Ioana Agache, Josep M. Anto, Claus Bachert, Anna Bedbrook, Karl‐Christian Bergmann, Sinthia Bosnic‐Anticevich, Isabelle Bosse, Jan Brozek, Moises A. Calderon, Giorgio W. Canonica, Luigi Caraballo, Victoria Cardona, Thomas Casale, Lorenzo Cecchi, Derek Chu, Elisio Costa, Alvaro A. Cruz, Wienczyslawa Czarlewski, Stephen R. Durham, George Du Toit, Mark Dykewicz, Motohiro Ebisawa, Jean Luc Fauquert, Montserrat Fernandez‐Rivas, Wytske J. Fokkens, João Fonseca, Jean‐François Fontaine, Roy Gerth van Wijk, Tari Haahtela, Susanne Halken, Peter W. Hellings, Despo Ierodiakonou, Tomohisa Iinuma, Juan Carlos Ivancevich, Lars Jacobsen, Marek Jutel, Igor Kaidashev, Musa Khaitov, Omer Kalayci, Jörg Kleine Tebbe, Ludger Klimek, Marek L. Kowalski, Piotr Kuna, Violeta Kvedariene, Stefania La Grutta, Désirée Larenas‐Linemann, Susanne Lau, Daniel Laune, Lan Le, Karin Lodrup Carlsen, Olga Lourenço, Hans‐Jørgen Malling, Gert Marien, Enrica Menditto, Gregoire Mercier, Joaquim Mullol, Antonella Muraro, Robyn O’Hehir, Yoshitaka Okamoto, Giovanni B. Pajno, Hae‐Sim Park, Petr Panzner, Giovanni Passalacqua, Nhan Pham‐Thi, Graham Roberts, Ruby Pawankar, Christine Rolland, Nelson Rosario, Dermot Ryan, Bolesław Samolinski, Mario Sanchez‐Borges, Glenis Scadding, Mohamed H. Shamji, Aziz Sheikh, Gunter J. Sturm, Ana Todo Bom, Sanna Toppila‐Salmi, Maryline Valentin‐Rostan, Arunas Valiulis, Erkka Valovirta, Maria‐Teresa Ventura, Ulrich Wahn, Samantha Walker, Dana Wallace, Susan Waserman, Arzu Yorgancioglu, Torsten Zuberbier
Journal: Allergy (2019)

Abstract Allergen immunotherapy (AIT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence‐based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including healthcare professionals. The decision to prescribe AIT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as the availability of good‐quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomarkers that can predict AIT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate pharmacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow‐up of patients.
Abstract 2095: Cardiac-targeted RNA Interference Against STIM1 Using a Recombinant AAV9 Vector Limits the Progression of Heart Failure in Rats
Authors: Jean-sebastien Hulot, Dongtak Jeong, Kleopatra Rapti, Manuel Ramos-Kuri, Cedric Vrignaud, Anne-Marie Lompre, Roger Hajjar
Journal: Circulation (2009)

Background: Activation of the calcineurin/NFAT signaling pathway promotes pathological remodeling of the heart. Stromal interaction molecule 1 (STIM1), a transmembrane endoplasmic reticulum calcium...
QTc dispersion and vulnerability to ventricular fibrillation
Authors: A. W Haider, S. Naz
Journal: BMJ (1996)

ment when they surely must have their own vari- ability data?The claim that the differences seen in this study were greater than the variability published earlier gives the impression that readers are asked to accept apples and oranges as identical.The third is relevance.The study reports values of QTc dispersion without QT duration, QT dispersion, and heart rate.Despite some probably appropriate criticism, Bazett's formula indicates that the duration of the QT interval depends on the heart rate.However, we fail to see why QT dispersion should depend not only on heart rate but also on the duration of QT interval in the same mathematical way.Heart rate itself is an important prognostic indicator in coronary artery disease.
Comparative Efficacy of Therapeutics for Chronic Cancer Pain: A Bayesian Network Meta-Analysis
Authors: Rongzhong Huang, Lihong Jiang, Yu Cao, Hongli Liu, Minsheng Ping, Wei Li, Yu Xu, Jie Ning, Yuqing Chen, Xiaojing Wang
Journal: Journal of Clinical Oncology (2019)

PURPOSE Opioids are the primary choice for managing chronic cancer pain. However, many nonopioid therapies are currently prescribed for chronic cancer pain with little published evidence comparing their efficacy. METHODS Electronic databases were searched for randomized controlled trials (RCTs) comparing any systemic pharmaceutical intervention and/or combination thereof in treating chronic cancer pain. The primary outcome was global efficacy reported as an odds ratio (OR). The secondary outcome was change in pain intensity reported as a standardized mean difference (SMD). RESULTS We included 81 RCTs consisting of 10,003 patients investigating 11 medication classes. Most RCTs (80%) displayed low risk of bias. The top-ranking classes for global efficacy were nonopioid analgesics (network OR, 0.30; 95% credibility interval [CrI], 0.13 to 0.67), nonsteroidal anti-inflammatory drugs (network OR, 0.44; 95% CrI, 0.22 to 0.90), and opioids (network OR, 0.49; 95% CrI, 0.27 to 0.86), whereas the top-ranked interventions were lidocaine (network OR, 0.04; 95% CrI, 0.01 to 0.18; surface under the cumulative ranking curve analysis [SUCRA] score, 98.1), codeine plus aspirin (network OR, 0.22; 95% CrI, 0.08 to 0.63; SUCRA score, 81.1), and pregabalin (network OR, 0.29; 95% CrI, 0.08 to 0.92; SUCRA score, 73.8). In terms of reducing pain intensity, we found that no class was superior to placebo, whereas the following top-ranked interventions were superior to placebo: ziconotide (network SMD, −24.98; 95% CrI, −32.62 to −17.35; SUCRA score, 99.8), dezocine (network SMD, −13.56; 95% CrI, −23.37 to −3.69; SUCRA score, 93.5), and diclofenac (network SMD, −11.22; 95% CrI, −15.91 to −5.80; SUCRA score, 92.9). CONCLUSION There are significant differences in efficacy among current regimens for chronic cancer pain. Our evidence suggests that certain nonopioid analgesics and nonsteroidal anti-inflammatory drugs can serve as effectively as opioids in managing chronic cancer pain.
Corrigendum to ‘Thermosensitive nanocomposite gel for intra-tumoral two-photon photodynamic therapy’ [Journal of Controlled Release 298 (2019) 99–109]
Authors: Lei Luo, Qi Zhang, Yonghuang Luo, Zhonggui He, Xiaohe Tian, Giuseppe Battaglia
Journal: Journal of Controlled Release (2019)
Correlation of 99mTc-TRODAT-1 SPECT Imaging Findings and Clinical Staging of Parkinson Disease
Authors: Vanshika Gupta, Rajeev Ranjan, Ritu Verma, Ethel S. Belho, Dharmender Malik, Harsh Mahajan
Journal: Clinical Nuclear Medicine (2019)

The aims of this study were to evaluate Tc-TRODAT-1 SPECT imaging patterns and to assess their correlation with disease severity in clinically diagnosed patients of Parkinson disease (PD).The study included 241 patients with clinically diagnosed idiopathic Parkinson disease who underwent Tc-TRODAT-1 SPECT/CT scan. Binding ratios were calculated for each striatum, caudate, and putamen individually, by drawing region of interest. Occipital cortex region of interest was taken for background correction. Correlation of binding ratio with increasing clinical stage was derived, as described by modified Hoehn and Yahr scale.Median binding ratio was least in the contralateral putamen for all stages of modified Hoehn and Yahr. A statistically significant negative correlation was found between increasing disease severity and binding ratio in all subregions of striatum. Patients were clinically categorized into postural instability and gait disorder group and tremor-dominant PD group. No significant asymmetry was found between the left and right striatum in patients belonging to postural instability and gait disorder group and in those with bilateral tremors without lateralization.Tc-TRODAT-1 SPECT is useful in early detection and in assessing disease severity of PD. A significant asymmetry with the contralateral side being affected more than the ipsilateral side can be attributed to tremor-dominant patients. The binding ratio of the ipsilateral striatum may serve useful as a marker of remaining functional dopaminergic neuronal reserve in the striatum.
Donalda M Smith
Authors: Sally Hay, Moira Houston
Journal: BMJ (2019)

Having completed her highers at Dollar Academy at the age of 16, Donalda Morgan was initially too young to enrol on a medical course and so studied botany for a year at Edinburgh University, taking up medicine there as soon as she was old enough.

Donalda’s career initially took her to Newcastle Children’s Hospital, where she worked on a team pioneering the treatment of children with tuberculosis with antibiotics. As a …
Association Between Topical Corticosteroid Use and Type 2 Diabetes in Two European Population-Based Adult Cohorts
Authors: Yuki M.F. Andersen, Alexander Egeberg, Lu Ban, Sonia Gran, Hywel C. Williams, Nick A. Francis, Filip K. Knop, Gunnar H. Gislason, Lone Skov, Jacob P. Thyssen
Journal: Diabetes Care (2019)

Topical corticosteroids (CSs) are commonly used to treat inflammatory skin conditions including eczema and psoriasis. Although topical CS package inserts describe hyperglycemia and glycosuria as adverse drug reactions, it is unclear whether topical CS use in real life is also associated with an increased risk of type 2 diabetes (T2D).Two matched case-control studies and one cohort study were conducted using routinely collected health care data from Denmark and the U.K. A total of 115,218 and 54,944 adults were identified as case subjects with new-onset T2D in the Danish and U.K. case-control study, respectively. For the Danish cohort study, 2,689,473 adults were included. The main exposure was topical CSs, and the outcome was incident T2D.Topical CS was significantly associated with T2D in the Danish (adjusted odds ratio [OR] 1.25 [95% CI 1.23-1.28]) and U.K. (adjusted OR 1.27 [95% CI 1.23-1.31]) case-control studies. Individuals who were exposed to topical CSs had significantly increased risk of incident T2D (adjusted hazard ratio 1.27 [95% CI 1.26-1.29]). We observed significant dose-response relationships between T2D and increasing potency of topical CSs in the two Danish studies. The results were consistent across all sensitivity analyses.We found a positive association between topical CS prescribing and incident T2D in Danish and U.K. adult populations. Clinicians should be cognizant of possible diabetogenic effects of potent topical CSs.
Validity of the EQ‐5D in pemphigus
Authors: B. Tamási, V. Brodszky, M. Péntek, L. Gulácsi, K. Hajdu, M. Sárdy, A. Szegedi, Z. Bata‐Csörgő, Á. Kinyó, F. Rencz
Journal: British Journal of Dermatology (2019)

Pemphigus is a group of autoimmune skin diseases that cause blisters and wounds on the skin and/or mucous membranes such as inside the mouth. It is an uncommon disease with around 15 new cases yearly per million people. The two most common clinical forms are pemphigus vulgaris and foliaceus. Pemphigus can still be life threatening, and the symptoms may cause significant difficulties for patients in their everyday life. This study, from Hungary, aimed to assess the health status and quality of life in patients with pemphigus vulgaris and foliaceus. The authors surveyed 109 pemphigus patients, and collected data on demographics and clinical characteristics. Quality of life was assessed by the EQ‐5D general health status questionnaire. Overall, 50%, 43%, 43%, 42% and 19% of pemphigus patients reported problems regarding pain/discomfort, mobility, anxiety/depression, usual activities and self‐care, respectively. Patients having skin and mucosal symptoms, a larger number of comorbidities (other diseases occurring alongside pemphigus) and more severe disease experienced greater impairment of quality of life. No difference was found in quality of life scores between pemphigus vulgaris and foliaceus patients or between females and males. This study demonstrates that the EQ‐5D questionnaire is an accurate measure of quality of life in pemphigus patients. The EQ‐5D questionnaire allows comparisons between patients across a broad range of disease areas and people without those diseases. The EQ‐5D scores reported in this study can be useful for cost‐effectiveness analyses of new pemphigus treatments such as rituximab, and might help to improve patients’ access to more effective medicines, in a condition for which only limited treatment options have been available so far.
Homeostatic Roles of STING in Cell Proliferation and Chromosomal Instability
Authors: David Gius, Yueming Zhu
Journal: Cancer Research (2019)

Abstract In this issue of Cancer Research, Ranoa and colleagues report on the role of STING (stimulator of IFN genes, TMEM173) in regulating critical tumor cell–intrinsic functions including cell-cycle progression, chromosomal stability, and cellular response to therapeutic ionizing radiation. The authors used multiple methods including RNA expression profiling, molecular and biochemical techniques, cell biology, and reagents from genetically modified murine models to test their hypothesis that downregulating the STING pathway in cancer cells promotes cellular transformation through accumulation of chromosomal instability and premature progression of the cell cycle. Their findings demonstrate that STING is a tumor suppressor that inhibits cell proliferation by restricting entry to mitosis as well as protecting cells against aneuploidy. These findings significantly advance our understanding of the role of STING as a tumor gate keeper. See related article by Ranoa et al., p. 1465
Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study
Authors: Tim Palmer, Lynn Wallace, Kevin G Pollock, Kate Cuschieri, Chris Robertson, Kim Kavanagh, Margaret Cruickshank
Journal: BMJ (2019)

Abstract Objective To quantify the effect on cervical disease at age 20 years of immunisation with bivalent human papillomavirus (HPV) vaccine at age 12-13 years. Design Retrospective population study, 1988-96. Setting National vaccination and cervical screening programmes in Scotland. Participants 138 692 women born between 1 January 1988 and 5 June 1996 and who had a smear test result recorded at age 20. Main outcome measures Effect of vaccination on cytology results and associated histological diagnoses from first year of screening (while aged 20), calculated using logistic regression. Results 138 692 records were retrieved. Compared with unvaccinated women born in 1988, vaccinated women born in 1995 and 1996 showed an 89% reduction (95% confidence interval 81% to 94%) in prevalent cervical intraepithelial neoplasia (CIN) grade 3 or worse (from 0.59% (0.48% to 0.71%) to 0.06% (0.04% to 0.11%)), an 88% reduction (83% to 92%) in CIN grade 2 or worse (from 1.44% (1.28% to 1.63%) to 0.17% (0.12% to 0.24%)), and a 79% reduction (69% to 86%) in CIN grade 1 (from 0.69% (0.58% to 0.63%) to 0.15% (0.10% to 0.21%)). Younger age at immunisation was associated with increasing vaccine effectiveness: 86% (75% to 92%) for CIN grade 3 or worse for women vaccinated at age 12-13 compared with 51% (28% to 66%) for women vaccinated at age 17. Evidence of herd protection against high grade cervical disease was found in unvaccinated girls in the 1995 and 1996 cohorts. Conclusions Routine vaccination of girls aged 12-13 years with the bivalent HPV vaccine in Scotland has led to a dramatic reduction in preinvasive cervical disease. Evidence of clinically relevant herd protection is apparent in unvaccinated women. These data are consistent with the reduced prevalence of high risk HPV in Scotland. The bivalent vaccine is confirmed as being highly effective vaccine and should greatly reduce the incidence of cervical cancer. The findings will need to be considered by cervical cancer prevention programmes worldwide.
Abstract 18334: The Ecto-enzyme CD73 Prevents Venous Thrombosis by Inhibiting Neutrophil Extracellular Trap Formation
Authors: Yogendra Kanthi, He Meng, Srilakshmi Yalavarthi, David J Pinsky, Jason S Knight
Journal: Circulation (2017)

Background: Venous thrombosis (DVT) is a serious health concern, with growing incidence in an aging population. DVT is marked by sterile inflammation and neutrophil (PMN) activation. PMNs extrude t...
US Health Policy—2020 and Beyond
Authors: Karen E. Joynt Maddox, Howard Bauchner, Phil B. Fontanarosa
Journal: JAMA (2019)

Health care is always on the minds of the public, usually ranking among the top 3 concerns.Virtually all of the Democratic presidential candidates have discussed or will shortly detail health care proposals, whereas President Trump and the current administration recently expressed support for repealing the Affordable Care Act.With the presidential election just 18 months away, it is an opportune time to introduce a new health policy series in JAMA.While various proposals to improve US health care will certainly differ in content, they will all by necessity share a common theme-a focus on reducing health care costs.In 2017, US health care spending reached $3.5 trillion, and such costs now consume approximately 18% of the gross domestic product (GDP). 1Even though there has been a slight slowing in the annual growth of health care expenditures, 2 a recent projection suggested that by 2027, health care will consume 22% of the GDP, 3 outpacing the annual rate of inflation and increases in GDP over the next 5 years.This is an unsustainable trajectory.At the same time, there are also crises of access and equity.Recent estimates suggest that nearly 14% of US residents are uninsured, and these numbers are markedly higher among people living in poverty compared with those who are wealthier, as well as among racial and ethnic minority populations compared with white populations.According to the 2017 National Healthcare Quality and Disparities Report, an estimated 40% of adults reported lacking a usual source of care, of which 15% indicated a financial or insurance reason for lacking regular access; these figures are also higher among impoverished persons and individuals of racial or ethnic minority. 4Quality, though improving overall, remains inequitable as well: substantial differences across a range of quality domains persist for black and Hispanic individuals compared with white individuals.The key question for policy makers is whether there are achievable health policies that will reduce the annual increase in health care expenditures yet at the same time increase access to care (fewer uninsured or underinsured), improve quality, and reduce inequities.Feasible policies likely must also maintain choice, which the majority of people repeatedly maintain is important to them.To set the stage for a constructive policy debate, the first step requires defining the current starting point in coverage and spending (Table).For its population of 325 million in 2017, the United States spent $3.5 trillion on health care.Private health insurance covered approximately 197 million individuals and
Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis
Authors: Jong Jin Jeong, Xiaorong Gu, Ji Nie, Sriram Sundaravel, Hui Liu, Wen-Liang Kuo, Tushar D. Bhagat, Kith Pradhan, John Cao, Sangeeta Nischal, Kathy L. McGraw, Sanchari Bhattacharyya, Michael R. Bishop, Andrew Artz, Michael J. Thirman, Alison Moliterno, Peng Ji, Ross L. Levine, Lucy A. Godley, Ulrich Steidl, James J. Bieker, Alan F. List, Yogen Saunthararajah, Chuan He, Amit Verma, Amittha Wickrema
Journal: Cancer Discovery (2019)

Even though the Ten-eleven translocation (TET) enzymes catalyze the generation of 5-hydroxymethylcytosines required for lineage commitment and subsequent differentiation of stem cells into erythroid cells, the mechanisms that link extracellular signals to TET activation and DNA hydroxymethylation are unknown. We demonstrate that hematopoietic cytokines phosphorylate TET2, leading to its activation in erythroid progenitors. Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin. The activating JAK2V617F mutation seen in myeloproliferative disease patient samples and in mouse models is associated with increased TET activity and cytosine hydroxymethylation as well as genome-wide loss of cytosine methylation. These epigenetic and functional changes are also associated with increased expression of several oncogenic transcripts. Thus, we demonstrate that JAK2-mediated TET2 phosphorylation provides a mechanistic link between extracellular signals and epigenetic changes during hematopoiesis. SIGNIFICANCE: Identification of TET2 phosphorylation and activation by cytokine-stimulated JAK2 links extracellular signals to chromatin remodeling during hematopoietic differentiation. This provides potential avenues to regulate TET2 function in the context of myeloproliferative disorders and myelodysplastic syndromes associated with the JAK2V617F-activating mutation.This article is highlighted in the In This Issue feature, p. 681.
High Prevalence of Intracardiac Thrombi in Cardiac Amyloidosis
Authors: Ana Martinez-Naharro, Esther Gonzalez-Lopez, Andrej Corovic, Jesus G. Mirelis, A. John Baksi, James C. Moon, Pablo Garcia-Pavia, Julian D. Gillmore, Philip N. Hawkins, Marianna Fontana
Journal: Journal of the American College of Cardiology (2019)
Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion
Authors: Deepali V. Sawant, Hiroshi Yano, Maria Chikina, Qianxia Zhang, Mengting Liao, Chang Liu, Derrick J. Callahan, Zhe Sun, Tao Sun, Tracy Tabib, Arjun Pennathur, David B. Corry, James D. Luketich, Robert Lafyatis, Wei Chen, Amanda C. Poholek, Tullia C. Bruno, Creg J. Workman, Dario A. A. Vignali
Journal: Nature Immunology (2019)