tbuckley/cabot-search huggingface dataset:
Abstract 16391: Dpp4 Inhibitor Attenuates Obesity Induced Myocardial Fibrosis by Inhibiting TGF-β1 and Smad2/3 Pathways in High-Fat Diet-Induced Obesity Rat
Authors: Sang Hyun Ihm, Seul Ki Hong, Eun-Ho Choo, Kiyuk Chang
Journal: Circulation (2017)

Introduction and Hypothesis: Obesity-induced myocardial fibrosis may lead to diastolic dysfunction and ultimately heart failure. Activation of the transforming growth factor (TGF)-β1 and its downst...
Diffusion Histology Imaging Combining Diffusion Basis Spectrum Imaging (DBSI) and Machine Learning Improves Detection and Classification of Glioblastoma Pathology
Authors: Zezhong Ye, Richard L. Price, Xiran Liu, Joshua Lin, Qingsong Yang, Peng Sun, Anthony T. Wu, Liang Wang, Rowland H. Han, Chunyu Song, Ruimeng Yang, Sam E. Gary, Diane D. Mao, Michael Wallendorf, Jian L. Campian, Jr-Shin Li, Sonika Dahiya, Albert H. Kim, Sheng-Kwei Song
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Glioblastoma (GBM) is one of the deadliest cancers with no cure. While conventional MRI has been widely adopted to examine GBM clinically, accurate neuroimaging assessment of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation remains an unmet need in the clinical management of GBMs. Experimental Design: We employ a novel diffusion histology imaging (DHI) approach, combining diffusion basis spectrum imaging (DBSI) and machine learning, to detect, differentiate, and quantify areas of high cellularity, tumor necrosis, and tumor infiltration in GBM. Results: Gadolinium-enhanced T1-weighted or hyperintense fluid-attenuated inversion recovery failed to reflect the morphologic complexity underlying tumor in patients with GBM. Contrary to the conventional wisdom that apparent diffusion coefficient (ADC) negatively correlates with increased tumor cellularity, we demonstrate disagreement between ADC and histologically confirmed tumor cellularity in GBM specimens, whereas DBSI-derived restricted isotropic diffusion fraction positively correlated with tumor cellularity in the same specimens. By incorporating DBSI metrics as classifiers for a supervised machine learning algorithm, we accurately predicted high tumor cellularity, tumor necrosis, and tumor infiltration with 87.5%, 89.0%, and 93.4% accuracy, respectively. Conclusions: Our results suggest that DHI could serve as a favorable alternative to current neuroimaging techniques in guiding biopsy or surgery as well as monitoring therapeutic response in the treatment of GBM.
Communicating with children about COVID-19
Authors: Fiona Mitchell
Journal: The Lancet Infectious Diseases (2020)

The COVID-19 pandemic has created strange and difficult living conditions for many people. Children are likely to find it harder than adults to adapt their behaviour and accommodate the various restrictions being imposed on everyday living. A need for child-friendly resources to explain COVID-19—including how the virus is transmitted, the importance of following social distancing measures, and the effects of the virus—has been identified. For children directly affected by the pandemic—perhaps with a family member or friend who has developed COVID-19—the need to communicate very carefully about COVID-19 is clear.
Neurofibromin 1 gene Mutations Are Recurrent Events in Adult Patients with Acute Myeloid Leukemia (AML), Associate with Poor Outcome and Refine the Adverse European Leukemianet (ELN) Risk Category
Authors: Ann-Kathrin Eisfeld, Jessica Kohlschmidt, Krzysztof Mrózek, Alice S. Mims, Christopher J. Walker, James S. Blachly, Deedra Nicolet, Shelley Orwick, Sofia E. Maharry, Andrew Carroll, Bayard L. Powell, Jonathan E. Kolitz, Eunice S. Wang, Richard M. Stone, Albert de la Chapelle, John C. Byrd, Clara D. Bloomfield
Journal: Blood (2017)
Internally Responsive Nanomaterials for Activatable Multimodal Imaging of Cancer
Authors: Zachary T. Rosenkrans, Carolina A. Ferreira, Dalong Ni, Weibo Cai
Journal: Advanced Healthcare Materials (2020)

Abstract Advances in technology and nanomedicine have led to the development of nanoparticles that can be activated for multimodal imaging of cancer, where a stimulus induces a material modification that enhances image contrast. Multimodal imaging using nanomaterials with this capability can combine the advantages and overcome the limitations of any single imaging modality. When designed with stimuli‐responsive abilities, the target‐to‐background ratio of multimodal imaging nanoprobes increases because specific stimuli in the tumor enhance the signal. Several aspects of the tumor microenvironment can be exploited as an internal stimulus response for multimodal imaging applications, such as the pH gradient, redox processes, overproduction of various enzymes, or combinations of these. In this review, design strategies are discussed and an overview of the recent developments of internally responsive multimodal nanomaterials is provided. Properly implementing this approach improves noninvasive cancer diagnosis and staging as well as provides a method to monitor drug delivery and treatment response.
Epidemiology of gastroparesis: important answers and still more questions
Authors: Saam Dilmaghani, Michael Camilleri
Journal: Gut (2020)

Gastroparesis is a chronic gastrointestinal disorder characterised by symptoms of nausea, vomiting, early satiety, postprandial fullness, bloating and abdominal discomfort.1 Definitive diagnosis requires objective evidence of delayed gastric emptying (GE), typically assessed via scintigraphy or stable isotope breath tests with a standardised meal.2 The pathophysiological mechanisms and natural history of gastroparesis remain unclear, at least in part due to the paucity of a comprehensive, accurate and consistent description of the epidemiology.

The recently published study by Ye et al in Gut partly addresses this need as the first population-based study to describe the epidemiology and outcomes of gastroparesis in Europe. The study has a number of epidemiological strengths that make it particularly noteworthy, the most significant of which is that data acquisition used the Clinical Practice Research Datalink (CPRD) database in the UK. The CPRD is an anonymised data source of general practitioner records with 4.4 million active patients comprising 7% of the entire UK population. The CPRD is representative in terms of age, sex, ethnicity and body mass index.3 Over half of these individuals’ records also have linked data to secondary care and mortality records.3 After medical records review of these diverse electronic repositories, the authors identified over 1000 patients with a diagnosis of gastroparesis throughout the UK, facilitating prevalence estimates by …
siRNA nanoparticles targeting CaMKIIγ in lesional macrophages improve atherosclerotic plaque stability in mice
Authors: Wei Tao, Arif Yurdagul, Na Kong, Wenliang Li, Xiaobo Wang, Amanda C. Doran, Chan Feng, Junqing Wang, Mohammad Ariful Islam, Omid C. Farokhzad, Ira Tabas, Jinjun Shi
Journal: Science Translational Medicine (2020)

Targeted siRNA nanoparticles can specifically inhibit pro-atherogenic macrophage pathways to combat atherosclerotic vascular disease.
Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites
Authors: Fabian A. Grimm, William D. Klaren, Xueshu Li, Hans-Joachim Lehmler, Moumita Karmakar, Larry W. Robertson, Weihsueh A. Chiu, Ivan Rusyn
Journal: Environmental Health Perspectives (2020)

BACKGROUND: Xenobiotic metabolism is complex, and accounting for bioactivation and detoxification processes of chemicals remains among the most challenging aspects for decision making with in vitro new approach methods data.OBJECTIVES: Considering the physiological relevance of human organotypic culture models and their utility for high-throughput screening, we hypothesized that multidimensional chemical-biological profiling of chemicals and their major metabolites is a sensible alternative for the toxicological characterization of parent molecules vs. metabolites in vitro.METHODS: In this study, we tested 25 polychlorinated biphenyls (PCBs) [PCB 3, 11, 52, 126, 136, and 153 and their relevant metabolites (hydroxylated, methoxylated, sulfated, and quinone)] in concentration-response (10 nM-100 lM) for effects in human induced pluripotent stem cell (iPSC)derived cardiomyocytes (CMs) and endothelial cells (ECs) (iPSC-derived and HUVECs).Functional phenotypic end points included effects on beating parameters and intracellular Ca 2+ flux in CMs and inhibition of tubulogenesis in ECs.High-content imaging was used to evaluate cytotoxicity, mitochondrial integrity, and oxidative stress.RESULTS: Data integration of a total of 19 physicochemical descriptors and 36 in vitro phenotypes revealed that chlorination status and metabolite class are strong predictors of the in vitro cardiovascular effects of PCBs.Oxidation of PCBs, especially to di-hydroxylated and quinone metabolites, was associated with the most pronounced effects, whereas sulfation and methoxylation of PCBs resulted in diminished bioactivity.DISCUSSION: Risk characterization analysis showed that although in vitro derived effective concentrations exceeded the levels measured in the general population, risks cannot be ruled out due to the potential for population variability in susceptibility and the need to fill data gaps using read-across approaches.This study demonstrated a strategy for how in vitro data can be used to characterize human health risks from PCBs and their metabolites.
Assessing the extent of SARS-CoV-2 circulation through serological studies
Authors: Marion Koopmans, Bart Haagmans
Journal: Nature Medicine (2020)

The COVID-19 pandemic has highlighted the crucial importance of antibody surveys in estimating the incidence of SARS-CoV-2 infection at a population level. Studies in Brazil and China address the use of serology to obtain a better estimate of the infection rate.
Response to: ‘Microbiome in Sjögren’s syndrome: here we are’ by van der Meulen<i>et al</i>
Authors: Julia Manasson, Rebecca B Blank, Jose U Scher
Journal: Annals of the Rheumatic Diseases (2020)

We would like to thank van der Meulen et al for their interest in our review and their comments regarding the role of the microbiome in Sjogren's syndrome (SS). 1 2 As they correctly point out, SS was not mentioned in our review primarily because we, along with the editors, have decided to include the most studied rheumatic and autoimmune conditions as they pertain to microbiome research.We agree that SS is a common disorder with an intriguing and yet to be fully elucidated etiopathogenesis, and that the characterisation of the microbiome in this context is indeed worth pursuing.We also note that the disease entities mentioned in our review were meant as examples of the types of studies currently being performed in the field.The purpose of the review is to outline techniques and strategies that can move microbiome research beyond correlative study designs and into the realm of mechanistic approaches that may have significantly more relevance to clinical practice irrespective of the disease process.][5][6][7][8][9][10][11] As we state in our review, in order for microbiome research to further the understanding of autoimmune disease pathogenesis, stratify patients and lead to the application of personalised therapies, the field must adopt state-of-the-art methods, 12 aim to study mechanisms rather than correlations, and allow for data validation and data sharing.We further agree with van der Meulen et al that microbiome studies should not be restricted to the gut and that interventional studies may be clinically impactful.In fact, both of these points were discussed in our manuscript (see sections on 'Navigating and addressing challenges in microbiome research' and 'What the future holds').The authors' suggestion that more than one rheumatic disease should be studied at a time is interesting, but would need to be pursued cautiously as there is established heterogeneity within even a single rheumatic disease (eg, systemic lupus erythematosus 13 or psoriatic arthritis 14 ).Exploring multiple diseases at a time would introduce additional variables, making it potentially difficult to interpret outcomes.We appreciate the extra dos and don'ts put forward by van der Meulen, et al.There are certainly other caveats to microbiome research not covered within the scope of our review, though we have set up a framework for what future studies should strive for in the context of this fluid discipline.
AB0424 PREDICTORS OF SLE FLARE-UP AND PREMATURE DELIVERY IN PREGNANCY
Authors: C. H. Liao, L. C. Wang, S. C. Hsieh, B. L. Chiang
Journal: Annals of the Rheumatic Diseases (2020)

Background: Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease that affects many women of child-bearing age, with potentially severe consequences on pregnancy outcome. SLE flare-ups may occur during pregnancy and the post-partum period. Previous studies documenting the incidence and risk factors of flare-up of SLE during pregnancy and puerperium had partially discordant results. Objectives: We aimed to delineate the pregnancy complications of women with SLE, as well as neonatal outcomes of their offspring, and hoped to clarify the incidence and risk factors of SLE flare-ups during pregnancy and puerperium. Methods: We retrospectively reviewed the medical records of SLE patients with previous records of pregnancies in our institution. Flare events during pregnancy and puerperium were documented. The pregnancy outcomes recorded include live births, intra-uterine fetal death (IUFD), premature delivery (&lt; 36 weeks of gestational age), NICU admission, and small for gestational age (SGA, &lt;10 th percentile). Univariate logistic regression was performed to determine the factors associated with disease relapse and pregnancy outcomes. Results: From January, 2000 to December, 2019, a total of 94 SLE patients with 139 pregnancies were identified. The overall live birth rate was 92.4% (134/145). Forty-six (34.3%) of the neonates were delivered prematurely. Forty-six (34.3%) of them were SGA. The admission rate to the neonatal intensive care unit was 25% (30/120). Nine (6.4%) were diagnosed to have SLE during pregnancy. The flare rate during pregnancy was 20% while post-partum 9.4%. The majority of the relapses during pregnancy occurred in the second trimester (46.2%), followed by the first trimester (30.8%), and the third trimester (23.1%). Low complement C3 (C3 &lt; 80mg/dl), thrombocytopenia (PLT &lt; 100*10 3 /uL) at conception, and low serum albumin level at the first trimester were associated with antepartum flare. Presence of disease flare and pre-eclampsia in pregnancy, and low serum albumin level at conception were significantly associated with premature delivery. Conclusion: Low complement C3 and thrombocytopenia at conception, and low serum albumin level at the first trimester were associated with disease flare-up during pregnancy. Patients with relative low serum albumin level at conception, or presence of eclampsia or disease flare-up during pregnancy had a higher risk of premature delivery. References: [1]Shaharir SS, Mohamed Said MS, Mohd R, et al. Predictors of SLE relapse in pregnancy and post-partum among multi-ethnic patients in Malaysia. PloS one 2019; 14 (9):e0222343. [2]Bundhun PK, Soogund MZ, Huang F. Impact of systemic lupus erythematosus on maternal and fetal outcomes following pregnancy: A meta-analysis of studies published between years 2001-2016. Journal of autoimmunity 2017; 79 :17-27. Disclosure of Interests: : None declared
Doctor as murderer
Authors: Bill O'Neill
Journal: BMJ (2000)

News p 331 

Harold Shipman, a general practitioner from Greater Manchester, has been convicted of murdering 15 of his patients. Inevitably, his conviction raises serious concerns for clinicians, patients, and society. How could such crimes go undetected? What lessons can be learnt and can similar murders by doctors be prevented in future?

Serial killers in health care like Shipman and Beverly Allitt are particularly shocking because they damage the trust that exists between clinicians and their patients. In 1993 Allitt, a nurse working on a paediatric ward, was convicted of murdering four children, attempting to murder three, and causing grievous bodily harm to six.1

Like many singlehanded doctors, Harold Shipman had over 3000 patients in his care. His patients seemed to like him. Until the suspicions began to gather that eventually led to his prosecution, few concerns were raised about his clinical competence. Evidence emerged that he had falsified the notes of some of his patients, but this was not incompetent record keeping: rather, it was done to conceal his crimes.

In 1976 Shipman was convicted of several offences relating to the misuse of pethidine, and this conviction was reported to the General Medical Council. Shipman sought treatment and no further action was taken. This conviction adds to all the other concerns raised, although no evidence of recent drug misuse has been presented. Moroever, it important not to appear to conclude that drug misusers turn into serial killers. Since the 1970s new procedures have …
P2X7 Receptor Activity Limits Accumulation of T Cells within Tumors
Authors: Andrea Romagnani, Elsa Rottoli, Emilia Maria Cristina Mazza, Tanja Rezzonico-Jost, Benedetta De Ponte Conti, Michele Proietti, Michela Perotti, Elisa Civanelli, Lisa Perruzza, Alberico L. Catapano, Andrea Baragetti, Elena Tenedini, Enrico Tagliafico, Simonetta Falzoni, Francesco Di Virgilio, Giuseppe Danilo Norata, Silvio Bicciato, Fabio Grassi
Journal: Cancer Research (2020)

Extracellular ATP (eATP) is a signaling molecule that variably affects all cells of the immune system either directly or after hydrolysis to adenosine. Although eATP is virtually absent in the interstitium of normal tissues, it can be present in the hundreds of micromolar range in tumors, a concentration compatible with activation of the ATP-gated ionotropic P2X7 receptor. Here, we show that P2X7 activity in tumor-infiltrating lymphocytes (TIL) induces cellular senescence and limits tumor suppression. P2X7 stimulation affected cell cycling of effector T cells and resulted in generation of mitochondrial reactive oxygen species and p38 MAPK-dependent upregulation of cyclin-dependent kinase inhibitor 1A (Cdkn1a, encoding for p21Waf1/Cip1). Lack of P2X7 promoted a transcriptional signature that correlated with enhanced cytotoxic T-cell response in human solid tumors. In mice, transfer of tumor-specific T cells with deletion of P2rx7 significantly reduced tumor growth and extended survival. Collectively, these findings uncover a purinergic checkpoint that can be targeted to improve the efficacy of cancer immunotherapy strategies. SIGNIFICANCE: These findings suggest that the purinergic checkpoint P2X7 may be targeted to enhance T-cell-mediated cancer immunotherapy and improve T effector cell accumulation in the tumor microenvironment. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/18/3906/F1.large.jpg.
Extracellular vesicle-based Nanotherapeutics: Emerging frontiers in anti-inflammatory therapy
Authors: Tao-Tao Tang, Bin Wang, Lin-Li Lv, Bi-Cheng Liu
Journal: Theranostics (2020)

Dysregulated inflammation is a complicated pathological process involved in various diseases, and the treatment of inflammation-linked disorders currently represents an enormous global burden. Extracellular vesicles (EVs) are nanosized, lipid membrane-enclosed vesicles secreted by virtually all types of cells, which act as an important intercellular communicative medium. Considering their capacity to transfer bioactive substances, both unmodified and engineered EVs are increasingly being explored as potential therapeutic agents or therapeutic vehicles. Moreover, as the nature's own delivery tool, EVs possess many desirable advantages, such as stability, biocompatibility, low immunogenicity, low toxicity, and biological barrier permeability. The application of EV-based therapy to combat inflammation, though still in an early stage of development, has profound transformative potential. In this review, we highlight the recent progress in EV engineering for inflammation targeting and modulation, summarize their preclinical applications in the treatment of inflammatory disorders, and present our views on the anti-inflammatory applications of EV-based nanotherapeutics.
Circulating microRNA‐15b‐5p as a biomarker for asthma‐COPD overlap
Authors: Keita Hirai, Toshihiro Shirai, Takayuki Shimoshikiryo, Megumi Ueda, Yasuhiro Gon, Shuichiro Maruoka, Kunihiko Itoh
Journal: Allergy (2020)

Abstract Background It remains unclear how to characterize different subtypes of asthma and chronic obstructive pulmonary disease (COPD). We previously described serum periostin and chitinase‐3‐like protein 1 (YKL‐40) as useful markers for asthma‐COPD overlap (ACO). MicroRNAs (miRNAs) are now recognized as markers for identifying the pathophysiological features in several diseases. This study aimed to identify circulating miRNAs that could discriminate patients with ACO from patients with asthma or COPD. Methods This study included two independent cohorts. First, we screened 84 miRNAs for expression levels in patients with ACO (n = 6) or asthma (n = 6) using a quantitative real‐time PCR array. The miRNAs showing at least a 2‐fold difference in the discovery phase were analyzed in 30 patients each with asthma, COPD, or ACO in the replication phase. The diagnostic accuracy was evaluated using the area under the receiver operating characteristic curve (AUROC). Results Nine miRNAs were identified in the discovery phase. Five of these miRNAs (miR‐148a‐3p, miR‐15b‐5p, miR‐223‐3p, miR‐23a‐3p, and miR‐26b‐5p) had lower levels in ACO patients and could discriminate between ACO patients and patients with either asthma or COPD. miR‐15b‐5p was the most accurate miRNA for the discrimination of patients with ACO (AUROC, 0.71). Moreover, the combined assessment of miR‐15b‐5p, serum periostin, and YKL‐40 (AUROC, 0.80) improved diagnostic accuracy for ACO compared with the combined model of periostin and YKL‐40 (AUROC, 0.69). Conclusions Circulating miR‐15b‐5p is a potential marker for identifying patients with ACO. By elucidating the molecular pathways controlled by miRNAs, we may better understand the pathophysiology of ACO.
Comparison of Organoid Swelling and <i>In Vivo</i> Biomarkers of CFTR Function to Determine Effects of Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation
Authors: Simon Y. Graeber, Peter van Mourik, Annelotte M. Vonk, Evelien Kruisselbrink, Stephanie Hirtz, Cornelis K. van der Ent, Marcus A. Mall, Jeffrey M. Beekman
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

"Comparison of Organoid Swelling and In Vivo Biomarkers of CFTR Function to Determine Effects of Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation." American Journal of Respiratory and Critical Care Medicine, 202(11), pp. 1589–1592
Medical Leave Associated With COVID-19 Among Emergency Medical System Responders and Firefighters in New York City
Authors: David J. Prezant, Rachel Zeig-Owens, Theresa Schwartz, Yang Liu, Karen Hurwitz, Shenecia Beecher, Michael D. Weiden
Journal: JAMA Network Open (2020)

This cohort study examines use of medical leave among emergency medical service (EMS) responders and firefighters in New York, New York, during the coronavirus disease 2019 (COVID-19) pandemic compared with earlier periods.