tbuckley/cabot-search huggingface dataset:
Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation
Authors: Agata Cieslak, Guillaume Charbonnier, Melania Tesio, Eve-Lyne Mathieu, Mohamed Belhocine, Aurore Touzart, Charlotte Smith, Guillaume Hypolite, Guillaume P. Andrieu, Joost H.A. Martens, Eva Janssen-Megens, Marta Gut, Ivo Gut, Nicolas Boissel, Arnaud Petit, Denis Puthier, Elizabeth Macintyre, Hendrik G. Stunnenberg, Salvatore Spicuglia, Vahid Asnafi
Journal: The Journal of Experimental Medicine (2020)

Cell differentiation is accompanied by epigenetic changes leading to precise lineage definition and cell identity. Here we present a comprehensive resource of epigenomic data of human T cell precursors along with an integrative analysis of other hematopoietic populations. Although T cell commitment is accompanied by large scale epigenetic changes, we observed that the majority of distal regulatory elements are constitutively unmethylated throughout T cell differentiation, irrespective of their activation status. Among these, the TCRA gene enhancer (Eα) is in an open and unmethylated chromatin structure well before activation. Integrative analyses revealed that the HOXA5-9 transcription factors repress the Eα enhancer at early stages of T cell differentiation, while their decommission is required for TCRA locus activation and enforced αβ T lineage differentiation. Remarkably, the HOXA-mediated repression of Eα is paralleled by the ectopic expression of homeodomain-related oncogenes in T cell acute lymphoblastic leukemia. These results highlight an analogous enhancer repression mechanism at play in normal and cancer conditions, but imposing distinct developmental constraints.
<i>ACE2</i>and<i>TMPRSS2</i>expression by clinical, HLA, immune, and microbial correlates across 34 human cancers and matched normal tissues: implications for SARS-CoV-2 COVID-19
Authors: Riyue Bao, Kyle Hernandez, Lei Huang, Jason John Luke
Journal: Journal for ImmunoTherapy of Cancer (2020)

Pandemic COVID-19 by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) infection is facilitated by the ACE2 receptor and protease TMPRSS2. Modestly sized case series have described clinical factors associated with COVID-19, while ACE2 and TMPRSS2 expression analyses have been described in some cell types. Patients with cancer may have worse outcomes to COVID-19.We performed an integrated study of ACE2 and TMPRSS2 gene expression across and within organ systems, by normal versus tumor, across several existing databases (The Cancer Genome Atlas, Census of Immune Single Cell Expression Atlas, The Human Cell Landscape, and more). We correlated gene expression with clinical factors (including but not limited to age, gender, race, body mass index, and smoking history), HLA genotype, immune gene expression patterns, cell subsets, and single-cell sequencing as well as commensal microbiome.Matched normal tissues generally display higher ACE2 and TMPRSS2 expression compared with cancer, with normal and tumor from digestive organs expressing the highest levels. No clinical factors were consistently identified to be significantly associated with gene expression levels though outlier organ systems were observed for some factors. Similarly, no HLA genotypes were consistently associated with gene expression levels. Strong correlations were observed between ACE2 expression levels and multiple immune gene signatures including interferon-stimulated genes and the T cell-inflamed phenotype as well as inverse associations with angiogenesis and transforming growth factor-β signatures. ACE2 positively correlated with macrophage subsets across tumor types. TMPRSS2 was less associated with immune gene expression but was strongly associated with epithelial cell abundance. Single-cell sequencing analysis across nine independent studies demonstrated little to no ACE2 or TMPRSS2 expression in lymphocytes or macrophages. ACE2 and TMPRSS2 gene expression associated with commensal microbiota in matched normal tissues particularly from colorectal cancers, with distinct bacterial populations showing strong associations.We performed a large-scale integration of ACE2 and TMPRSS2 gene expression across clinical, genetic, and microbiome domains. We identify novel associations with the microbiota and confirm host immunity associations with gene expression. We suggest caution in interpretation regarding genetic associations with ACE2 expression suggested from smaller case series.
Novel integrin binding peptides in cancer therapy
Authors: Olulanu H. Aina, Xiaobing Wang, Aimin Song, See-Hyoung Park, Nian-Huan Yao, Kit S. Lam
Journal: Cancer Research (2006)

1126  We had previously reported on the discovery of novel alpha-3 integrin binding peptides through screening “one- bead one-compound” combinatorial cyclic peptide libraries with live ovarian adenocarcinoma cell lines [1]. We have shown that these ligands can be used as effective probes to image ovarian tumor xenografts both optically [2] and with positron emission tomography. Based on the results obtained from the primary and secondary library screens, we have designed and synthesized four tertiary libraries that can be used to further optimize our lead compounds. These libraries include (a) main chain modification with three diversity points, (b) side chain modification with three diversity points, (c) main chain and N-terminal modifications, and (d) N-terminal extensions with two diversity points. By using this sequential iterative screening approach with a number of different combinatorial libraries, we can rapidly probe the conformational spaces surrounding the initial lead compound. We have also identified other novel peptides from random peptide library screening which have a common motif that bind to ovarian adenocarcinomas as well as transition cell tumors. Preliminary data shows that one of these identified peptides preferentially binds to beta-1 integrin. These peptides could potentially be used as carrier to delivery radionuclides or cytotoxic drugs to the target tumor. 1. Aina, O.H., et al., Identification of novel targeting peptides for human ovarian cancer cells using “one-bead one-compound” combinatorial libraries. Mol Cancer Ther, 2005. 4(5): p. 806-13. 2. Aina, O.H., et al., Near- Infrared optical imaging of ovarian cancer xenografts with novel alpha-3 integrin binding peptide “OA02”. Molecular Imaging, 2005.
The role of chest radiography in confirming covid-19 pneumonia
Authors: Joanne Cleverley, James Piper, Melvyn M Jones
Journal: BMJ (2020)

What you need to know• A normal chest radiograph does not exclude covid-19 pneumonia • No single feature of covid-19 pneumonia on a chest radiograph is specific or diagnostic, but a combination of multifocal peripheral lung changes of ground glass opacity and/or consolidation, which are most commonly bilateral, may be present • Diagnosis might be complicated as covid-19 pneumonia may or may not be visible on chest radiograph; consider other causes for patients' respiratory symptoms Covid-19 is likely to remain an important differential diagnosis for the foreseeable future in anyone presenting to hospital with a flu-like illness, lymphopenia on full blood count, and/or a change in normal sense of smell (anosmia) or taste. 1 2Most people with covid-19 infection do not develop pneumonia 3 ; however, chest radiography of people who are seriously ill with respiratory symptoms when they present to hospital can help to identify those with covid-19 pneumonia.In this article we offer advice to non-radiologists on how to look for changes on chest radiograph that may be suggestive of covid-19 pneumonia, as prompt review and report from an onsite or remote radiologist is not always available.The recommendations in this article are based on a combination of emerging evidence, current guidelines, and our clinical experience.For the radiograph examples used in this article, we cannot confirm whether each patient tested positive for covid-19 because we did not have access or ethical approval to access these patients' clinical records; however, they were all diagnosed with covid-19 pneumonia as they had supportive radiographical features during the covid-19 pandemic.
OP0015 The disease course of patients with rheumatoid arthritis in remission; a prospective 2 year follow-up study
Authors: ET Molenaar, AE Voskuyl, HJ Dinant, PD Bezemer, BA Dijkmans
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To assess the prevalence of persistent remission and factors associated with persistent remission in a large cohort of RA patients in remission. <h3>Methods</h3> RA patients in remission according to the ACR/Pinals criteria were evaluated every 3 months for disease activity during 2 years. Factors measured at baseline and possibly associated with persistent remission were evaluated. <h3>Results</h3> Of the 180 RA patients included 93 (52%) experienced persistent remission. Those patients had significantly (p &lt; 0.05) less tender joints, lower Ritchie score, lower VAS score, lower serum IgM-RF and IgA-RF levels, lower HAQ score at baseline when compared to patients suffering an exacerbation. DMARD use was not associated with persistent remission. In a multivariate analysis, the following variables were independently associated with persistent remission: DAS &lt; 1.6 (odds ratio with 95% CI: 3.7, 1.5–9.5) and VAS &lt; 12 (1.1, 1.0–1.2). The area under the curve of the DAS &lt; 1.6 in the first year was associated with remission in the second year (9.9, 4.1–24). <h3>Conclusion</h3> Persistent remission occurs frequently and is associated with a low disease activity score (DAS), in particular with a low cumulative DAS. The use of a cumulative DAS may be a tool in taking therapeutic decisions.
Local injection of CCL19-expressing mesenchymal stem cells augments the therapeutic efficacy of anti-PD-L1 antibody by promoting infiltration of immune cells
Authors: Yuichi Iida, Rintaro Yoshikawa, Akihiko Murata, Hitoshi Kotani, Yasuhiro Kazuki, Mitsuo Oshimura, Yumi Matsuzaki, Mamoru Harada
Journal: Journal for ImmunoTherapy of Cancer (2020)

Mesenchymal stem/stromal cells (MSC) accumulate and reside in tumor sites.Taking advantage of this feature in anticancer therapy, immortalized murine MSC (iMSC) were genetically altered to produce chemokine (C-C motif) ligand 19 (iMSC/CCL19), which attracts dendritic cells (DC) and T lymphocytes. Thereafter, iMSC/CCL19 were examined for their therapeutic efficacy using a syngeneic CT26 colon carcinoma cell line.Co-injection of iMSC/CCL19 into mice significantly suppressed the in vivo growth of CT26 cells compared with that of CCL19-expressing immortalized fibroblasts (iFib/CCL19). This anticancer effect was not observed when injected in CT26-bearing nude mice. Co-injected iMSC/CCL19 survived longer than iFib/CCL19 in the tumor sites. In a therapeutic model, local injection of iMSC/CCL19 suppressed the tumor growth, and increased IFN (interferon)-γ+ CD8+ T cells and CCR7+ DC infiltration in tumor site was observed when treated with iMSC/CCL19, but not with iMSC. This antitumor effect was completely negated by depletion of CD4+ cells and partially negated by depletion of CD8+ cells. Furthermore, the antitumor effects induced by local injection of iMSC/CCL19 were augmented by additional therapy with anti-programmed death (PD)-ligand 1 (PD-L1) antibody, but not with anti-PD-1 antibody. This combination therapy cured most of the tumors in CT26-bearing mice.These results suggest that local therapy with iMSC/CCL19 can suppress tumor growth via effective recruitment of CCR7+ DC into tumor sites and increase IFN-γ+ CD8+ T cells, and that combination with anti-PD-L1 antibody therapy can be a powerful anticancer therapy.
Comorbid Conditions in Newly Diagnosed Patients with Acute Promyelocytic Leukemia (APL) in Real World Patients; Decreased Induction Mortality Despite a High Comorbid Index
Authors: Stephanie Debragga, Kathryn Sarah Simon, Prachi Kharkhanis, Sheldon Bolds, Catherine R. Caprara, Martha L. Arellano, Anand Jillella, Vamsi Kota
Journal: Blood (2017)
Abstract 10442: In vitro Drug Screening Model for Cardiac Fibrosis Using Human Induced Pluripotent Stem Cell Derived Cardiac Tissue Provides Drug Repositioning of Anti-fibrotic Drugs for Cardiac Fibrosis
Authors: Hiroko Iseoka, Shigeru Miyagawa, Yoshiki Sakai, Akima Harada, Yoshiki Sawa
Journal: Circulation (2019)

Background: Cardiac fibrosis (CF) is one of major causes of heart failure (HF) and development in new medications targeted to CF is crucial for treatment of HF. Critical point in drug development m...
Association Between Citations, Altmetrics, and Article Views in Pediatric Research
Authors: Andrew J. Giustini, David M. Axelrod, Brian P. Lucas, Alan R. Schroeder
Journal: JAMA Network Open (2020)

This cross-sectional study examines the association between article citations, Altmetric attention scores, and cumulative page views of pediatric research articles from 4 high-impact medical journals.
PTH-072 An exploratory study of the impact of primary care faecal calprotectin testing on referrals to secondary care
Authors: N Taylor, H Everitt, S Latter, K Burrill, E Efrem, F Cummings
Journal: Gut (2017)

Introduction  NICE recommend faecal calprotectin (FC) testing to help differentiate between irritable bowel syndrome and other pathologies including inflammatory bowel disease (IBD) in adults for whom specialist assessment is being considered. We aimed to explore the impact of introducing GP FC testing on referrals to secondary care.  Method  GPs within Southampton City and West Hampshire CCGs were invited to request FC in adults under 45 with symptoms that could initiate referral. Before requesting electronically, GPs answered questions on patient history and if they planned to refer the patient. GP/hospital data was collected electronically from April 2015-June 2016 and reviewed according to FC (  Results  59/64 (92%) of GP surgeries used FC testing. 410/435 samples received were processed: 66 (16%) positive, 33 (8%) indeterminate, 311 (76%) negative. 85/410 (21%) patients were referred to secondary care (60% positive/indeterminate FC). Mean monthly gastroenterology (including non-IBD) referral rates were unchanged from 2014/15 to 2015/16 (187 vs. 186/mth). 16/410 were diagnosed with IBD (19% of FC referrals, all positive/indeterminate FC). Of 66 patients with positive FC, only 43 (65%) were referred, with no referral/appointment on record for the remaining 23.  When asked ‘would you refer even if FC was negative?’ in 55/410 cases GPs responded ‘yes’, but only referred 22 (40%). Of 176/410 cases where the response was ‘no’, 13 (7%) were referred. When asked ‘would you refer if FC was not available?’ in 205/410 cases GPs responded ‘yes’ but only referred 52 (25%). Of 34/410 cases where the response was ‘no’, 4 (12%) were referred. GPs were twice as likely to report planning to refer patients who ultimately had a positive FC than those with a negative FC (24% vs. 11%), suggesting these patients may have symptoms of greater concern.  56/85 (66%) of referred patients (14 with negative FC) underwent lower GI endoscopy (30/56 (53%) normal, 16/56 (29%) IBD, 4/56 (7%) microscopic colitis, 1/56 (2%) cancer, 5/56 (9%) other). Mean times from referral to outpatient clinic and endoscopy: 69 and 93 days. Despite being at higher risk of IBD, the mean time from referral to clinic for patients with positive FC was only slightly less than for negative FC (64 vs. 78 days).  Conclusion  FC testing was requested by most GP practices but in low numbers and a significant number of patients with positive FC were not referred. FC did appear to influence GP decision-making regarding referral. Local pathways will be developed to introduce a Positive FC clinic to streamline referrals and aim to improve time to IBD diagnosis.  Disclosure of Interest  None Declared
No cashew allergy in infants introduced to cashew by age 1 year
Authors: Rachel L. Peters, Danny Ye Barret, Victoria X. Soriano, Vicki McWilliam, Adrian J. Lowe, Anne-Louise Ponsonby, Mimi L.K. Tang, Shyamali C. Dharmage, Lyle C. Gurrin, Jennifer J. Koplin, Kirsten P. Perrett
Journal: Journal of Allergy and Clinical Immunology (2020)
Enanthem in Patients With COVID-19 and Skin Rash
Authors: Juan Jimenez-Cauhe, Daniel Ortega-Quijano, Dario de Perosanz-Lobo, Patricia Burgos-Blasco, Sergio Vañó-Galván, Montse Fernandez-Guarino, Diego Fernandez-Nieto
Journal: JAMA Dermatology (2020)

Figure 1).Their HAP scores gradually increased, and the hypotrichosis in the patient with TRPS1 did not improve (Figure 2A).Hair shaft diameters were increased in every participant with LIPH pathogenic variants (Figure 2B andC).There were no serious adverse events, but some mild adverse events were reported (dry skin on the scalp, trichiasis, and mild hypertrichosis on the entire body).Discussion | Lysophosphatidic acids bind the P2Y5 receptor in the hair follicle epithelium and activate hair growth. 5In ARWH due to LIPH pathogenic variants, loss-of-function variants in LIPH lead to a deficiency of lysophosphatidic acids and insufficient activation of P2Y5.The present prospective interventional study suggests that minoxidil could be associated with improvements in hypotrichosis in ARWH owing to LIPH pathogenic variants.There appears to be a binary response to minoxidil, with one group responding better than the other.The data on causative pathogenic variants suggest that it is unrelated to the LIPH pathogenic variants.Among the 8 patients with ARWH due to LIPH pathogenic variants, 5 patients were unrelated, and the other 3 were from 1 family.All 3 members of the family were in the group responding better.Thus, we cannot exclude the possibility that the family had an unknown genetic modifying factor affecting the efficacy of minoxidil.
Hepatitis B vaccine and NK cells: a new player in memory
Authors: Maike Hofmann, Robert Thimme
Journal: Gut (2020)

Figure 1 Hepatitis B virus (HBV) antigen-specific NK-cell responses in hepatitis B (HepB)vaccinated individuals and patients chronically infected with HBV.Increased degranulation of natural killer (NK) cells is detectable on stimulation with HBsAg-pulsed monocyte-derived dendritic cells (moDC) after HepB vaccination and in chronic HBV infection.HBcAg-pulsed moDCs, however, only mediate an enhanced degranulation of NK cells obtained from chronically HBV-infected patients.This probably reflects different antigen exposure in HepB vaccination versus chronic HBV infection.on July 19,
Iron chelation rescues hemolytic anemia and skin photosensitivity in congenital erythropoietic porphyria
Authors: Jean-Marc Blouin, Cécile Ged, Magalie Lalanne, Isabelle Lamrissi-Garcia, Fanny Morice-Picard, Pierre Costet, Raêd Daher, François Moreau-Gaudry, Aurélie Bedel, Hervé Puy, Laurent Gouya, Zoubida Karim, Emmanuel Richard
Journal: Blood (2020)
Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19
Authors: Eugenio D. Hottz, Isaclaudia G. Azevedo-Quintanilha, Lohanna Palhinha, Lívia Teixeira, Ester A. Barreto, Camila R. R. Pão, Cassia Righy, Sérgio Franco, Thiago M. L. Souza, Pedro Kurtz, Fernando A. Bozza, Patrícia T. Bozza
Journal: Blood (2020)
Seven things organisations should be doing to combat racism
Authors: Esther Choo
Journal: The Lancet (2020)

In the USA, the racial disparities in COVID-19 health outcomes collided with national conversations about racism sparked by the police killing of George Floyd. These events stimulated many organisations, including health-care institutions, to scramble to vocalise their stances on racial equity. The coming years will show if these statements translate into fundamental, lasting change. There are seven actions I hope to see from health-care organisations committed to addressing structural racism and building equitable environments.
Durable and Specific Inhibition of ROR1 Signaling Associates with Prolonged Progression Free Survival in Patients with Chronic Lymphocytic Leukemia Treated with Cirmtuzumab
Authors: Michael Choi, George F. Widhopf II, Jian Yu, Liguang Chen, Md. Kamrul Hasan, Laura Z. Rassenti, Emily Pittman, Karen Messer, Charlene Gutierrez, Reilly Lilianna Kidwell, Charles E. Prussak, Januario E Castro, Catriona Jamieson, Thomas J. Kipps
Journal: Blood (2017)
Stroke Thrombolysis With Tenecteplase to Reduce Emergency Department Spread of Coronavirus Disease 2019 and Shortages of Alteplase
Authors: Steven J. Warach, Jeffrey L. Saver
Journal: JAMA Neurology (2020)

Department Spread of Coronavirus Disease 2019 and Shortages of AlteplaseMeasures to reduce emergency department staff exposure to the severe acute respiratory syndrome coronavirus 2 have focused on screening and use of personal protective equipment.Reducing the time and intensity of interactions with individuals with known or suspected cases of coronavirus disease 2019 (COVID-19) is also desirable, insofar as such reductions do not compromise the quality or outcomes of care.The situation of an acute stroke emergency is a particularly vulnerable situation for exposure and transmission, since a substantial proportion of patients are unable to provide a history to screen them out for COVID-19.Tenecteplase was developed as a plasminogen activator with greater fibrin specificity and reduced clearance compared with alteplase, allowing single-bolus administration. 1In 2000, the US Food and Drug Administration approved tenecteplase to reduce mortality in acute myocardial infarction.Since then, randomized clinical trials and meta-analyses on ischemic stroke have demonstrated that tenecteplase has noninferior safety and efficacy relative to the standard intravenous stroke thrombolytic agent alteplase and may be superior for early recanalization. 2,3rior to the COVID-19 pandemic, some stroke centers, including ours at the University of Texas-Austin Dell Medical School and Ascension Texas, had switched to tenecteplase as the stroke thrombolytic agent because of its workflow advantages and potential time savings relative to alteplase, especially in the time to initiate an interfacility transfer for thrombectomy or a higher level of care (Box).Tenecteplase is given as a single, 5-second intravenous bolus that requires approximately 2 minutes to mix, prepare, and administer, whereas alteplase requires preparation of both a bolus syringe containing 10% of the weight-based dose and an intravenous pump set up for infusion of the remaining 90% of the dose over 60 minutes.The simpler tenecteplase workflow may be additionally advantageous during the COVID-19 pandemic.Eliminating the alteplase 1-hour infusion and the dedicated second intravenous catheter that it requires reduces staff time in close proximity to the patient and removes the intravenous infusion pump that accompanies the patient through other hospital departments and wards, presenting its own set of surfaces for a virus to settle on and staff to touch.In addition, after published case observations 4 suggested that thrombolysis with alteplase may be beneficial as a treatment for the acute respiratory distress syndrome associated with COVID-19, some centers worldwide have been using alteplase for this potential additional indication and more rapidly consuming their VIEWPOINT