tbuckley/cabot-search huggingface dataset:
An Arabidopsis Secondary Metabolite Directly Targets Expression of the Bacterial Type III Secretion System to Inhibit Bacterial Virulence
Authors: Wei Wang, Jing Yang, Jian Zhang, Yong-Xin Liu, Caiping Tian, Baoyuan Qu, Chulei Gao, Peiyong Xin, Shujing Cheng, Wenjing Zhang, Pei Miao, Lei Li, Xiaojuan Zhang, Jinfang Chu, Jianru Zuo, Jiayang Li, Yang Bai, Xiaoguang Lei, Jian-Min Zhou
Journal: Cell Host & Microbe (2020)
When COVID-19 meets centralized, personalized power
Authors: Yuen Yuen Ang
Journal: Nature Human Behaviour (2020)

The debate over whether autocracies or democracies are better at fighting epidemics is misguided. Under President Xi Jinping's centralized command, his administration has both succeeded and failed at handling the COVID-19 crisis. While it effectively curbed infections within China after the virus had spread, it failed to stem the outbreak before it went global.
Hypertension, the renin–angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19
Authors: Reinhold Kreutz, Engi Abd El-Hady Algharably, Michel Azizi, Piotr Dobrowolski, Tomasz Guzik, Andrzej Januszewicz, Alexandre Persu, Aleksander Prejbisz, Thomas Günther Riemer, Ji-Guang Wang, Michel Burnier
Journal: Cardiovascular Research (2020)

Abstract Systemic arterial hypertension (referred to as hypertension herein) is a major risk factor of mortality worldwide, and its importance is further emphasized in the context of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection referred to as COVID-19. Patients with severe COVID-19 infections commonly are older and have a history of hypertension. Almost 75% of patients who have died in the pandemic in Italy had hypertension. This raised multiple questions regarding a more severe course of COVID-19 in relation to hypertension itself as well as its treatment with renin–angiotensin system (RAS) blockers, e.g. angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). We provide a critical review on the relationship of hypertension, RAS, and risk of lung injury. We demonstrate lack of sound evidence that hypertension per se is an independent risk factor for COVID-19. Interestingly, ACEIs and ARBs may be associated with lower incidence and/or improved outcome in patients with lower respiratory tract infections. We also review in detail the molecular mechanisms linking the RAS to lung damage and the potential clinical impact of treatment with RAS blockers in patients with COVID-19 and a high cardiovascular and renal risk. This is related to the role of angiotensin-converting enzyme 2 (ACE2) for SARS-CoV-2 entry into cells, and expression of ACE2 in the lung, cardiovascular system, kidney, and other tissues. In summary, a critical review of available evidence does not support a deleterious effect of RAS blockers in COVID-19 infections. Therefore, there is currently no reason to discontinue RAS blockers in stable patients facing the COVID-19 pandemic.
Abstract 11861: Burden of Peripheral Artery Disease and Incident CVD and Mortality
Authors: Jonathan Unkart, Michael H Criqui, Maria Rosario G Araneta, Joachim H Ix, Kunihiro Matsushita, Matthew A Allison
Journal: Circulation (2019)

Introduction: The ankle brachial index (ABI), a measure of peripheral artery disease (PAD), is associated with cardiovascular disease (CVD) events and mortality. However, analyses traditionally onl...
Corrigendum to “Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity”” [Prog. Retina Eye Res. 73 (2019) 100764]
Authors: Francis L. Munier, Maja Beck-Popovic, Guillermo L. Chantada, David Cobrinik, Tero T. Kivelä, Dietmar Lohmann, Philippe Maeder, Annette C. Moll, Angel Montero Carcaboso, Alexandre Moulin, Paula Schaiquevich, Ciara Bergin, Paul J. Dyson, Susan Houghton, Francesco Puccinelli, Yvan Vial, Marie-Claire Gaillard, Christina Stathopoulos
Journal: Progress in Retinal and Eye Research (2020)
What Is Post–Intensive Care Syndrome (PICS)?
Authors: Samuel Kosinski, Rima A. Mohammad, Mari Pitcher, Evan Haezebrouck, Antoinette B. Coe, Deena K. Costa, Hallie C. Prescott, Theodore J. Iwashyna, Jakob I. McSparron
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

"What Is Post–Intensive Care Syndrome (PICS)?." American Journal of Respiratory and Critical Care Medicine, 201(8), pp. P15–P16
Abstract 15840: Echocardiographic Predictors of Occult Diastolic Dysfunction by Fluid Challenge in Pulmonary Hypertension
Authors: Vineet Agrawal, Michele D’Alto, Meng Xu, Robert Naeije, Ivan M Robbins, Tufik R Assad, John L Newman, Meredith E Pugh, Anna R Hemnes, Evan L Brittain
Journal: Circulation (2018)

Introduction: Identification of diastolic dysfunction (DD) in patients with PH has important prognostic and therapeutic implications. Right heart catheterization (RHC) with fluid challenge often id...
Icariside Ⅱ, a main compound in Epimedii Folium, induces idiosyncratic hepatotoxicity by enhancing NLRP3 inflammasome activation
Authors: Zhilei Wang, Guang Xu, Hongbo Wang, Xiaoyan Zhan, Yuan Gao, Nian Chen, Ruisheng Li, Xueai Song, Yuming Guo, Ruichuang Yang, Ming Niu, Jiabo Wang, Youping Liu, Xiaohe Xiao, Zhaofang Bai
Journal: Acta Pharmaceutica Sinica B (2020)

Idiosyncratic drug-induced liver injury (IDILI) is an infrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs. Epimedii Folium (EF), the widely used herbal medicine, has shown to cause idiosyncratic liver injury, but the underlying mechanisms are poorly understood. Increasing evidence has indicated that most cases of IDILI are immune mediated. Here, we report that icariside Ⅱ (ICS Ⅱ), the major active and metabolic constituent of EF, causes idiosyncratic liver injury by promoting NLRP3 inflammasome activation. ICS Ⅱ exacerbates NLRP3 inflammasome activation triggered by adenosine triphosphate (ATP) and nigericin, but not silicon dioxide (SiO2), monosodium urate (MSU) crystal or cytosolic lipopolysaccharide (LPS). Additionally, the activation of NLRC4 and AIM2 inflammasomes is not affected by ICS Ⅱ. Mechanistically, synergistic induction of mitochondrial reactive oxygen species (mtROS) is a crucial contributor to the enhancing effect of ICS Ⅱ on ATP- or nigericin-induced NLRP3 inflammasome activation. Importantly, in vivo data show that a combination of non-hepatotoxic doses of LPS and ICS Ⅱ causes the increase of aminotransferase activity, hepatic inflammation and pyroptosis, which is attenuated by Nlrp3 deficiency or pretreatment with MCC950 (a specific NLRP3 inflammasome inhibitor). In conclusion, these findings demonstrate that ICS Ⅱ causes idiosyncratic liver injury through enhancing NLRP3 inflammasome activation and suggest that ICS Ⅱ may be a risk factor and responsible for EF-induced liver injury.
Targeting p63 Upregulation Abrogates Resistance to MAPK Inhibitors in Melanoma
Authors: Ankit Patel, Lucia Fraile Garcia, Viviana Mannella, Luke Gammon, Tiffanie-Marie Borg, Tania Maffucci, Maria Scatolini, Giovanna Chiorino, Elisabetta Vergani, Monica Rodolfo, Andrea Maurichi, Christian Posch, Rubeta N. Matin, Catherine A. Harwood, Daniele Bergamaschi
Journal: Cancer Research (2020)

Abstract Targeting the MAPK pathway by combined inhibition of BRAF and MEK has increased overall survival in advanced BRAF-mutant melanoma in both therapeutic and adjuvant clinical settings. However, a significant proportion of tumors develop acquired resistance, leading to treatment failure. We have previously shown p63 to be an important inhibitor of p53-induced apoptosis in melanoma following genotoxic drug exposure. Here, we investigated the role of p63 in acquired resistance to MAPK inhibition and show that p63 isoforms are upregulated in melanoma cell lines chronically exposed to BRAF and MEK inhibition, with consequent increased resistance to apoptosis. This p63 upregulation was the result of its reduced degradation by the E3 ubiquitin ligase FBXW7. FBXW7 was itself regulated by MDM2, and in therapy-resistant melanoma cell lines, nuclear accumulation of MDM2 caused downregulation of FBXW7 and consequent upregulation of p63. Consistent with this, both FBXW7-inactivating mutations and MDM2 upregulation were found in melanoma clinical samples. Treatment of MAPK inhibitor–resistant melanoma cells with MDM2 inhibitor Nutlin-3A restored FBXW7 expression and p63 degradation in a dose-dependent manner and sensitized these cells to apoptosis. Collectively, these data provide a compelling rationale for future investigation of Nutlin-3A as an approach to abrogate acquired resistance of melanoma to MAPK inhibitor targeted therapy. Significance: Upregulation of p63, an unreported mechanism of MAPK inhibitor resistance in melanoma, can be abrogated by treatment with the MDM2 inhibitor Nutlin-3A, which may serve as a strategy to overcome resistance.
A Case of Acute Myeloid Leukemia with Maturation (AML-M2) with C-MYC Amplification in Homogenous Staining Region (hsr) and Double Minutes (dmin)
Authors: Seungok Lee, Myungshin Kim, Jihyang Lim, Yonggoo Kim, Kyungja Han, Heeje Kim, Woo-Sung Min
Journal: Blood (2008)
Metagenomics Reveals a Core Macrolide Resistome Related to Microbiota in Chronic Respiratory Disease
Authors: Micheál Mac Aogáin, Kenny J. X. Lau, Zhao Cai, Jayanth Kumar Narayana, Rikky W. Purbojati, Daniela I. Drautz-Moses, Nicolas E. Gaultier, Tavleen K. Jaggi, Pei Yee Tiew, Thun How Ong, Mariko Siyue Koh, Albert Lim Yick Hou, John A. Abisheganaden, Krasimira Tsaneva-Atanasova, Stephan C. Schuster, Sanjay H. Chotirmall
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Long-term antibiotic use for managing chronic respiratory disease is increasing; however, the role of the airway resistome and its relationship to host microbiomes remains unknown.Objectives: To evaluate airway resistomes and relate them to host and environmental microbiomes using ultradeep metagenomic shotgun sequencing.Methods: Airway specimens from 85 individuals with and without chronic respiratory disease (severe asthma, chronic obstructive pulmonary disease, and bronchiectasis) were subjected to metagenomic sequencing to an average depth exceeding 20 million reads. Respiratory and device-associated microbiomes were evaluated on the basis of taxonomical classification and functional annotation including the Comprehensive Antibiotic Resistance Database to determine airway resistomes. Co-occurrence networks of gene–microbe association were constructed to determine potential microbial sources of the airway resistome. Paired patient-inhaler metagenomes were compared (n = 31) to assess for the presence of airway–environment overlap in microbiomes and/or resistomes.Measurements and Main Results: Airway metagenomes exhibit taxonomic and metabolic diversity and distinct antimicrobial resistance patterns. A “core” airway resistome dominated by macrolide but with high prevalence of β-lactam, fluoroquinolone, and tetracycline resistance genes exists and is independent of disease status or antibiotic exposure. Streptococcus and Actinomyces are key potential microbial reservoirs of macrolide resistance including the ermX, ermF, and msrD genes. Significant patient-inhaler overlap in airway microbiomes and their resistomes is identified where the latter may be a proxy for airway microbiome assessment in chronic respiratory disease.Conclusions: Metagenomic analysis of the airway reveals a core macrolide resistome harbored by the host microbiome.
The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression
Authors: Peng Huang, Scott A. Peslak, Xianjiang Lan, Eugene Khandros, Jennifer A. Yano, Malini Sharma, Cheryl A. Keller, Belinda Giardine, Kunhua Qin, Osheiza Abdulmalik, Ross C. Hardison, Junwei Shi, Gerd A. Blobel
Journal: Blood (2020)
Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia
Authors: Noelle V. Frey, Saar Gill, Elizabeth O. Hexner, Stephen Schuster, Sunita Nasta, Alison Loren, Jakub Svoboda, Edward Stadtmauer, Daniel J. Landsburg, Anthony Mato, Bruce L. Levine, Simon F. Lacey, Jan Joseph Melenhorst, Elizabeth Veloso, Avery Gaymon, Edward Pequignot, Xinhe Shan, Wei-Ting Hwang, Carl H. June, David L. Porter
Journal: Journal of Clinical Oncology (2020)

To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 107) or high (5 × 108) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months).At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups (P = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not (P = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR (P < .0001). Toxicity was comparable in both dose groups.In patients with advanced CLL, a 5 × 108 dose of CART-19 may be more effective than 5 × 107 CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.
Covid-19: Trump stokes protests against social distancing measures
Authors: Owen Dyer
Journal: BMJ (2020)

<h3>Introduction</h3> This study was aimed to investigate the mechanisms of advanced glycation end products (AGEs) in promoting invasion and metastasis of breast cancer. <h3>Research design and methods</h3> Patients with 131 breast cancer were enrolled in a cohort and followed up to investigate the association between AGEs and metastasis. Serum AGE concentrations were detected by ELISA. Breast cancer MDA-MB-231 cells were exposed to generated AGE-bovine serum albumin (BSA). CCK-8 assay was used to select the non-cytotoxic concentrations of AGE-BSA. Small interfering RNA was used to knock down Toll-like receptor 4 (TLR4). Migration and invasion were evaluated by wound healing and transwell assays. Real-time PCR and western blotting were used to detect the gene expressions. <h3>Results</h3> In the cohort study, metastasis incidence was significantly correlated with serum AGE concentrations in patients with breast cancer (adjusted OR=1.75, 95% CI=1.20 to 2.57, p=0.004). During follow-up, metastasis interval was significantly shorter in diabetic than non-diabetic subjects. In the in vitro study, AGE-BSA incubation significantly promoted migration and invasion of cancer cells in a concentration-dependent manner. AGE-BSA dramatically increased expressions of receptor for AGEs (RAGE), TLR4, myeloid differentiation factor (MyD88), matrix metalloproteinase 9 (MMP9), promoted nuclear translocation of nuclear factor κB (NFκB) p65, but decreased the expression of inhibitor of NFκB (IκBα). <i>TLR4</i> silencing significantly suppressed migration and invasion of cancer cells exposed to AGE-BSA. <i>TLR4</i> silencing reduced the expression of MyD88 and MMP9, as well as nuclear translocation of NFκB p65 but increased IκBα expression in AGE-BSA-incubated breast cancer cells. <h3>Conclusions</h3> AGEs are correlated with metastasis of breast cancer. AGEs’ promoting effects on migration and invasion of breast cancer cells via activating RAGE/TLR4/MyD88 signaling were suggested as the involved mechanism.
Response to: ‘Successful treatment of plasma exchange for refractory systemic juvenile idiopathic arthritis complicated with macrophage activation syndrome and severe lung disease’ by Sato<i>et al</i>
Authors: Vivian E Saper, Guangbo Chen, R Paul Guillerman, Purvesh Khatri, Randy Q Cron, Elizabeth D Mellins
Journal: Annals of the Rheumatic Diseases (2020)

We were very interested to read the correspondence from Dr. Sato and colleagues describing a case of systemic juvenile idiopathic arthritis (sJIA) with associated diffuse lung disease.1 The patient in this new report shares a number of features with cases occurring after exposure to interleukin (IL)-1 or IL-6 inhibitors (n=46) that we recently detailed in an international case series.2 Lung disease complicating sJIA remains a clinical challenge with significant mortality, and we thank the authors for sharing their experience.

One of the typical features of this type of lung disease, as illustrated by this case report, is minimal respiratory symptoms despite significant abnormalities on chest CT. The predominant chest CT pattern in our series, as observed in this case, is septal thickening with or without ground-glass opacities, sometimes together with peribronchovascular consolidation. Also like the patient in this report, a majority of cases in our series had refractory sJIA. However, a significant number (~40%) responded to initial treatment, …
COVID-19 infection in Crohn’s disease under treatment with adalimumab
Authors: Antonio Tursi, Gioacchino Angarano, Laura Monno, Annalisa Saracino, Fabio Signorile, Aurelia Ricciardi, Alfredo Papa
Journal: Gut (2020)

Jin et al described recently 74 cases of people having COVID-19 and experiencing gastrointestinal symptoms.1 In Italy, we are managing a dramatically increasing number of people infected with severe acute respiratory syndrome corona virus 2, the virus causing COVID-19.2 3 Despite the Italian Government has implemented extraordinary measures to restrict viral spread, including significant decrease of air and train traffic within the country, cases are increasing (>75 000 people until 26 March 2020) also in other regions than Lombardy, which is the main Italian region affected from COVID-19 (>35 000 people until 26 March 2020).4 This means that a lot of people under immunosuppressive-immunomodulating therapies could be infected by this virus, and that the immunosuppressive status could influence both the status of the basic disease and both the course of pulmonary disease.

A 30-year-old male was admitted on emergency department of the Bari University Hospital, Puglia Region, Southern Italy, on 12 March 2020 (with a low number of cases until that date) due to sudden occurrence …
FS118, a Bispecific Antibody Targeting LAG-3 and PD-L1, Enhances T-Cell Activation Resulting in Potent Antitumor Activity
Authors: Matthew Kraman, Mustapha Faroudi, Natalie L. Allen, Katarzyna Kmiecik, Daniel Gliddon, Claire Seal, Alexander Koers, Mateusz M. Wydro, Sarah Batey, Julia Winnewisser, Lesley Young, Mihriban Tuna, Jacqueline Doody, Michelle Morrow, Neil Brewis
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Although programmed death-ligand 1 (PD-L1) antibody–based therapy has improved the outcome of patients with cancer, acquired resistance to these treatments limits their clinical efficacy. FS118 is a novel bispecific, tetravalent antibody (mAb2) against human lymphocyte activation gene-3 (LAG-3) and PD-L1 with the potential to reinvigorate exhausted immune cells and overcome resistance mechanisms to PD-L1 blockade. Here, using FS118 and a murine surrogate, we characterized the activity and report a novel mechanism of action of this bispecific antibody. Experimental Design: This study characterizes the binding activity and immune function of FS118 in cell lines and human peripheral blood mononuclear cells and further investigates its antitumor activity and mechanism of action using a surrogate murine bispecific antibody (mLAG-3/PD-L1 mAb2). Results: FS118 demonstrated simultaneous binding to LAG-3 and PD-L1 with high affinity and comparable or better activity than the combination of the single component parts of the mAb2 in blocking LAG-3- and PD-L1–mediated immune suppression and enhancing T-cell activity. In syngeneic tumor mouse models, mLAG-3/PD-L1 mAb2 significantly suppressed tumor growth. Mechanistic studies revealed decreased LAG-3 expression on T cells following treatment with the mouse surrogate mLAG-3/PD-L1 mAb2, whereas LAG-3 expression increased upon treatment with the combination of mAbs targeting LAG-3 and PD-L1. Moreover, following binding of mLAG-3/PD-L1 mAb2 to target-expressing cells, mouse LAG-3 is rapidly shed into the blood. Conclusions: This study demonstrates a novel benefit of the bispecific approach over a combination of mAbs and supports the further development of FS118 for the treatment of patients with cancer.
CD45−/ALDHlow/SSEA-4+/Oct-4+/CD133+/CXCR4+/Lin− Very Small Embryonic-Like (VSEL) Stem Cells Isolated from Umbilical Cord Blood as Potential Long Term Repopulating Hematopoietic Stem Cells
Authors: Ewa K Zuba-Surma, Magdalena Kucia, Rui Liu, Mariusz Z Ratajczak, Janina Ratajczak
Journal: Blood (2008)
Population-based studies in systemic lupus erythematosus: immune thrombocytopenic purpura or ‘blood-dominant’ lupus?
Authors: Antonis Fanouriakis, George Bertsias, Dimitrios T Boumpas
Journal: Annals of the Rheumatic Diseases (2020)

Thanks to their large sample size, thus reducing the risk of selection and participation bias, population-based studies can provide high-quality data on the prevalence and incidence, natural history and treatment, correlates and associations of a disease, and healthcare utilisation.1 Several nationwide research databases exist in the world, one of the oldest in Sweden dating back to 1955. The Taiwan National Health Insurance Research Database (NHIRD) is one of the largest nationwide population databases, covering approximately 23 million residents in Taiwan and data of more than 99% of the population. Using this unique database, investigators have asked important questions regarding the heredity and coaggregation of autoimmune diseases, such as systemic lupus erythematosus (SLE), Sjogren’s syndrome and myasthenia gravis.2–4 

Immune thrombocytopenic purpura (ITP), formerly known as idiopathic thrombocytopenic purpura, is an immune-mediated acquired disease of adults and children characterised by a transient or persistent decrease of platelet counts and, depending on the degree of thrombocytopenia, increased risk of bleeding.5 In ΙΤP, an abnormal T cell response, supported by splenic T follicular helper cells, stimulates the proliferation and differentiation of autoreactive B cells producing antiplatelet autoantibodies that facilitate platelet phagocytosis by macrophages, predominantly in the spleen. Macrophages also contribute to the perpetuation of the autoimmune response in ITP, functioning as the principal antigen-presenting cells. Inappropriate bone marrow production due to an immune response against megakaryocytes may also exacerbate thrombocytopenia, while the level of …