TREM1 regulates antifungal immune responses in invasive pulmonary aspergillosis.

Pattern recognition receptors (PRRs) are responsible for Aspergillus fumigatus recognition by innate immunity and its subsequent immune signaling. The triggering receptor expressed on myeloid cells 1 (TREM1) is a recently characterized pro-inflammatory receptor constitutively expressed on the surface of neutrophils and macrophages. A soluble form (sTREM1) of this protein that can be detected in human body fluids has been identified. Here we investigated the role of TREM1 during invasive pulmonary aspergillosis (IPA). IPA patients displayed significantly higher levels of sTREM1 in bronchoalveolar lavages when compared to control patients. Functional analysis in TREM1 showed that the levels of sTREM1 and TREM1 pathway-related cytokines were influenced by single nucleotide polymorphisms in TREM1. In addition, we confirmed a role of TREM1 on antifungal host defense against A. fumigatus in a murine model of IPA. TREM1 deficiency increased susceptibility to infection in the immunosuppressed murine host. Deletion of TREM1 showed delayed innate and adaptive immune responses and impaired pro-inflammatory cytokine responses. The absence of TREM1 in primary macrophages attenuated the TLR signaling by altering the expression of both receptor and effector proteins that are critical to the response against A. fumigatus. In this study, and for the first time, we demonstrate the key role for the TREM1 receptor pathway during IPA.This work was supported by the Fundação para a Ciência e a Tecnologia [PTDC/SAU-SER/29635/2017]; Fundação para a Ciência e a Tecnologia [UIDB/50026/2020 and UIDP/50026/2020]; Fundação para a Ciência e a Tecnologia [PTDC/MED-GEN/28778/2017]; H2020 Excellent Science [NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023)]; Instituto de Salud Carlos III [RD16/CIII/0004/0003]; Instituto de Salud Carlos III [PI18CIII/00045]; Instituto de Salud Carlos III [MPY 1277/15]; Ministerio de Ciencia, Innovación y Universidades [RTI2018-099114-B-I00]; Associação Viver a Ciência (PT) [SFRH/BD/136814/2018]; “la Caixa” Foundation [ID 100010434].S

Using Values Affirmation to Reduce the Effects of Stereotype Threat on Hypertension Disparities: Protocol for the Multicenter Randomized Hypertension and Values (HYVALUE) Trial

AddThis Sharing Buttons Share to Facebook 1Share to TwitterShare to LinkedInShare to PinterestShare to CiteULikeShare to Mendeley &nbsp;Citation Please cite as: Daugherty SL, Vupputuri S, Hanratty R, Steiner JF, Maertens JA, Blair IV, Dickinson LM, Helmkamp L, Havranek EP Using Values Affirmation to Reduce the Effects of Stereotype Threat on Hypertension Disparities: Protocol for the Multicenter Randomized Hypertension and Values (HYVALUE) Trial JMIR Res Protoc 2019;8(3):e12498 DOI: 10.2196/12498 PMID: 30907744 PMCID: 6452278 &nbsp;Export Metadata END for: Endnote BibTeX for: BibDesk, LaTeX RIS for: RefMan, Procite, Endnote, RefWorks Add this article to your Mendeley library Add this article to your CiteULike library Download: &nbsp; &nbsp; Published on 25.03.19 in Vol 8, No 3 (2019): March Preprints (earlier versions) of this paper are available at http://preprints.jmir.org/preprint/12498, first published Oct 12, 2018. This paper is in the following e-collection/theme issue: RCTs - Protocols/Proposals (funded, already peer-reviewed, non-eHealth) Hypertension Prevention and Treatment Article Cited By (0) Tweetations (4) Metrics Protocol Using Values Affirmation to Reduce the Effects of Stereotype Threat on Hypertension Disparities: Protocol for the Multicenter Randomized Hypertension and Values (HYVALUE) Trial Stacie L Daugherty1, MD, MSPH&nbsp;;&nbsp; Suma Vupputuri2, PhD&nbsp;;&nbsp; Rebecca Hanratty3, MD&nbsp;;&nbsp; John F Steiner4, MD, MPH&nbsp;;&nbsp; Julie A Maertens5, PhD&nbsp;;&nbsp; Irene V Blair6, PhD&nbsp;;&nbsp; L Miriam Dickinson5, PhD&nbsp;;&nbsp; Laura Helmkamp5, MS&nbsp;;&nbsp; Edward P Havranek7, MD&nbsp; 1University of Colorado Denver, School of Medicine, Department of Medicine, Division of Cardiology, Adult and Child Consortium for Health Outcomes Research and Delivery Science, Aurora, CO, United States 2Kaiser Permanente Mid-Atlantic States, Mid-Atlantic Permanente Research Institute, Rockville, MD, United States 3Denver Health and Hospital Authority, Department of Medicine, Denver, CO, United States 4Kaiser Permanente Colorado, Institute for Health Research, Denver, CO, United States 5University of Colorado Denver, Adult and Child Consortium for Health Outcomes Research and Delivery Science, Aurora, CO, United States 6University of Colorado Boulder, Department of Psychology and Neuroscience, Boulder, CO, United States 7University of Colorado School of Medicine, Adult and Child Consortium for Health Outcomes Research and Delivery Science, Denver Health and Hospital Authority, Department of Medicine, Denver, CO, United States Corresponding Author: Stacie L Daugherty, MD, MSPH University of Colorado Denver School of Medicine, Department of Medicine, Division of Cardiology Adult and Child Consortium for Health Outcomes Research and Delivery Science 12605 E. 16th Avenue Mailstop B130, PO Box 6511 Aurora, CO, 80045 United States Phone: 1 303 724 2088 Fax:1 303 724 2094 Email: [email protected] ABSTRACT Background: Medication nonadherence is a significant, modifiable contributor to uncontrolled hypertension. Stereotype threat may contribute to racial disparities in adherence by hindering a patient&rsquo;s ability to actively engage during a clinical encounter, resulting in reduced activation to adhere to prescribed therapies. Objective: The Hypertension and Values (HYVALUE) trial aims to examine whether a values-affirmation intervention improves medication adherence (primary outcome) by targeting racial stereotype threat. Methods: The HYVALUE trial is a patient-level, blinded randomized controlled trial comparing a brief values-affirmation writing exercise with a control writing exercise among black and white patients with uncontrolled hypertension. We are recruiting patients from 3 large health systems in the United States. The primary outcome is patients&rsquo; adherence to antihypertensive medications, with secondary outcomes of systolic and diastolic blood pressure over time, time for which blood pressure is under control, and treatment intensification. We are comparing the effects of the intervention among blacks and whites, exploring possible moderators (ie, patients&rsquo; prior experiences of discrimination and clinician racial bias) and mediators (ie, patient activation) of intervention effects on outcomes. Results: This study was funded by the National Heart, Lung, and Blood Institute. Enrollment and follow-up are ongoing and data analysis is expected to begin in late 2020. Planned enrollment is 1130 patients. On the basis of evidence supporting the effectiveness of values affirmation in educational settings and our pilot work demonstrating improved patient-clinician communication, we hypothesize that values affirmation disrupts the negative effects of stereotype threat on the clinical interaction and can reduce racial disparities in medication adherence and subsequent health outcomes. Conclusions: The HYVALUE study moves beyond documentation of race-based health disparities toward testing an intervention. We focus on a medical condition&mdash;hypertension, which is arguably the greatest contributor to mortality disparities for black patients. If successful, this study will be the first to provide evidence for a low-resource intervention that has the potential to substantially reduce health care disparities across a wide range of health care conditions and populations. </section

Status Update and Interim Results from the Asymptomatic Carotid Surgery Trial-2 (ACST-2)

Objectives: ACST-2 is currently the largest trial ever conducted to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in patients with severe asymptomatic carotid stenosis requiring revascularization. Methods: Patients are entered into ACST-2 when revascularization is felt to be clearly indicated, when CEA and CAS are both possible, but where there is substantial uncertainty as to which is most appropriate. Trial surgeons and interventionalists are expected to use their usual techniques and CE-approved devices. We report baseline characteristics and blinded combined interim results for 30-day mortality and major morbidity for 986 patients in the ongoing trial up to September 2012. Results: A total of 986 patients (687 men, 299 women), mean age 68.7 years (SD ± 8.1) were randomized equally to CEA or CAS. Most (96%) had ipsilateral stenosis of 70-99% (median 80%) with contralateral stenoses of 50-99% in 30% and contralateral occlusion in 8%. Patients were on appropriate medical treatment. For 691 patients undergoing intervention with at least 1-month follow-up and Rankin scoring at 6 months for any stroke, the overall serious cardiovascular event rate of periprocedural (within 30 days) disabling stroke, fatal myocardial infarction, and death at 30 days was 1.0%. Conclusions: Early ACST-2 results suggest contemporary carotid intervention for asymptomatic stenosis has a low risk of serious morbidity and mortality, on par with other recent trials. The trial continues to recruit, to monitor periprocedural events and all types of stroke, aiming to randomize up to 5,000 patients to determine any differential outcomes between interventions. Clinical trial: ISRCTN21144362. © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved

Identification of New Markers of Alcohol-Derived DNA Damage in Humans

Alcohol consumption is a risk factor for the development of several cancers, including those of the head and neck and the esophagus. The underlying mechanisms of alcohol-induced carcinogenesis remain unclear; however, at these sites, alcohol-derived acetaldehyde seems to play a major role. By reacting with DNA, acetaldehyde generates covalent modifications (adducts) that can lead to mutations. Previous studies have shown a dose dependence between levels of a major acetaldehyde-derived DNA adduct and alcohol exposure in oral-cell DNA. The goal of this study was to optimize a mass spectrometry (MS)-based DNA adductomic approach to screen for all acetaldehyde-derived DNA adducts to more comprehensively characterize the genotoxic effects of acetaldehyde in humans. A high-resolution/-accurate-mass data-dependent constant-neutral-loss-MS3 methodology was developed to profile acetaldehyde-DNA adducts in purified DNA. This resulted in the identification of 22 DNA adducts. In addition to the expected N2-ethyldeoxyguanosine (after NaBH3CN reduction), two previously unreported adducts showed prominent signals in the mass spectra. MSn fragmentation spectra and accurate mass were used to hypothesize the structure of the two new adducts, which were then identified as N6-ethyldeoxyadenosine and N4-ethyldeoxycytidine by comparison with synthesized standards. These adducts were quantified in DNA isolated from oral cells collected from volunteers exposed to alcohol, revealing a significant increase after the exposure. In addition, 17 of the adducts identified in vitro were detected in these samples confirming our ability to more comprehensively characterize the DNA damage deriving from alcohol exposures

Identification of New Markers of Alcohol-Derived DNA Damage in Humans

Alcohol consumption is a risk factor for the development of several cancers, including those of the head and neck and the esophagus. The underlying mechanisms of alcohol-induced carcinogenesis remain unclear; however, at these sites, alcohol-derived acetaldehyde seems to play a major role. By reacting with DNA, acetaldehyde generates covalent modifications (adducts) that can lead to mutations. Previous studies have shown a dose dependence between levels of a major acetaldehyde-derived DNA adduct and alcohol exposure in oral-cell DNA. The goal of this study was to optimize a mass spectrometry (MS)-based DNA adductomic approach to screen for all acetaldehyde-derived DNA adducts to more comprehensively characterize the genotoxic effects of acetaldehyde in humans. A high-resolution/-accurate-mass data-dependent constant-neutral-loss-MS3 methodology was developed to profile acetaldehyde-DNA adducts in purified DNA. This resulted in the identification of 22 DNA adducts. In addition to the expected N2-ethyldeoxyguanosine (after NaBH3CN reduction), two previously unreported adducts showed prominent signals in the mass spectra. MSn fragmentation spectra and accurate mass were used to hypothesize the structure of the two new adducts, which were then identified as N6-ethyldeoxyadenosine and N4-ethyldeoxycytidine by comparison with synthesized standards. These adducts were quantified in DNA isolated from oral cells collected from volunteers exposed to alcohol, revealing a significant increase after the exposure. In addition, 17 of the adducts identified in vitro were detected in these samples confirming our ability to more comprehensively characterize the DNA damage deriving from alcohol exposures

Treatment outcomes in patients with proven/probable vs possible invasive mould disease in a phase III trial comparing isavuconazole vs voriconazole

Treatment outcomes in patients with proven/probable vs possible invasive mould disease (IMD; 2008 European Organisation for Research and Treatment of Cancer/Mycoses Study Group [EORTC/MSG] criteria) needed further assessment. The Phase III SECURE trial compared isavuconazole vs voriconazole for treatment of IMD. This post hoc analysis assessed all-cause mortality (ACM) through day 42 (primary endpoint) and day 84, overall and clinical success at end of treatment (EOT), and drug-related treatment-emergent adverse events (TEAEs) in subgroups with proven/probable or possible IMD. Of 516 randomised patients, 304 (58.9%) had proven/probable IMD and 164 (31.8%) had possible IMD as per EORTC/MSG criteria; 48 did not have IMD. Across treatment groups, day 42 and day 84 ACM were numerically lower for possible vs proven/probable IMD (day 42: 17.1% vs 21.1%; P = 0.3, day 84: 26.2% vs 32.6%; P = 0.15). Overall and clinical success at EOT were significantly higher for possible IMD compared with proven/probable IMD (48.2% vs 36.2%; P = 0.01, 75.0% vs 63.1%; P = 0.01 respectively). Fewer drug-related TEAEs were reported with isavuconazole compared with voriconazole in patients with either proven/probable or possible IMD. Compared with patients with proven/probable IMD, those with possible IMD demonstrated higher overall and clinical success rates, supporting early initiation of antifungal treatment.status: publishe

Screening DNA Damage in the Rat Kidney and Liver by Untargeted DNA Adductomics

Air pollution, tobacco smoke, and red meat are associated with renal cell cancer (RCC) risk in the United States and Western Europe; however, the chemicals that form DNA adducts and initiate RCC are mainly unknown. Aristolochia herbaceous plants are used for medicinal purposes in Asia and worldwide. They are a significant risk factor for upper tract urothelial carcinoma (UTUC) and RCC to a lesser extent. The aristolochic acid (AA) 8-methoxy-6-nitrophenanthro-[3,4-d]-1,3-dioxolo-5-carboxylic acid (AA-I), a component of Aristolochia herbs, contributes to UTUC in Asian cohorts and in Croatia, where AA-I exposure occurs from ingesting contaminated wheat flour. The DNA adduct of AA-I, 7-(2′-deoxyadenosin-N6-yl)-aristolactam I, is often detected in patients with UTUC, and its characteristic A:T-to-T:A mutational signature occurs in oncogenes and tumor suppressor genes in AA-associated UTUC. Identifying DNA adducts in the renal parenchyma and pelvis caused by other chemicals is crucial to gaining insights into unknown RCC and UTUC etiologies. We employed untargeted screening with wide-selected ion monitoring tandem mass spectrometry (wide-SIM/MS2) with nanoflow liquid chromatography/Orbitrap mass spectrometry to detect DNA adducts formed in rat kidneys and liver from a mixture of 13 environmental, tobacco, and dietary carcinogens that may contribute to RCC. Twenty DNA adducts were detected. DNA adducts of 3-nitrobenzanthrone (3-NBA), an atmospheric pollutant, and AA-I were the most abundant. The nitrophenanthrene moieties of 3-NBA and AA-I undergo reduction to their N-hydroxy intermediates to form 2′-deoxyguanosine (dG) and 2′-deoxyadenosine (dA) adducts. We also discovered a 2′-deoxycytidine AA-I adduct and dA and dG adducts of 10-methoxy-6-nitro-phenanthro-[3,4-d]-1,3-dioxolo-5-carboxylic acid (AA-III), an AA-I isomer and minor component of the herbal extract assayed, signifying AA-III is a potent kidney DNA-damaging agent. The roles of AA-III, other nitrophenanthrenes, and nitroarenes in renal DNA damage and human RCC warrant further study. Wide-SIM/MS2 is a powerful scanning technology in DNA adduct discovery and cancer etiology characterization