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Background Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai Bio Me Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. Results We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in Bio Me that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. Conclusion In sum, by integrating genetic and electronic medical record data, and leveraging one of the world’s largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.

Transforming growth factor β1 (TGFβ1)-null mice die from complications due to an early-onset multifocal inflammatory disorder. We show here that cardiac cells are hyperproliferative and that intercellular adhesion molecule 1 (ICAM-1) is elevated. To determine which phenotypes are primarily caused by a deficiency in TGFβ1 from those that are secondary to inflammation, we applied immunosuppressive therapy and genetic combination with the severe combined immunodeficiency (SCID) mutation to inhibit the inflammatory response. Treatment with antibodies to the leukocyte function-associated antigen 1 doubled longevity, reduced inflammation, and delayed heart cell proliferation. TGFβ1-null SCID mice displayed no inflammation or cardiac cell proliferation, survived to adulthood, and exhibited normal major histocompatibility complex II (MHC II) and ICAM-1 levels. TGFβ1-null pups born to a TGFβ1-null SCID mother presented no gross congenital heart defects, indicating that TGFβ1 alone does not play an essential role in heart development. These results indicate that lymphocytes are essential for the inflammatory response, cardiac cell proliferation, and elevated MHC II and ICAM-1 expression, revealing a vital role for TGFβ1 in regulating lymphocyte proliferation and activation, which contribute to the maintenance of self tolerance.

PD-1 expression is a hallmark of both early antigen-specific T cell activation and later chronic stimulation, suggesting key roles in both naive T cell priming and memory T cell responses. Although significant similarities exist between T cells and NK cells, there are critical differences in their biology and functions reflecting their respective adaptive and innate immune effector functions. Expression of PD-1 on NK cells is controversial despite rapid incorporation into clinical cancer trials. Our objective was to stringently and comprehensively assess expression of PD-1 on both mouse and human NK cells under multiple conditions and using a variety of readouts. We evaluated NK cells from primary human tumor samples, after ex vivo culturing, and from multiple mouse tumor and viral models using flow cytometry, quantitative reverse-transcriptase PCR (qRT-PCR), and RNA-Seq for PD-1 expression. We demonstrate that, under multiple conditions, human and mouse NK cells consistently lack PD-1 expression despite the marked upregulation of other activation/regulatory markers, such as TIGIT. This was in marked contrast to T cells, which were far more prominent within all tumors and expressed PD-1. These data have important implications when attempting to discern NK from T cell effects and to determine whether PD-1 targeting can be expected to have direct effects on NK cell functions.

Protease-activated receptors (PARs) represent a unique family of seven-transmembrane G protein-coupled receptors, which are enzymatically cleaved to expose a truncated extracellular N terminus that acts as a tethered activating ligand. PAR-1 is cleaved and activated by the serine protease α -thrombin, is expressed in various tissues (e.g., platelets and vascular cells), and is involved in cellular responses associated with hemostasis, proliferation, and tissue injury. We have discovered a series of potent peptide-mimetic antagonists of PAR-1, exemplified by RWJ-56110. Spatial relationships between important functional groups of the PAR-1 agonist peptide epitope SFLLRN were employed to design and synthesize candidate ligands with appropriate groups attached to a rigid molecular scaffold. Prototype RWJ-53052 was identified and optimized via solid-phase parallel synthesis of chemical libraries. RWJ-56110 emerged as a potent, selective PAR-1 antagonist, devoid of PAR-1 agonist and thrombin inhibitory activity. It binds to PAR-1, interferes with PAR-1 calcium mobilization and cellular function (platelet aggregation; cell proliferation), and has no effect on PAR-2, PAR-3, or PAR-4. By flow cytometry, RWJ-56110 was confirmed as a direct inhibitor of PAR-1 activation and internalization, without affecting N-terminal cleavage. At high concentrations of α -thrombin, RWJ-56110 fully blocked activation responses in human vascular cells, albeit not in human platelets; whereas, at high concentrations of SFLLRN-NH2, RWJ-56110 blocked activation responses in both cell types. Thus, thrombin activates human platelets independently of PAR-1, i.e., through PAR-4, which we confirmed by PCR analysis. Selective PAR-1 antagonists, such as RWJ-56110, should serve as useful tools to study PARs and may have therapeutic potential for treating thrombosis and restenosis.

Background The emergency department is a critical juncture in the trajectory of care of patients with serious, life-limiting illness. Implementation of a clinical decision support (CDS) tool automates identification of older adults who may benefit from palliative care instead of relying upon providers to identify such patients, thus improving quality of care by assisting providers with adhering to guidelines. The Primary Palliative Care for Emergency Medicine (PRIM-ER) study aims to optimize the use of the electronic health record by creating a CDS tool to identify high risk patients most likely to benefit from primary palliative care and provide point-of-care clinical recommendations. Methods A clinical decision support tool entitled Emergency Department Supportive Care Clinical Decision Support (Support-ED) was developed as part of an institutionally-sponsored value based medicine initiative at the Ronald O. Perelman Department of Emergency Medicine at NYU Langone Health. A multidisciplinary approach was used to develop Support-ED including: a scoping review of ED palliative care screening tools; launch of a workgroup to identify patient screening criteria and appropriate referral services; initial design and usability testing via the standard System Usability Scale questionnaire, education of the ED workforce on the Support-ED background, purpose and use, and; creation of a dashboard for monitoring and feedback. Results The scoping review identified the Palliative Care and Rapid Emergency Screening (P-CaRES) survey as a validated instrument in which to adapt and apply for the creation of the CDS tool. The multidisciplinary workshops identified two primary objectives of the CDS: to identify patients with indicators of serious life limiting illness, and to assist with referrals to services such as palliative care or social work. Additionally, the iterative design process yielded three specific patient scenarios that trigger a clinical alert to fire, including: 1) when an advance care planning document was present, 2) when a patient had a previous disposition to hospice, and 3) when historical and/or current clinical data points identify a serious life-limiting illness without an advance care planning document present. Monitoring and feedback indicated a need for several modifications to improve CDS functionality. Conclusions CDS can be an effective tool in the implementation of primary palliative care quality improvement best practices. Health systems should thoughtfully consider tailoring their CDSs in order to adapt to their unique workflows and environments. The findings of this research can assist health systems in effectively integrating a primary palliative care CDS system seamlessly into their processes of care. Trial registration ClinicalTrials.gov Identifier: NCT03424109 . Registered 6 February 2018, Grant Number: AT009844–01.

PD-1 expression is a hallmark of both early antigen-specific T cell activation and later chronic stimulation, suggesting key roles in both naive T cell priming and memory T cell responses. Although significant similarities exist between T cells and NK cells, there are critical differences in their biology and functions reflecting their respective adaptive and innate immune effector functions. Expression of PD-1 on NK cells is controversial despite rapid incorporation into clinical cancer trials. Our objective was to stringently and comprehensively assess expression of PD-1 on both mouse and human NK cells under multiple conditions and using a variety of readouts. We evaluated NK cells from primary human tumor samples, after ex vivo culturing, and from multiple mouse tumor and viral models using flow cytometry, quantitative reverse-transcriptase PCR (qRT-PCR), and RNA-Seq for PD-1 expression. We demonstrate that, under multiple conditions, human and mouse NK cells consistently lack PD-1 expression despite the marked upregulation of other activation/regulatory markers, such as TIGIT. This was in marked contrast to T cells, which were far more prominent within all tumors and expressed PD-1. These data have important implications when attempting to discern NK from T cell effects and to determine whether PD-1 targeting can be expected to have direct effects on NK cell functions.

Emissions from the potential installation of distributed energy resources (DER) in the place of current utility-scale power generators have been introduced into an emissions inventory of the northeastern United States. A methodology for predicting future market penetration of DER that considers economics and emission factors was used to estimate the most likely implementation of DER. The methodology results in spatially and temporally resolved emission profiles of criteria pollutants that are subsequently introduced into a detailed atmospheric chemistry and transport model of the region. The DER technology determined by the methodology includes 62% reciprocating engines, 34% gas turbines, and 4% fuel cells and other emerging technologies. The introduction of DER leads to retirement of 2625 MW of existing power plants for which emissions are removed from the inventory. The air quality model predicts maximum differences in air pollutant concentrations that are located downwind from the central power plants that were removed from the domain. Maximum decreases in hourly peak ozone concentrations due to DER use are 10 ppb and are located over the state of New Jersey. Maximum decreases in 24-hr average fine particulate matter (PM 2.5 ) concentrations reach 3 μg/m3 and are located off the coast of New Jersey and New York. The main contribution to decreased PM 2.5 is the reduction of sulfate levels due to significant reductions in direct emissions of sulfur oxides (SO x ) from the DER compared with the central power plants removed. The scenario presented here represents an accelerated DER penetration case with aggressive emission reductions due to removal of highly emitting power plants. Such scenario provides an upper bound for air quality benefits of DER implementation scenarios.