Is atrial fibrillation in HFpEF a distinct phenotype? Insights from multiparametric MRI and circulating biomarkers.

Background: Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) frequently co-exist. There is a limited understanding on whether this coexistence is associated with distinct alterations in myocardial remodelling and mechanics. We aimed to determine if patients with atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) represent a distinct phenotype.

Evaluation of BMS-986142, a reversible Bruton's tyrosine kinase inhibitor, for the treatment of rheumatoid arthritis: a phase 2, randomised, double-blind, dose-ranging, placebo-controlled, adaptive design study.

Background: Bruton's tyrosine kinase (BTK) is a promising biological target for rheumatoid arthritis treatment. This study examined safety, efficacy, and pharmacokinetics of BMS-986142, an oral, reversible BTK inhibitor. The aim was to compare the efficacy of BMS-986142 with placebo on a background of methotrexate in patients with moderate-to-severe rheumatoid arthritis and inadequate response to methotrexate.

Development, Characterization, and Radiation Dosimetry Studies of F-BMS-986229, a F-Labeled PD-L1 Macrocyclic Peptide PET Tracer.

Purpose: In cancer immunotherapy, the blockade of the interaction between programmed death-1 and its ligand (PD-1:PD-L1) has proven to be one of the most promising strategies. However, as mechanisms of resistance to PD-1/PD-L1 inhibition include variability in tumor cell PD-L1 expression in addition to standard tumor biopsy PD-L1 immunohistochemistry (IHC), a comprehensive and quantitative approach for measuring PD-L1 expression is required. Herein, we report the development and characterization of an F-PD-L1-binding macrocyclic peptide as a PET tracer for the comprehensive evaluation of tumor PD-L1 expression in cancer patients.

The discovery and evaluation of [F]BMS-986229, a novel macrocyclic peptide PET radioligand for the measurement of PD-L1 expression and in-vivo PD-L1 target engagement.

Purpose: A same-day PET imaging agent capable of measuring PD-L1 status in tumors is an important tool for optimizing PD-1 and PD-L1 treatments. Herein we describe the discovery and evaluation of a novel, fluorine-18 labeled macrocyclic peptide-based PET ligand for imaging PD-L1.

Methods: [F]BMS-986229 was synthesized via copper mediated click-chemistry to yield a PD-L1 PET ligand with picomolar affinity and was tested as an in-vivo tool for assessing PD-L1 expression.

Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Compensated Cirrhosis (FALCON 2): A Randomized Phase 2b Study.

Background & Aims: Pegbelfermin is a polyethylene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) with compensated cirrhosis.

Methods: FALCON 2 (NCT03486912) was a randomized (1:1:1:1), double-blind, placebo-controlled study.

Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Stage 3 Fibrosis (FALCON 1): A Randomized Phase 2b Study.

Background & Aims: Pegbelfermin is a polyethlene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) and stage 3 (bridging) fibrosis.

Methods: The FALCON 1 study (NCT03486899) was a multicenter, randomized (1:1:1:1), double-blind, placebo-controlled study.

Effect of pegbelfermin on NASH and fibrosis-related biomarkers and correlation with histological response in the FALCON 1 trial.

Background & Aims: FALCON 1 was a phase IIb study of pegbelfermin in patients with non-alcoholic steatohepatitis (NASH) and stage 3 fibrosis. This FALCON 1 analysis aimed to further assess the effect of pegbelfermin on NASH-related biomarkers, correlations between histological assessments and non-invasive biomarkers, and concordance between the week 24 histologically assessed primary endpoint response and biomarkers.

Methods: Blood-based composite fibrosis scores, blood-based biomarkers, and imaging biomarkers were evaluated for patients with available data from FALCON 1 at baseline through week 24.

Yes-Associated Protein 1 Inhibition Induces Immunogenic Cell Death and Synergizes With Radiation and PD-1 Blockade.

Purpose: Danger signals released by ionizing radiation (IR) can theoretically stimulate immune activation in the tumor environment (TME), but IR alone is not sufficient to induce an effective immune response in clinical practice. In this study, we investigated whether inhibition of yes-associated protein 1 (YAP1) could induce immunogenic cell death (ICD) and whether the combination of YAP1 inhibition with IR could increase in vivo immune infiltration and thereby boost a tumor response to immunotherapy.

Methods And Materials: First, the expression of ICD markers, markers of T-cell activation, and key proteins involved in innate immune signaling were measured after YAP1 inhibition.

LPA antagonist BMS-986020 changes collagen dynamics and exerts antifibrotic effects in vitro and in patients with idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with limited treatment options. A phase 2 trial (NCT01766817) showed that twice-daily treatment with BMS-986020, a lysophosphatidic acid receptor 1 (LPA) antagonist, significantly decreased the slope of forced vital capacity (FVC) decline over 26 weeks compared with placebo in patients with IPF. This analysis aimed to better understand the impact of LPA antagonism on extracellular matrix (ECM)-neoepitope biomarkers and lung function through a post hoc analysis of the phase 2 study, along with an in vitro fibrogenesis model.

Excessive Activation of Notch Signaling in Macrophages Promote Kidney Inflammation, Fibrosis, and Necroptosis.

Diabetic nephropathy (DN) is one of the main causes of end-stage renal disease (ESRD). Existing treatments cannot control the progression of diabetic nephropathy very well. In diabetic nephropathy, Many monocytes and macrophages infiltrate kidney tissue.

Implementation of the OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Scoring System in a randomized phase IIb study of abatacept in psoriatic arthritis.

Objectives: To investigate if the OMERACT PsA MRI Scoring System (PsAMRIS), including a novel total inflammation score, shows sensitivity to change with an agent (abatacept) known to impact clinical outcomes in PsA.

Methods: We performed a post hoc analysis of a randomized phase IIb study of abatacept in patients with PsA and inadequate DMARD response. Participants received one of three abatacept dosing regimens [ABA3, ABA10 or ABA30/10 mg/kg (30 mg/kg switched to 10 mg/kg after two doses)] or placebo until day 169, then ABA10 through day 365.

Evaluation of a PEGylated Fibroblast Growth Factor 21 Variant Using Novel Preclinical Magnetic Resonance Imaging and Magnetic Resonance Elastography in a Mouse Model of Nonalcoholic Steatohepatitis.

Background: Treatments for nonalcoholic steatohepatitis (NASH) are urgently needed. Hepatic fat fraction and shear stiffness quantified by magnetic resonance imaging (MRI-HFF) and magnetic resonance elastography (MRE-SS), respectively, are biomarkers for hepatic steatosis and fibrosis.

Purpose: This study assessed the longitudinal effects of fibroblast growth factor 21 variant (polyethylene glycol [PEG]-FGF21v) on MRI-HFF and MRE-SS in a NASH mouse model.

BMS-986263 in patients with advanced hepatic fibrosis: 36-week results from a randomized, placebo-controlled phase 2 trial.

Background And Aims: Hepatic fibrosis secondary to HCV infection can lead to cirrhosis and hepatic decompensation. Sustained virologic response (SVR) is possible with direct-acting antiviral drug regimens; however, patients with advanced fibrosis have an increased risk for HCC. Heat shock protein 47 (HSP47), a key collagen chaperone, has been implicated in fibrosis development.

The value of imaging and clinical outcomes in a phase II clinical trial of a lysophosphatidic acid receptor antagonist in idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease characterized by worsening dyspnea and lung function and has a median survival of 2-3 years. Forced vital capacity (FVC) is the primary endpoint used most commonly in IPF clinical trials as it is the best surrogate for mortality. This study assessed quantitative scores from high-resolution computed tomography (HRCT) developed by machine learning as a secondary efficacy endpoint in a 26-week phase II study of BMS-986020 - an LPA receptor antagonist - in patients with IPF.

The FALCON program: Two phase 2b randomized, double-blind, placebo-controlled studies to assess the efficacy and safety of pegbelfermin in the treatment of patients with nonalcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis.

Background: Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD); no approved therapies for NASH currently exist. Pegbelfermin (PGBF), a human fibroblast growth factor 21 analog, has metabolic effects that may provide benefit for patients with NASH.

Design: The FALCON 1 and 2 studies are phase 2b, multicenter, double-blind, placebo-controlled, randomized trials to assess safety and efficacy of PGBF treatment in patients who have histologically-confirmed NASH with stage 3 liver fibrosis (FALCON 1; NCT03486899) or compensated cirrhosis (FALCON 2; NCT03486912).

Identification of Non-Small Cell Lung Cancer Sensitive to Systemic Cancer Therapies Using Radiomics.

Purpose: Using standard-of-care CT images obtained from patients with a diagnosis of non-small cell lung cancer (NSCLC), we defined radiomics signatures predicting the sensitivity of tumors to nivolumab, docetaxel, and gefitinib.

Experimental Design: Data were collected prospectively and analyzed retrospectively across multicenter clinical trials [nivolumab, = 92, CheckMate017 (NCT01642004), CheckMate063 (NCT01721759); docetaxel, = 50, CheckMate017; gefitinib, = 46, (NCT00588445)]. Patients were randomized to training or validation cohorts using either a 4:1 ratio (nivolumab: 72T:20V) or a 2:1 ratio (docetaxel: 32T:18V; gefitinib: 31T:15V) to ensure an adequate sample size in the validation set.

Zinc supplementation inhibits the high glucose‑induced EMT of peritoneal mesothelial cells by activating the Nrf2 antioxidant pathway.

The high glucose (HG)‑induced epithelial‑mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) serves an important role in peritoneal fibrosis (PF) during peritoneal dialysis. Our previous study reported that zinc (Zn) supplementation prevented the HG‑induced EMT of rat PMCs in vitro. In the present study, the role of Zn in HG‑induced EMT was investigated in vivo using a rat model of PF.

Upregulation of miR-335 ameliorates myocardial ischemia reperfusion injury via targeting hypoxia inducible factor 1-alpha subunit inhibitor.

MicroRNA-335 (miR-335) is implicated in several pathophysiological processes, including tumorigenesis, lipid metabolism and ischemic stroke; however, whether miR-335 plays a role in modulating myocardial ischemia reperfusion injury (MIRI) is still unknown. This study is aimed to explore the role and mechanism of miR-335 in the pathophysiological process of MIRI. Specifically, miR-335 mimics or a chemically modified agomiR-335 were transfected or injected into H9c2 cells and Wistar rats to upregulate miR-335 expression and , respectively.

Selective production of phase-separable product from a mixture of biomass-derived aqueous oxygenates.

Selective conversion of an aqueous solution of mixed oxygenates produced by biomass fermentation to a value-added single product is pivotal for commercially viable biomass utilization. However, the efficiency and selectivity of the transformation remains a great challenge. Herein, we present a strategy capable of transforming ~70% of carbon in an aqueous fermentation mixture (ABE: acetone-butanol-ethanol-water) to 4-heptanone (4-HPO), catalyzed by tin-doped ceria (Sn-ceria), with a selectivity as high as 86%.

Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease.

Background: There are no effective treatments or validated clinical response markers in systemic sclerosis (SSc). We assessed imaging biomarkers and performed gene expression profiling in a single-arm open-label clinical trial of tyrosine kinase inhibitor dasatinib in patients with SSc-associated interstitial lung disease (SSc-ILD).

Methods: Primary objectives were safety and pharmacokinetics.

Evaluation of the Lysophosphatidic Acid Receptor Type 1 Radioligand C-BMT-136088 for Lung Imaging in Rhesus Monkeys.

The lysophosphatidic acid receptor type 1 (LPA1) is 1 of 6 known receptors of the extracellular signaling molecule lysophosphatidic acid. It mediates effects such as cell proliferation, migration, and differentiation. In the lung, LPA1 is involved in pathways leading, after lung tissue injury, to pulmonary fibrosis instead of normal healing, by mediating fibroblast recruitment and vascular leakage.

Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils.

The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRβ-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice.

1,25(OH)2D3 inhibits high glucose-induced apoptosis and ROS production in human peritoneal mesothelial cells via the MAPK/P38 pathway.

The regulation of cell proliferation, differentiation and immunomodulation are affected by 1,25(OH)2D3. However, its function during apoptosis and oxidative stress in human peritoneal mesothelial cells (HPMCs) remains unknown. The aim of the present study was to investigate whether the regulation of apoptosis and oxidative stress have therapeutic relevance in peritoneal dialysis (PD) therapy.

Overexpression of Aiolos in Peripheral Blood Mononuclear Cell Subsets from Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis.

Genetic studies demonstrate that the Aiolos polymorphisms contribute to the susceptibility to autoimmune diseases. The purpose of the study was to investigate the Aiolos expression in lymphocytes and monocytes in the peripheral blood from patients with SLE and RA, and to explore the correlation between Aiolos expression in cell subsets and laboratory measurements. Peripheral blood mononuclear cells (PBMC) from 32 patients with SLE, 35 patients with RA, and 37 healthy controls were purified.

Expression and Polymorphisms of Lysosome-Associated Protein Transmembrane 5 (LAPTM5) in Patients with Systemic Lupus Erythematosus in a Chinese Population.

Lysosome-associated protein transmembrane 5 (LAPTM5) have been demonstrated a role in the prevention of lymphocyte hyperactivation, and its deficiency is involved in the immunological dysfunction of mouse models. The aim of this study was to detect mRNA expression of LAPTM5 in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE), and to assess association between LAPTM5 single nucleotide polymorphisms (SNPs) (rs10798801, rs4614309, rs1188348, and rs1188349) and SLE in a Chinese population. Real-time transcription-polymerase chain reaction analysis was used to determine expression of LAPTM5 mRNA in PBMCs from 132 patients with SLE and 62 healthy controls.