Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis.

Although three-dimensional (3D) genome architecture is crucial for gene regulation, its role in disease remains elusive. We traced the evolution and malignant transformation of colorectal cancer (CRC) by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth in persons with familial adenomatous polyposis (FAP). Our analysis revealed a substantial progressive loss of genome-wide cis-regulatory connectivity at early malignancy stages, correlating with nonlinear gene regulation effects.

Thermokarst landscape exhibits large nitrous oxide emissions in Alaska's coastal polygonal tundra.

Global atmospheric concentrations of nitrous oxide have been increasing over previous decades with emerging research suggesting the Arctic as a notable contributor. Thermokarst processes, increasing temperature, and changes in drainage can cause degradation of polygonal tundra landscape features resulting in elevated, well-drained, unvegetated soil surfaces that exhibit large nitrous oxide emissions. Here, we outline the magnitude and some of the dominant factors controlling variability in emissions for these thermokarst landscape features in the North Slope of Alaska.

How can the findings of the EMAX trial on long-acting bronchodilation in chronic obstructive pulmonary disease be applied in the primary care setting?

This review addresses outstanding questions regarding initial pharmacological management of chronic obstructive pulmonary disease (COPD). Optimizing initial treatment improves clinical outcomes in symptomatic patients, including those with low exacerbation risk. Long-acting muscarinic antagonist/long-acting β-agonist (LAMA/LABA) dual therapy improves lung function versus LAMA or LABA monotherapy, although other treatment benefits have been less consistently observed.

Taxonomic and functional restoration of tallgrass prairie soil microbial communities in comparison to remnant and agricultural soils.

Restoring ecosystems requires the re-establishment of diverse soil microbial communities that drive critical ecosystem functions. In grasslands, restoration and management require the application of disturbances like fire and grazing. Disturbances can shape microbial taxonomic composition and potentially functional composition as well.

Single-cell analysis of the nervous system at small and large scales with instant partitions.

Single-cell RNA sequencing is a new frontier across all biology, particularly in neuroscience. While powerful for answering numerous neuroscience questions, limitations in sample input size, and initial capital outlay can exclude some researchers from its application. Here, we tested a recently introduced method for scRNAseq across diverse scales and neuroscience experiments.

Using simulated wildland fire to assess microbial survival at multiple depths from biocrust and bare soils.

Introduction: Surface soil microbial communities are directly exposed to the heat from wildland fires. Due to this, the microbial community composition may be stratified within the soil profile with more heat tolerant microbes near the surface and less heat tolerant microbes, or mobile species found deeper in the soil. Biological soil crusts, biocrusts, are found on the soil surface and contain a diverse microbial community that is directly exposed to the heat from wildland fires.

A longitudinal circulating tumor DNA-based model associated with survival in metastatic non-small-cell lung cancer.

One of the great challenges in therapeutic oncology is determining who might achieve survival benefits from a particular therapy. Studies on longitudinal circulating tumor DNA (ctDNA) dynamics for the prediction of survival have generally been small or nonrandomized. We assessed ctDNA across 5 time points in 466 non-small-cell lung cancer (NSCLC) patients from the randomized phase 3 IMpower150 study comparing chemotherapy-immune checkpoint inhibitor (chemo-ICI) combinations and used machine learning to jointly model multiple ctDNA metrics to predict overall survival (OS).

Mortality Risk and Serious Cardiopulmonary Events in Moderate-to-Severe COPD: Post Hoc Analysis of the IMPACT Trial.

Background: In the InforMing the Pathway of COPD Treatment (IMPACT) trial, single-inhaler fluticasone furoate (FF) /umeclidinium (UMEC) /vilanterol (VI) significantly reduced severe exacerbation rates and all-cause mortality (ACM) risk versus UMEC/VI among patients with chronic obstructive pulmonary disease (COPD). This post hoc analysis aimed to define the risk of ACM during and following a moderate/severe exacerbation, and further determine the benefit-risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI using a cardiopulmonary composite adverse event (AE) endpoint.

Methods: The 52-week, double-blind IMPACT trial randomized patients with symptomatic COPD and ≥1 exacerbation in the prior year 2:2:1 to once-daily FF/UMEC/VI 100/62.

Single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol versus dual therapy in current and former smokers with COPD: IMPACT trial post hoc analysis.

Background: Smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). In IMPACT, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy significantly reduced moderate/severe exacerbation rates and improved lung function and health status versus FF/VI or UMEC/VI in COPD patients. This post hoc analysis investigated trial outcomes by smoking status.

Years After a Fire, Biocrust Microbial Communities are Similar to Unburned Communities in a Coastal Grassland.

Microbial communities are integral for ecosystem processes and their taxonomic composition and function may be altered by a disturbance such as fire. Biocrusts are composed of macroscopic and microscopic organisms and are important for a variety of ecosystem functions, such as nutrient cycling and erosion control. We sought to understand if biocrust community composition and function were altered 1 year after a prescribed fire and 6 years after a wildfire in a coastal California grassland on San Clemente Island.

Mostly natural sequencing-by-synthesis for scRNA-seq using Ultima sequencing.

Here we introduce a mostly natural sequencing-by-synthesis (mnSBS) method for single-cell RNA sequencing (scRNA-seq), adapted to the Ultima genomics platform, and systematically benchmark it against current scRNA-seq technology. mnSBS uses mostly natural, unmodified nucleotides and only a low fraction of fluorescently labeled nucleotides, which allows for high polymerase processivity and lower costs. We demonstrate successful application in four scRNA-seq case studies of different technical and biological types, including 5' and 3' scRNA-seq, human peripheral blood mononuclear cells from a single individual and in multiplex, as well as Perturb-Seq.

Time-Dependent Risk of Cardiovascular Events Following an Exacerbation in Patients With Chronic Obstructive Pulmonary Disease: Post Hoc Analysis From the IMPACT Trial.

Background The association between chronic obstructive pulmonary disease exacerbations and increased cardiovascular event risk has not been adequately studied in a heterogenous population with both low and high cardiovascular risk. Methods and Results This post hoc analysis of the IMPACT (Informing the Pathway of COPD Treatment) trial (N=10 355 symptomatic patients with chronic obstructive pulmonary disease at risk of exacerbations) evaluated time-dependent risk of cardiovascular adverse events of special interest (CVAESI) following exacerbations and impact of exacerbation history, cardiovascular risk factors, and study treatment on this association. Risk (time-to-first) of CVAESI or CVAESI resulting in hospitalization or death was assessed during and 1 to 30, 31 to 90, and 91 to 365 days after resolution of moderate or severe exacerbations.

Effect of Recent Exacerbation History on the Efficacy of Once-Daily Single-Inhaler Fluticasone Furoate/Umeclidinium/Vilanterol Triple Therapy in Patients with Chronic Obstructive Pulmonary Disease in the FULFIL Trial.

Background: In the FULFIL trial, once-daily single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) resulted in reduced moderate/severe exacerbation rates and conferred significant improvements in lung function and health status in patients with chronic obstructive pulmonary disease (COPD) versus twice-daily budesonide/formoterol (BUD/FOR) dual therapy.

Methods: FULFIL was a Phase III, randomized, double-blind, double-dummy, parallel-group study. Patients ≥40 years of age with symptomatic COPD were randomized 1:1 to FF/UMEC/VI 100/62.

Effect of chronic mucus hypersecretion on treatment responses to inhaled therapies in patients with chronic obstructive pulmonary disease: Post hoc analysis of the IMPACT trial.

Background And Objective: Chronic mucus hypersecretion (CMH) is a clinical phenotype of COPD. This exploratory post hoc analysis assessed relationship between CMH status and treatment response in IMPACT.

Methods: Patients were randomized to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.

Single-Inhaler Triple Therapy in Patients with Advanced COPD: Bayesian Modeling of the Healthcare Resource Utilization Data and Associated Costs from the IMPACT Trial.

Objectives: In the IMPACT trial (NCT02164513), triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) showed clinical benefit compared with dual therapy with either FF/VI or UMEC/VI in the treatment of chronic obstructive pulmonary disease (COPD). We used data from IMPACT to determine whether this translated into differences in COPD-related healthcare resource utilization (HRU) costs in a United Kingdom (UK) setting.

Methods: In a within-trial analysis, individual patient data from the IMPACT intention-to-treat (ITT) population were analyzed to estimate rates of COPD-related HRU with FF/UMEC/VI, FF/VI, or UMEC/VI.

Applying key learnings from the EMAX trial to clinical practice and future trial design in COPD.

Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a large, multicentre, multi-national, randomised, double-blind, 24-week trial. EMAX evaluated the efficacy and safety of dual bronchodilator therapy with umeclidinium bromide (UMEC)/vilanterol (VI) versus monotherapy with either UMEC or salmeterol (SAL) in symptomatic patients with chronic obstructive pulmonary disease (COPD) at low exacerbation risk who were not taking concomitant inhaled corticosteroid (ICS). EMAX generated evidence covering a wide range of patient-centred endpoints in COPD in addition to measures of lung function, clinical deterioration and safety.

Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq.

A central goal of genetics is to define the relationships between genotypes and phenotypes. High-content phenotypic screens such as Perturb-seq (CRISPR-based screens with single-cell RNA-sequencing readouts) enable massively parallel functional genomic mapping but, to date, have been used at limited scales. Here, we perform genome-scale Perturb-seq targeting all expressed genes with CRISPR interference (CRISPRi) across >2.

International Differences in the Frequency of Chronic Obstructive Pulmonary Disease Exacerbations Reported in Three Clinical Trials.

Exacerbations of chronic obstructive pulmonary disease (COPD) are an important endpoint in multinational clinical treatment trials, but the observed event rate is often lower than anticipated and appears to vary between countries. We investigated whether systematic differences in national exacerbation rates might explain this observed variation. We reviewed data from three large multicenter international randomized trials conducted over an 18-year period with different designs and clinical severities of COPD, comparing bronchodilator and/or inhaled corticosteroids with bronchodilators alone and/or placebo.

Aboveground competition influences density-dependent effects of cordgrass on sediment biogeochemistry.

Interspecific interactions between plants influence plant phenotype, distribution, abundance, and community structure. Each of these can, in turn, impact sediment biogeochemistry. Although the population and community level impacts of these interactions have been extensively studied, less is known about their effect on sediment biogeochemistry.

Disease Burden and Healthcare Utilization Among Patients with Chronic Obstructive Pulmonary Disease (COPD) in England.

Purpose: Clinical guidelines for COPD management suggest pharmacologic treatment algorithms based on symptoms and exacerbation history. As previous research has suggested that prescribing patterns are not always aligned with these recommendations, this study investigated the burden of disease in patients with COPD receiving, and persisting on, new inhaled maintenance therapy.

Patients And Methods: This was a retrospective observational study using two linked electronic databases containing health records of patients in England.