Association of bronchial disease on CT imaging and clinical definitions of chronic bronchitis in a single-center COPD phenotyping study.

INTRODUCTION: Chronic Bronchitis (CB) represents a phenotype of chronic obstructive pulmonary disease (COPD). While several definitions have been used for diagnosis, the relationship between clinical definitions and radiologic assessment of bronchial disease (BD) has not been well studied. The aim of this study was to evaluate the relationship between three clinical definitions of CB and radiographic findings of BD in spirometry-defined COPD patients. METHODS: A cross-sectional analysis was performed from a COPD phenotyping study. It was a prospective observational cohort. Participants had spirometry-defined COPD and available chest CT imaging. Comparison between CB definitions, Medical Research Council (CBMRC), St. George's Respiratory Questionnaire (CBSGRQ), COPD Assessment Test (CBCAT) and CT findings were performed using Cohen's Kappa, univariate and multivariate logistic regressions. RESULTS: Of 112 participants, 83 met inclusion criteria. Demographics included age of 70.1 ± 7.0 years old, predominantly male (59.0 %), 45.8 ± 30.8 pack-year history, 21.7 % actively smoking, and mean FEV1 61.5 ± 21.1 %. With MRC, SGRQ and CAT definitions, 22.9 %, 36.6 % and 28.0 % had CB, respectively. BD was more often present in CB compared to non-CB patients; however, it did not have a statistically significant relationship between any of the CB definitions. CBSGRQ had better agreement with radiographically assessed BD compared to the other two definitions. CONCLUSION: Identification of BD on CT was associated with the diagnoses of CB. However, agreement between imaging and definitions were not significant, suggesting radiologic findings of BD and criteria defining CB may not identify the same COPD phenotype. Research to standardize imaging and clinical methods is needed for more objective identification of COPD phenotypes.

Assembling a Hippo: the evolutionary emergence of an animal developmental signaling pathway.

Decades of work in developmental genetics has given us a deep mechanistic understanding of the fundamental signaling pathways underlying animal development. However, little is known about how these pathways emerged and changed over evolutionary time. Here, we review our current understanding of the evolutionary emergence of the Hippo pathway, a conserved signaling pathway that regulates tissue size in animals. This pathway has deep evolutionary roots, emerging piece by piece in the unicellular ancestors of animals, with a complete core pathway predating the origin of animals. Recent functional studies in close unicellular relatives of animals and early-branching animals suggest an ancestral function of the Hippo pathway in cytoskeletal regulation, which was subsequently co-opted to regulate proliferation and animal tissue size.

The Hippo kinase cascade regulates a contractile cell behavior and cell density in a close unicellular relative of animals.

The genomes of close unicellular relatives of animals encode orthologs of many genes that regulate animal development. However, little is known about the function of such genes in unicellular organisms or the evolutionary process by which these genes came to function in multicellular development. The Hippo pathway, which regulates cell proliferation and tissue size in animals, is present in some of the closest unicellular relatives of animals, including the amoeboid organism Capsaspora owczarzaki. We previously showed that the Capsaspora ortholog of the Hippo pathway nuclear effector Yorkie/YAP/TAZ (coYki) regulates actin dynamics and the three-dimensional morphology of Capsaspora cell aggregates, but is dispensable for cell proliferation control (Phillips et al., 2022). However, the function of upstream Hippo pathway components, and whether and how they regulate coYki in Capsaspora, remained unknown. Here, we analyze the function of the upstream Hippo pathway kinases coHpo and coWts in Capsaspora by generating mutant lines for each gene. Loss of either kinase results in increased nuclear localization of coYki, indicating an ancient, premetazoan origin of this Hippo pathway regulatory mechanism. Strikingly, we find that loss of either kinase causes a contractile cell behavior and increased density of cell packing within Capsaspora aggregates. We further show that this increased cell density is not due to differences in proliferation, but rather actomyosin-dependent changes in the multicellular architecture of aggregates. Given its well-established role in cell density-regulated proliferation in animals, the increased density of cell packing in coHpo and coWts mutants suggests a shared and possibly ancient and conserved function of the Hippo pathway in cell density control. Together, these results implicate cytoskeletal regulation but not proliferation as an ancestral function of the Hippo pathway kinase cascade and uncover a novel role for Hippo signaling in regulating cell density in a proliferation-independent manner.

Practical Considerations in Dose Extrapolation from Animals to Humans.

Animal studies are an important component of drug product development and the regulatory review process since modern practices have been in place, for almost a century. A variety of experimental systems are available to generate aerosols for delivery to animals in both liquid and solid forms. The extrapolation of deposited dose in the lungs from laboratory animals to humans is challenging because of genetic, anatomical, physiological, pharmacological, and other biological differences between species. Inhaled drug delivery extrapolation requires scrutiny as the aerodynamic behavior, and its role in lung deposition is influenced not only by the properties of the drug aerosol but also by the anatomy and pulmonary function of the species in which it is being evaluated. Sources of variability between species include the formulation, delivery system, and species-specific biological factors. It is important to acknowledge the underlying variables that contribute to estimates of dose scaling between species.