Monocyte and macrophage regulation of pulmonary fibrosis

In this thesis I examined the role of circulating monocytes and lung macrophages in the pathogenesis of the early fibrotic, progressive fibrotic and resolution phases of pulmonary fibrosis. Pulmonary fibrosis with destruction of lung architecture and consequent respiratory failure and death represents a massive worldwide health burden. Although idiopathic pulmonary fibrosis (IPF) is the archetypal and most common cause of lung fibrosis, numerous respiratory diseases can progress to pulmonary fibrosis, and this usually signifies a worse prognosis. Importantly, the incidence and prevalence of IPF continue to rise and it remains one of the few respiratory conditions for which there are no effective therapies. The mechanisms resulting in pulmonary fibrosis are controversial. Early work in the 1980s and 1990s suggested that lung macrophages were important. However, at the turn of the 21st century there was a shift to a belief that pulmonary fibrosis resulted from aberrant wound healing as a consequence of repetitive epithelial injury from an as yet unknown cause. However, with the ever expanding knowledge of the importance of macrophages in other fibrotic conditions such as the kidney and liver, the potential importance of macrophages in pulmonary fibrosis has become more pertinent. Using an in vivo depletional strategy in several murine models of lung fibrosis, in conjunction with human studies, I sought to characterise the role of circulating monocytes and lung macrophages in the pathogenesis of pulmonary fibrosis. I have established that circulating monocytes and lung macrophages are not critical for the development of early lung fibrosis. In contrast, circulating monocytes and lung macrophages are important during the progressive fibrotic phase of lung fibrosis. Furthermore, my data suggest that the pro-fibrotic alternatively activated macrophages may be the sub-class of macrophages that mediate this fibrogenic effect. In addition and in contrast, I have established that lung macrophages are required for the resolution of fibrosis. This finding is in keeping with important work performed in the field of liver fibrosis. There is an ever increasing literature examining the role of matrix metalloproteinases (MMPs) during tissue fibrosis and repair. My work has suggested that during lung fibrosis there may be compartmental specific functions of MMPs that regulate lung fibrogenesis, although more work is required before this exciting finding can be properly defined

Pan-urologic cancer genomic subtypes that transcend tissue of origin

AbstractUrologic cancers include cancers of the bladder, kidney, prostate, and testes, with common molecular features spanning different types. Here, we show that 1954 urologic cancers can be classified into nine major genomic subtypes, on the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy number, and RNA and protein expression). Tissue dominant effects are first removed computationally in order to define these subtypes, which reveal common processes—reflecting in part tumor microenvironmental influences—driving cellular behavior across tumor lineages. Six of the subtypes feature a mixture of represented cancer types as defined by tissue or cell of origin. Differences in patient survival and in the manifestation of specific pathways—including hypoxia, metabolism, NRF2-ARE, Hippo, and immune checkpoint—can further distinguish the subtypes. Immune checkpoint markers and molecular signatures of macrophages and T cell infiltrates are relatively high within distinct subsets of each cancer type studied. The pan-urologic cancer genomic subtypes would facilitate information sharing involving therapeutic implications between tissue-oriented domains.</jats:p

Pregnancy Outcomes in Women With a History of Previable, Preterm Prelabor Rupture of Membranes:

To characterize subsequent pregnancy outcomes among women with a history of previable, preterm prelabor rupture of membranes (PROM) and assess factors associated with recurrent preterm birth