Brain metastases occur in almost one-third of adult patients with solid tumor malignancies and lead to considerable patient morbidity and mortality. The rising incidence of brain metastases has been ascribed to the development of better imaging and screening techniques and the formulation of better systemic therapies. Until recently, the multimodal management of brain metastases focused primarily on the utilization of neurosurgical techniques, with varying combinations of whole-brain radiation therapy and stereotactic radio-surgical procedures. Over the past 2 decades, in particular, the increment in knowledge pertaining to molecular genetics and the pathogenesis of brain metastases has led to significant developments in targeted therapies and immunotherapies. This review article highlights the recent updates in the management of brain metastases with an emphasis on novel systemic therapies.
The airway epithelium is subjected to insults such as cigarette smoke (CS), a primary cause of Chronic Obstructive Pulmonary Disease (COPD) and serves as an excellent model to study cell plasticity. Both CS-exposed and COPD-patient derived epithelia (CHBE) display quantitative evidence of cellular plasticity, with loss of specialized apical features and a transcriptional profile suggestive of partial epithelial to mesenchymal transition, albeit with distinct cell motion indicative of cellular unjamming. These injured/diseased cells have an increased fraction of polymerized actin, due to loss of the actin-severing protein, cofilin-1. Decreasing polymerized actin restores the jammed state in both CHBE and CS exposed epithelia, indicating that the fraction of polymerized actin is critical in unjamming the epithelia. Kinetic energy spectral analysis suggests that loss of cofilin-1 results in unjamming, similar to that seen with both CS exposure and in CHBE cells. Our data suggest that in response to chronic injury, although epithelial cells display evidence of pEMT, their movement is more consistent with cellular unjamming. Inhibitors of actin polymerization rectify the unjamming features of the monolayer.
†K. Nishida and B. Ghosh contributed equally to this work. P a g e 2 o f 3 8One Sentence Summary: Environmental toxins undermine tissue integrity by manipulating transitions from jammed to unjammed states, thereby mimicking or inducing disease. AbstractEpithelial surfaces lining the lung serve as the primary environmental gaseous interface, and are subject to common life-limiting diseases, including COPD (Chronic Obstructive Pulmonary Disease). Despite the critical role of epithelial cells in pulmonary health and disease, quantitative models are lacking but are required given the large patient to patient variability to characterize the epithelial plasticity that follows injury. We have identified a series of assessments to quantitatively identify the changes that occur in the epithelium and to identify targets that reverse injury. The injured epithelium has decreased ciliary function and monolayer height, which in the case of cells derived from COPD patients results in an overall disorganization of structure.Injury causes the cells to shift to an unjammed state, with corresponding increases in the velocity correlation length implicating cell shape and stiffness as fundamental to the injury response.Specific inhibitors of actin polymerization (LatA), of MAPK/ERK kinase (U0126) and Nrf-2 pathway activation (CDDO-Me) push the epithelium back towards a jammed state with decreased cell movement and correlation length, as well as improve barrier function and CBF.These studies attest to cell intrinsic properties that allow for a transition to an unjammed state, and that quantitative phenotypic analysis can identify potential specific pharmacologic targets in a given patient and provide insight into basic mechanisms of cellular damage.
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