A dynamic model of inorganic arsenic-induced carcinogenesis reveals an epigenetic mechanism for epithelial-mesenchymal plasticity.

Inorganic arsenic (iAs) causes cancer by initiating dynamic transitions between epithelial and mesenchymal cell phenotypes. These transitions transform normal cells into cancerous cells, and cancerous cells into metastatic cells. Most in vitro models assume that transitions between states are binary and complete, and do not consider the possibility that intermediate, stable cellular states might exist. In this paper, we describe a new, two-hit in vitro model of iAs-induced carcinogenesis that extends to 28 weeks of iAs exposure. Through week 17, the model faithfully recapitulates known and expected phenotypic, genetic, and epigenetic characteristics of iAs-induced carcinogenesis. By 28 weeks, however, exposed cells exhibit stable, intermediate phenotypes and epigenetic properties, and key transcription factor promoters (SNAI1, ZEB1) enter an epigenetically poised or bivalent state. These data suggest that key epigenetic transitions and cellular states exist during iAs-induced epithelial-to-mesenchymal transition (EMT), and that it is important for our in vitro models to encapsulate all aspects of EMT and the mesenchymal-to-epithelial transition (MET). In so doing, and by understanding the epigenetic systems controlling these transitions, we might find new, unexpected opportunities for developing targeted, cell state-specific therapeutics.

Respiratory motor function in individuals with centronuclear myopathies.

UNLABELLED: I NTRODUCTION: Individuals with X-linked myotubular myopathy (XLMTM) and other centronuclear myopathies (CNMs) frequently have profound respiratory insufficiency that requires support early in life. Still, few quantitative data exist to characterize respiratory motor function in CNM. METHODS: We evaluated the reliance upon mechanical ventilation (MV), ventilatory kinematics, unassisted tidal volumes, and maximal respiratory pressures in 14 individuals with CNMs, including 10 boys with XLMTM. RESULTS: Thirteen participants required full-time, invasive MV. Maximal inspiratory pressures were higher in subjects who breathed unsupported at least 1 hour/day as compared with 24-hour MV users [33.7 (11.9-42.3) vs. 8.4 (6.0-10.9) cm H(2)O, P < 0.05]. Years of MV dependence correlated significantly with MEP (r = -0.715, P < 0.01). CONCLUSIONS: Respiratory function in CNMs may be related to deconditioning from prolonged MV and/or differences in residual respiratory muscle strength. Results from this study may assist in evaluating severe respiratory insufficiency in neuromuscular clinical care and research.

Primary palliative care clinic pilot project demonstrates benefits of a nurse practitioner-directed clinic providing primary and palliative care.

PURPOSE: The purpose of the Primary Palliative Care Pilot Project was to determine if patients with a life-limiting illness who receive their primary care and palliative care from a consistent provider via a nurse practitioner (NP)-founded and-directed Primary Palliative Care Clinic at a public hospital would have improved symptom management and decreased emergency department utilization over time. DATA SOURCES: All patients followed in the Harborview Primary Palliative Care Clinic from January to March 2010. CONCLUSIONS: The results of this project demonstrate that patients with a life-limiting illness who receive their primary care and palliative care in an NP-founded and -directed Primary Palliative Care Clinic have decreased utilization of the emergency department, and some experience improvement in symptom assessment scores. IMPLICATIONS FOR PRACTICE: Palliative care providers and administrators should explore opportunities to expand outpatient palliative care clinics with an emphasis on primary care and continuity of care. NPs by experience and education are ideally suited to manage both primary and palliative care needs for people at the end of life.