Activin A-Expressing Polymorphonuclear Myeloid-Derived Suppressor Cells Infiltrate Skeletal and Cardiac Muscle and Promote Cancer Cachexia.

Cachexia is a major cause of death in cancer and leads to wasting of cardiac and skeletal muscle, as well as adipose tissue. Various cellular and soluble mediators have been postulated in driving cachexia; however, the specific mechanisms behind this muscle wasting remain poorly understood. In this study, we found polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to be critical for the development of cancer-associated cachexia. Significant expansion of PMN-MDSCs was observed in the cardiac and skeletal muscles of cachectic murine models. Importantly, the depletion of this cell subset, using depleting anti-Ly6G Abs, attenuated this cachectic phenotype. To elucidate the mechanistic involvement of PMN-MDSCs in cachexia, we examined major mediators, that is, IL-6, TNF-α, and arginase 1. By employing a PMN-MDSC-specific Cre-recombinase mouse model, we showed that PMN-MDSCs were not maintained by IL-6 signaling. In addition, PMN-MDSC-mediated cardiac and skeletal muscle loss was not abrogated by deficiency in TNF-α or arginase 1. Alternatively, we found PMN-MDSCs to be critical producers of activin A in cachexia, which was noticeably elevated in cachectic murine serum. Moreover, inhibition of the activin A signaling pathway completely protected against cardiac and skeletal muscle loss. Collectively, we demonstrate that PMN-MDSCs are active producers of activin A, which in turn induces cachectic muscle loss. Targeting this immune/hormonal axis will allow the development of novel therapeutic interventions for patients afflicted with this debilitating syndrome.

The business case for better buildings.

The buildings in which customers receive services are inherently part of the service experience. Given the high stress of illness, healthcare facility designs are especially likely to have a meaningful impact on customers. In the past, a handful of visionary "healing environments" such as the Lucille Packard Children's Hospital at Stanford University in Palo Alto, California; Griffin Hospital in Derby, Connecticut; Woodwinds Health Campus in St. Paul, Minnesota; and San Diego Children's Hospital were built by values-driven chief executive officers and boards and aided by philanthropy when costs per square foot exceeded typical construction costs. Designers theorized that such facilities might have a positive impact on patients' health outcomes and satisfaction. But limited evidence existed to show that such exemplary health facilities were superior to conventional designs in actually improving patient outcomes and experiences and the organization's bottom line. More evidence was needed to assess the impact of innovative health facility designs. Beginning in 2ooo, a research collaborative of progressive healthcare organizations voluntarily came together with The Center for Health Design to evaluate their new buildings. Various "Pebble Projects" are now engaged in three-year programs of evaluation, using comparative research instruments and outcome measures. Pebble Projects include hospital replacements, critical care units, cancer units, nursing stations, and ambulatory care centers. The Pebble experiences are synthesized here in a composite 3oo-bed "Fable Hospital" to present evidence in support of the business case for better buildings as a key component of better, safer, and less wasteful healthcare. The evidence indicates that the one-time incremental costs of designing and building optimal facilities can be quickly repaid through operational savings and increased revenue and result in substantial, measurable, and sustainable financial benefits.

The business case for better buildings.

Beginning in 2000, a research collaborative of progressive healthcare organizations came together with The Center for Health Design to evaluate the impact of their new buildings on patient outcomes. Those organizations are now engaged in three-year programs of evaluation, using comparative research instruments and outcome measures. Their experiences are synthesized here in a composite 300-bed "Fable Hospital" to present evidence in support of the business case for better buildings as a key component of better, safer, and less wasteful health care.