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PDF file - 358K, MDSC(+bone mets), which become osteoclasts was the only population that had elevated NO levels

PDF file - 100K, MDSC(+bone mets) did not express macrophage marker F4/80 during osteoclast differentiation and can induce bone destruction in vivo

PDF file - 372K, MDSC(+bone mets) was the only population that differentiated into osteoclasts

PDF file - 205K, Western blot analysis of HIF-1α, ERK and PI3K in MDSC from different tissue sources

PDF file - 103K, Nitric oxide levels are elevated in MDSC(+bone mets) as they differentiated into osteoclasts

PDF file - 169K, MDSC(+bone mets) from gemcitabine treated mice failed to differentiate into osteoclasts

PDF file - 108K, In vivo bone destruction mediated by MDSC requires NO production

PDF file - 143K, Isolation and characterization of MDSC from murine breast cancer model

PDF file - 128K

Congenital heart disease (CHD) is the most common birth defect for infants born in the United States, with approximately 36,000 affected infants born annually. While mortality rates for children with CHD have significantly declined, there is a growing population of individuals with CHD living into adulthood prompting the need to optimise long-term development and quality of life. For infants with CHD, pre- and post-surgery, there is an increased risk of developmental challenges and feeding difficulties. Feeding challenges carry profound implications for the quality of life for individuals with CHD and their families as they impact short- and long-term neurodevelopment related to growth and nutrition, sensory regulation, and social-emotional bonding with parents and other caregivers. Oral feeding challenges in children with CHD are often the result of medical complications, delayed transition to oral feeding, reduced stamina, oral feeding refusal, developmental delay, and consequences of the overwhelming intensive care unit (ICU) environment. This article aims to characterise the disruptions in feeding development for infants with CHD and describe neurodevelopmental factors that may contribute to short- and long-term oral feeding difficulties.

Summary Background: Continuous peripheral nerve blocks (CPNBs) are increasingly used to control postoperative and chronic pain. At our pediatric oncology institution, the duration of CPNBs is often prolonged. The risk of catheter-associated infection with prolonged CPNBs has not been previously investigated. Aim: We analyzed the incidence of CPNB-related infection and its relation to catheter duration, catheter site, intensive care stay, and antibiotic coverage. Methods: All CPNBs placed at our institution between August 1, 2005 and October 31, 2010 were studied. Primary diagnosis and the site, indication, duration, and infectious adverse effects of CPNBs were obtained from our Pain Service QI database. Patients’ age and sex, antibiotic administration, and number of days in intensive care were collected from patients’ medical records. Results: The use of 179 catheters in 116 patients was evaluated. Mean age at CPNB placement was 15.1 years (median, 14.7; range, 0.4–26.9). The most frequent indication for CPNB was surgery (89.4%), most commonly orthopedic (78.8%). Mean CPNB duration was 7.2 days (median, 5.0; range, 1–81 days). Two cases (1.12%) of CPNBs developed signs of infection, both associated with femoral catheters. The infections were mild and necessitated catheter removal at days 10 and 13, respectively. Conclusion: Nerve block catheter-associated infections are infrequent at our institution despite prolonged CPNB use. Both patients with infection had femoral catheters and prolonged catheter (≥10 days) use.

Enhanced bone destruction is a hallmark of various carcinomas such as breast cancer, where osteolytic bone metastasis is associated with increased morbidity and mortality. Immune cells contribute to osteolysis in cancer growth, but the factors contributing to aggressive bone destruction are not well understood. In this study, we show the importance of myeloid-derived suppressor cells (MDSC) in this process at bone metastatic sites. Because MDSC originate from the same myeloid lineage as macrophages, which are osteoclast precursors, we hypothesized that MDSC may undergo osteoclast differentiation and contribute to enhanced bone destruction and tumor growth. Using an immunocompetent mouse model of breast cancer bone metastasis, we confirmed that MDSC isolated from the tumor-bone microenvironment differentiated into functional osteoclasts both in vitro and in vivo. Mechanistic investigations revealed that nitric oxide signaling was critical for differentiation of MDSC into osteoclasts. Remarkably, osteoclast differentiation did not occur in MDSC isolated from control or tumor-bearing mice that lacked bone metastasis, signifying the essential cross-talk between tumor cells and myeloid progenitors in the bone microenvironment as a requirement for osteoclast differentiation of MDSC. Overall, our results identify a wholly new facet to the multifunctionality of MDSC in driving tumor progression, in this case as a novel osteoclast progenitor that specifically drives bone metastasis during cancer progression. Cancer Res; 73(2); 672–82. ©2012 AACR.

Elevated levels of plasmacytoid dendritic cells (pDC) have been reported in breast cancer patients, but the significance remains undefined. Using three immunocompetent mouse models of breast cancer bone metastasis, we identified a key role for pDC in facilitating tumor growth through immunosuppression and aggressive osteolysis. Following infiltration of macrophages upon breast cancer dissemination, there was a steady increase in pDC within the bone, which resulted in a sustained Th2 response along with elevated levels of regulatory T cells and myeloid-derived suppressor cells. Subsequently, pDC and CD4+ T cells, producing osteolytic cytokines, increased with tumor burden, causing severe bone damage. Microcomputed tomography and histology analyses of bone showed destruction of femur and tibia. The therapeutic significance of this finding was confirmed by depletion of pDC, which resulted in decreased tumor burden and bone loss by activating tumor-specific cytolytic CD8+ T cells and decreasing suppressor cell populations. Thus, pDC depletion may offer a novel adjuvant strategy to therapeutically influence breast cancer bone metastasis.