In the context of an innate macrophage response remained unknown. HIF-1a is a potent coping mechanism utilized by macrophages in response to a hypoxic microenvironment used to help mediate the necessary cellular mechanisms in order to maintain activity and viability. Moreover, hypoxia can result in the activation of the NFkB pathway where it has been shown that downstream signaling of TNF-a has a critical role in the biologic reactivity to implants, implant performance and bone loss. Both our in vitro and in vivo findings indicate Co-alloy is a potent stimuli, eliciting a hypoxic or hypoxic-like microenvironment that can increase the production and stabilization of HIF-1a protein leading to pro-angiogenesis signaling. Importantly this is the first report of a mechanism that can account for the unusual tissue reactions that often preferentially accompany high levels of Cobalt metal debris in failed metal-on-metal hip replacements. These data demonstrate that Co-alloy particles induced significant biologic effects, even at low doses, causing macrophages to respond with increases in HIF-1a, TNF-a, VEGF and ROS. In contrast, Ti-alloy particles produced similar effects only at higher challenge doses of particles. Therefore, the hypoxic/hypoxic-like induction of HIF-1a protein in response to metal implant debris may explain how certain kinds of metal-releasing orthopedic implants produce both necrosis/ toxicity and neogenic tissue responses resulting in unique mechanisms of poor implant performance. It is well established that hypoxia can induce inflammation and vise versa, e.g. NFkB, that subsequently results in the production of pro-inflammatory cytokines, such as TNF-a. We observed HIF-1a production was enough to induce NFkB activation by observing increased TNF-a, production a signature cytokine of NFkb activation.The adsorption state obtained by aMD provides a considerably more realistic prediction than the ‘unfinished’ adsorption state after 20 ns of classical simulation. The next step in characterizing protein adsorption processes will be the utilization of aMD for studying a variety of different protein-surface interactions including initial orientation and topology dependences. Comparison to experiment is for instance possible by an analysis of the secondary structure content of the adsorbed protein or by determining the forces necessary for protein desorption. B-cell chronic lymphocytic leukemia, which is characterized by a progressive accumulation of leukemia cells that coexpress CD5 and CD19 surface antigens, is the most common hematologic malignancy in the Western hemisphere. Despite significant progress in CLL research and novel therapies for the disease, CLL remains incurable, and its pathobiology is still not fully understood. MicroRNAs are small noncoding RNAs, 19?C 24 nucleotides in length, that regulate gene expression. MiRs are expressed aberrantly in human neoplasms including leukemia and lymphoma. Aberrantly expressed miRs repress multiple genes by inhibiting translation, cleaving mRNA, and guiding deadenylation that initiates mRNA decay.