Lysophosphatidic acid (LPA) is both a potential marker and a therapeutic target for ovarian cancer. It is critical to identify the sources of elevated LPA levels in ascites and blood of patients with ovarian cancer. We show here that human peritoneal mesothelial cells constitutively produce LPA, which accounts for a significant portion of the chemotactic activity of the conditioned medium from peritoneal mesothelial cells to ovarian cancer cells. Both production of LPA by peritoneal mesothelial cells and the chemotactic activity in the conditioned medium can be blocked by HELSS [an inhibitor of the calcium-independent phospholipase A 2 (iPLA 2 )] and AACOCF 3 [an inhibitor of both cytosolic PLA 2 (cPLA 2 ) and iPLA 2 ]. Moreover, cell-based enzymatic activity assays for PLA 2 indicate that peritoneal mesothelial cells have strong constitutive PLA 2 activity. Receptors for LPA, LPA 2 , and LPA 3 are involved in the conditioned medium-induced chemotactic activity. Invasion of ovarian cancer cells into peritoneal mesothelial cells has also been analyzed and shown to require PLA 2 , LPA receptors, and the mitogen-activated protein/ extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase signaling pathway. Thus, we show here, for the first time, that human peritoneal mesothelial cells constitutively produce bioactive lipid signaling molecules, such as LPA, via iPLA 2 and/or cPLA 2 activities. Conditioned medium from peritoneal mesothelial cells stimulate migration, adhesion, and invasion of ovarian cancer cells, and may play similar roles in vivo.

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Calcium-independent phospholipase A 2 (iPLA 2 ) plays a pivotal role in phospholipid remodeling and many other biological processes, including inflammation and cancer development. iPLA 2 can be activated by caspase-3 via a proteolytic process in apoptotic cells. In this study we identify novel signaling and functional loops of iPLA 2 activation leading to migration of non-apoptotic human ovarian cancer cells. The extracellular matrix protein, laminin-10/11, but not collagen I, induces integrin-and caspase-3-dependent cleavage and activation of overexpressed and endogenous iPLA 2 . The truncated iPLA 2 (amino acids 514 -806) generates lysophosphatidic acid and arachidonic acid. Arachidonic acid is important for enhancing cell migration toward laminin-10/11. Lysophosphatidic acid activates Akt that in turn acts in a feedback loop to block the cleavage of poly-(ADP-ribose) polymerase and DNA fragmentation factor as well as prevent apoptosis. By using pharmacological inhibitors, blocking antibodies, and genetic approaches (such as point mutations, dominant negative forms of genes, and siRNAs against specific targets), we show that ␤ 1 , but not ␤ 4 , integrin is involved in iPLA 2 activation and cell migration to laminin-10/ 11. The role of caspase-3 in iPLA 2 activation and cell migration are supported by several lines of evidence. 1) Point mutation of Asp 513 (a cleavage site of caspase-3 in iPLA 2 ) to Ala blocks laminin-10/11-induced cleavage and activation of overexpressed iPLA 2 , whereas mutation of Asp 733 to Ala has no such effect, 2) treatment of inhibitors or a small interfering RNA against caspase-3 results in decreased cell migration toward laminin-10/11, and 3) selective caspase-3 inhibitor blocks cleavage of endogenous iPLA 2 induced by laminin-10/11. Importantly, small interfering RNA-mediated down-regulation of endogenous iPLA 2 expression in ovarian carcinoma HEY cells results in decreased migration toward laminin, suggesting that our findings are pathophysiologically important.

Objective To develop claims‐based measures of comprehensiveness of primary care physicians (PCPs) and summarize their associations with health care utilization and cost. Data Sources and Study Setting A total of 5359 PCPs caring for over 1 million Medicare fee‐for‐service beneficiaries from 1404 practices. Study Design We developed Medicare claims‐based measures of physician comprehensiveness (involvement in patient conditions and new problem management) and used a previously developed range of services measure. We analyzed the association of PCPs’ comprehensiveness in 2013 with their beneficiaries’ emergency department, hospitalizations rates, and ambulatory care‐sensitive condition (ACSC) admissions (each per 1000 beneficiaries per year), and Medicare expenditures (per beneficiary per month) in 2014, adjusting for beneficiary, physician, practice, and market characteristics, and clustering. Principal Findings Each measure varied across PCPs and had low correlation with the other measures—as intended, they capture different aspects of comprehensiveness. For patients whose PCPs’ comprehensiveness score was at the 75th vs 25th percentile (more vs less comprehensive), patients had lower service use (P < 0.05) in one or more measures: involvement with patient conditions: total Medicare expenditures, −$17.4 (−2.2 percent); hospitalizations, −5.5 (−1.9 percent); emergency department (ED) visits, −16.3 (−2.4 percent); new problem management: total Medicare expenditures, −$13.3 (−1.7 percent); hospitalizations, −7.0 (−2.4 percent); ED visits, −19.7 (−2.9 percent); range of services: ED visits, −17.1 (−2.5 percent). There were no significant associations between the comprehensiveness measures and ACSC admission rates. Conclusions These measures demonstrate strong content and predictive validity and reliability. Medicare beneficiaries of PCPs providing more comprehensive care had lower hospitalization rates, ED visits, and total Medicare expenditures.

Objectives. To develop and evaluate a board game designed to increase students' enjoyment of learning metabolic pathways; their familiarity with pathway reactions, intermediates, and regulation; and, their understanding of how pathways relate to one another and to selected biological conditions. Design. The board game, entitled Race to Glucose, was created as a team activity for first-year pharmacy students in the biochemistry curriculum. Assessment. A majority of respondents agreed that the game was helpful for learning regulation, intermediates, and interpathway relationships but not for learning reactions, formation of energetic molecules, or relationships, to biological conditions. There was a significant increase in students' scores on game-related examination questions (68.8% pretest vs. 81.3% posttest), but the improvement was no greater than that for examination questions not related to the game (12.5% vs. 10.9%). Conclusion. First-year pharmacy students considered Race to Glucose to be an enjoyable and helpful tool for learning intermediates, regulation, and interpathway relationships.