Expression of LDL receptor-related proteins (LRPs) in common solid malignancies correlates with patient survival

LDL receptor-related proteins (LRPs) are transmembrane receptors involved in endocytosis, cell-signaling, and trafficking of other cellular proteins. Considerable work has focused on LRPs in the fields of vascular biology and neurobiology. How these receptors affect cancer progression in humans remains largely unknown. Herein, we mined provisional data-bases in The Cancer Genome Atlas (TCGA) to compare expression of thirteen LRPs in ten common solid malignancies in patients. Our first goal was to determine the abundance of LRP mRNAs in each type of cancer. Our second goal was to determine whether expression of LRPs is associated with improved or worsened patient survival. In total, data from 4,629 patients were mined. In nine of ten cancers studied, the most abundantly expressed LRP was LRP1; however, a correlation between LRP1 mRNA expression and patient survival was observed only in bladder urothelial carcinoma. In this malignancy, high levels of LRP1 mRNA were associated with worsened patient survival. High levels of LDL receptor (LDLR) mRNA were associated with decreased patient survival in pancreatic adenocarcinoma. High levels of LRP10 mRNA were associated with decreased patient survival in hepatocellular carcinoma, lung adenocarcinoma, and pancreatic adenocarcinoma. LRP2 was the only LRP for which high levels of mRNA expression correlated with improved patient survival. This correlation was observed in renal clear cell carcinoma. Insights into LRP gene expression in human cancers and their effects on patient survival should guide future research

LDL receptor-related protein-1 regulates NFκB and microRNA-155 in macrophages to control the inflammatory response

LDL receptor-related protein-1 (LRP1) is an endocytic and cell-signaling receptor. In mice in which LRP1 is deleted in myeloid cells, the response to lipopolysaccharide (LPS) was greatly exacerbated. LRP1 deletion in macrophages in vitro, under the control of tamoxifen-activated Cre-ER(T) fusion protein, robustly increased expression of proinflammatory cytokines and chemokines. In LRP1-expressing macrophages, proinflammatory mediator expression was regulated by LRP1 ligands in a ligand-specific manner. The LRP1 agonists, α2-macroglobulin and tissue-type plasminogen activator, attenuated expression of inflammatory mediators, even in the presence of LPS. The antagonists, receptor-associated protein (RAP) and lactoferrin (LF), and LRP1-specific antibody had the entirely opposite effect, promoting inflammatory mediator expression and mimicking LRP1 deletion. NFκB was rapidly activated in response to RAP and LF and responsible for the initial increase in expression of proinflammatory mediators. RAP and LF also significantly increased expression of microRNA-155 (miR-155) after a lag phase of about 4 h. miR-155 expression reflected, at least in part, activation of secondary cell-signaling pathways downstream of TNFα. Although miR-155 was not involved in the initial induction of cytokine expression in response to LRP1 antagonists, miR-155 was essential for sustaining the proinflammatory response. We conclude that LRP1, NFκB, and miR-155 function as members of a previously unidentified system that has the potential to inhibit or sustain inflammation, depending on the continuum of LRP1 ligands present in the macrophage microenvironment

PAI1 blocks NMDA receptor-mediated effects of tissue-type plasminogen activator on cell signaling and physiology

The fibrinolysis proteinase tissue-type plasminogen activator (tPA, also known as PLAT) triggers cell signaling and regulates cell physiology. In PC12 cells, Schwann cells and macrophages, the N-methyl-D-aspartate receptor (NMDA-R) mediates tPA signaling. Plasminogen activator inhibitor-1 (PAI1, also known as SERPINE1) is a rapidly acting inhibitor of tPA enzyme activity. Although tPA-initiated cell signaling is not dependent on its enzyme active site, we show that tPA signaling is neutralized by PAI1. In PC12 cells, PAI1 blocked the ERK1/2 activation mediated by tPA as well as neurite outgrowth. In Schwann cells, PAI1 blocked tPA-mediated ERK1/2 activation and cell migration. In macrophages, PAI1 blocked the ability of tPA to inhibit IκBα phosphorylation and cytokine expression. The cell signaling activity of tPA-PAI1 complex was rescued when the complex was formed with PAI1R76E, which binds to LRP1 with decreased affinity, by pre-treating cells with the LRP1 antagonist receptor-associated protein and upon LRP1 gene silencing. The inhibitory role of LRP1 in tPA-PAI1 complex-initiated cell signaling was unanticipated given the reported role of LRP1 as an NMDA-R co-receptor in signaling responses elicited by free tPA or α2-macroglobulin. We conclude that PAI1 functions as an in-hibitor not only of the enzyme activity of tPA but also of tPA receptor-mediated activities

How much measurement independence is needed in order to demonstrate nonlocality?

If nonlocality is to be inferred from a violation of Bell's inequality, an important assumption is that the measurement settings are freely chosen by the observers, or alternatively, that they are random and uncorrelated with the hypothetical local variables. We study the case where this assumption is weakened, so that measurement settings and local variables are at least partially correlated. As we show, there is a connection between this type of model and models which reproduce nonlocal correlations by allowing classical communication between the distant parties, and a connection with models that exploit the detection loophole. We show that even if Bob's choices are completely independent, all correlations obtained from projective measurements on a singlet can be reproduced, with the correlation (measured by mutual information) between Alice's choice and local variables less than or equal to a single bit.Comment: 5 pages, 1 figure. v2 Various improvements in presentation. Results unchange

Addressing Adversities in Caring for Mental Health in Rural Settings: A Conversation with Rural Mental Healthcare Practice Co-founder Dr. Taryn S. Van Gilder-Pierce

Due to lack of mental healthcare facilities in rural areas, the population often resorts to private practice practitioners to address their need for mental health services. Dr. Taryn S. Van Gilder-Pierce and her husband, Dr. William D. Pierce founded their private practice in Yankton, SD in 2001. She has more than 25 years of training and experience treating individuals, married couples, families, and groups in rural South Dakota. The interview delves into the challenges faced by early career professionals in building a practice in remote areas and extends into the room for expansion within the field of rural mental health provision of services

The local content of all pure two-qubit states

The (non-)local content in the sense of Elitzur, Popescu, and Rohrlich (EPR2) [Phys. Lett. A 162, 25 (1992)] is a natural measure for the (non-)locality of quantum states. Its computation is in general difficult, even in low dimensions, and is one of the few open questions about pure two-qubit states. We present a complete solution to this long-lasting problem.Comment: 9 pages, 3 figure

Non-realism : deep thought or a soft option ?

The claim that the observation of a violation of a Bell inequality leads to an alleged alternative between nonlocality and non-realism is annoying because of the vagueness of the second term.Comment: 5 page

uPAR Induces Expression of Transforming Growth Factor β and Interleukin-4 in Cancer Cells to Promote Tumor-Permissive Conditioning of Macrophages

Cancer cells condition macrophages and other inflammatory cells in the tumor microenvironment so that these cells are more permissive for cancer growth and metastasis. Conditioning of inflammatory cells reflects, at least in part, soluble mediators (such as transforming growth factor β and IL-4) that are released by cancer cells and alter the phenotype of cells of the innate immune system. Signaling pathways in cancer cells that potentiate this activity are incompletely understood. The urokinase receptor (uPAR) is a cell-signaling receptor known to promote cancer cell survival, proliferation, metastasis, and cancer stem cell–like properties. The present findings show that uPAR expression in diverse cancer cells, including breast cancer, pancreatic cancer, and glioblastoma cells, promotes the ability of these cells to condition co-cultured bone marrow–derived macrophages so that the macrophages express significantly increased levels of arginase 1, a biomarker of the alternatively activated M2 macrophage phenotype. Expression of transforming growth factor β was substantially increased in uPAR-expressing cancer cells via a mechanism that requires uPA-initiated cell signaling. uPAR also controlled expression of IL-4 in cancer cells via a mechanism that involves activation of ERK1/2. The ability of uPAR to induce expression of factors that condition macrophages in the tumor microenvironment may constitute an important mechanism by which uPAR promotes cancer progression