A Cholecystokinin B Receptor-Specific Aptamer Does Not Activate Receptor Signaling

Targeted nanoparticles which deliver effective doses of chemotherapeutic drugs directly to pancreatic tumors could improve treatment efficacy without the toxicities associated with systemic drug administration. One protein on tumor cells that can be targeted by nanoparticles is a G-protein coupled cell surface receptor, the cholecystokinin B receptor (CCKBR). Previously, we had shown that attaching the CCKBR ligand gastrin to the surface of nanoparticles can enhance their up-take by tumors. The drawback of using gastrin is that it can also activate the receptor, causing tumor cell growth. This study shows that a DNA aptamer that binds to the CCKBR and enhances nanoparticle up-take by tumors does not activate this receptor. PANC-1 cells, a cultured human pancreatic cancer cell line, were treated for 24 h with CCKBR aptamer 1153. Cell lysates were run on Bis-Tris gels, transferred to membranes, blocked in 5% BSA and incubated overnight with primary antibodies, including antibodies directly against phosphorylated-Akt (Ser473), total Akt, and beta-actin, a protein loading control. Although the CCKBR aptamer 1153 is internalized by pancreatic cancer cells in a receptor-mediated fashion, it does not stimulate cell proliferation. Because of this, we anticipate that it will not activate CCKBR signaling. If aptamer 1153 does not activate downstream receptor signaling, our future work will test whether the aptamer could be used to specifically direct drug-containing nanoparticles to tumors, making chemotherapy treatments for pancreatic cancer patients more effective with fewer off-target effects and toxicity

Trunk muscle activity during dynamic exercises on land and in water for participants with and without chronic low back pain

Aquatic exercise is beneficial in managing Chronic Low Back Pain (CLBP), however information is lacking as to which exercises are appropriate for targeting specific muscle groups. Whilst there is greater understanding of trunk and hip muscle activation patterns on land, few studies have quantified activation patterns during aquaticrehabilitation exercises, and no studies have measured trunk muscle activity in adults with CLBP in an aquatic environment.The purpose of this study is to evaluate muscle activity in people with CLBP and controls in water and on land when they perform exercises involving dynamic upper and lower limb movements with a stable trunk and pelvis

Acyl-coenzyme a:Cholesterol Acyltransferase Promotes Oxidized LDL/Oxysterol-Induced Apoptosis in Macrophages

7-Ketocholesterol (7KC) is a cytotoxic component of oxidized low density lipoproteins (OxLDLs) and induces apoptosis in macrophages by a mechanism involving the activation of cytosolic phospholipase A2 (cPLA 2). In the current study, we examined the role of ACAT in 7KC-induced and OxLDL-induced apoptosis in murine macrophages. An ACAT inhibitor, Sandoz 58-035, suppressed 7KC-induced apoptosis in P388D1 cells and both 7KC-induced and OxLDL-induced apoptosis in mouse peritoneal macrophages (MPMs). Furthermore, compared with wild-type MPMs, ACAT-1-deficient MPMs demonstrated significant resistance to both 7KC-induced and OxLDL-induced apoptosis. Macrophages treated with 7KC accumulated ACAT-derived [14C]cholesteryl and [ 3H]7-ketocholesteryl esters. Tandem LC-MS revealed that the 7KC esters contained primarily saturated and monounsaturated fatty acids. An inhibitor of CPLA2, arachidonyl trifluoromethyl ketone, prevented the accumulation of 7KC esters and inhibited 7KC-induced apoptosis in P388B1 cells. The decrease in 7KC ester accumulation produced by the inhibition of cPLA 2 was reversed by supplementing with either oleic or arachidonic acid (AA); however, only AA supplementation restored the induction of apoptosis by 7KC. These results suggest that 7KC not only initiates the apoptosis pathway by activating cPLA2, as we have reported previously, but also participates in the downstream signaling pathway when esterified by ACAT to form 7KC-arachidonate

Superconductivity in a Mesoscopic Double Square Loop: Effect of Imperfections

We have generalized the network approach to include the effects of short-range imperfections in order to analyze recent experiments on mesoscopic superconducting double loops. The presence of weakly scattering imperfections causes gaps in the phase boundary $B(T)$ or $\Phi(T)$ for certain intervals of $T$, which depend on the magnetic flux penetrating each loop. This is accompanied by a critical temperature $T_c(\Phi)$, showing a smooth transition between symmetric and antisymmetric states. When the scattering strength of imperfections increases beyond a certain limit, gaps in the phase boundary $T_c(B)$ or $T_c(\Phi)$ appear for values of magnetic flux lying in intervals around half-integer $\Phi_0=hc/2e$. The critical temperature corresponding to these values of magnetic flux is determined mainly by imperfections in the central branch. The calculated phase boundary is in good agreement with experiment.Comment: 9 pages, 6 figure

Macrophage mal1 deficiency suppresses atherosclerosis in low-density lipoprotein receptor-null mice by activating peroxisome proliferator-activated receptor-γ-regulated genes

Objective- The adipocyte/macrophage fatty acid-binding proteins aP2 (FABP4) and Mal1 (FABP5) are intracellular lipid chaperones that modulate systemic glucose metabolism, insulin sensitivity, and atherosclerosis. Combined deficiency of aP2 and Mal1 has been shown to reduce the development of atherosclerosis, but the independent role of macrophage Mal1 expression in atherogenesis remains unclear. Methods and Results- We transplanted wild-type (WT), Mal1, or aP2 bone marrow into low-density lipoprotein receptor-null (LDLR) mice and fed them a Western diet for 8 weeks. Mal1→LDLR mice had significantly reduced (36%) atherosclerosis in the proximal aorta compared with control WT→LDLR mice. Interestingly, peritoneal macrophages isolated from Mal1-deficient mice displayed increased peroxisome proliferator-activated receptor-γ (PPARγ) activity and upregulation of a PPARγ-related cholesterol trafficking gene, CD36. Mal1 macrophages showed suppression of inflammatory genes, such as COX2 and interleukin 6. Mal1→LDLR mice had significantly decreased macrophage numbers in the aortic atherosclerotic lesions compared with WT→LDLR mice, suggesting that monocyte recruitment may be impaired. Indeed, blood monocytes isolated from Mal1→LDLR mice on a high-fat diet had decreased CC chemokine receptor 2 gene and protein expression levels compared with WT monocytes. Conclusion- Taken together, our results demonstrate that Mal1 plays a proatherogenic role by suppressing PPARγ activity, which increases expression of CC chemokine receptor 2 by monocytes, promoting their recruitment to atherosclerotic lesions. © 2011 American Heart Association, Inc

Measurement of the Zero Crossing in a Feshbach Resonance of Fermionic 6-Li

We measure a zero crossing in the scattering length of a mixture of the two lowest hyperfine states of 6-Li. To locate the zero crossing, we monitor the decrease in temperature and atom number arising from evaporation in a CO2 laser trap as a function of magnetic field B. The temperature decrease and atom loss are minimized for B=528(4) G, consistent with no evaporation. We also present preliminary calculations using potentials that have been constrained by the measured zero crossing and locate a broad Feshbach resonance at approximately 860 G, in agreement with previous theoretical predictions. In addition, our theoretical model predicts a second and much narrower Feshbach resonance near 550 G.Comment: Five pages, four figure

Macrophage Mal1 Deficiency Suppresses Atherosclerosis in Low-Density Lipoprotein Receptor -Null Mice by Activating Peroxisome Proliferator-Activated Receptor-g-Regulated Genes

Cataloged from PDF version of article.Objective-The adipocyte/macrophage fatty acid-binding proteins aP2 (FABP4) and Mal1 (FABP5) are intracellular lipid chaperones that modulate systemic glucose metabolism, insulin sensitivity, and atherosclerosis. Combined deficiency of aP2 and Mal1 has been shown to reduce the development of atherosclerosis, but the independent role of macrophage Mal1 expression in atherogenesis remains unclear. Methods and Results-We transplanted wild-type (WT), Mal1(-/-), or aP2(-/-) bone marrow into low-density lipoprotein receptor-null (LDLR(-/-)) mice and fed them a Western diet for 8 weeks. Mal1(-/-)-> LDLR(-/-) mice had significantly reduced (36%) atherosclerosis in the proximal aorta compared with control WT -> LDLR(-/-) mice. Interestingly, peritoneal macrophages isolated from Mal1-deficient mice displayed increased peroxisome proliferator-activated receptor-gamma (PPAR gamma) activity and upregulation of a PPAR gamma-related cholesterol trafficking gene, CD36. Mal1(-/-) macrophages showed suppression of inflammatory genes, such as COX2 and interleukin 6. Mal1(-/-)-> LDLR(-/-) mice had significantly decreased macrophage numbers in the aortic atherosclerotic lesions compared with WT -> LDLR(-/-) mice, suggesting that monocyte recruitment may be impaired. Indeed, blood monocytes isolated from Mal1(-/-)-> LDLR(-/-) mice on a high-fat diet had decreased CC chemokine receptor 2 gene and protein expression levels compared with WT monocytes. Conclusion-Taken together, our results demonstrate that Mal1 plays a proatherogenic role by suppressing PPAR gamma activity, which increases expression of CC chemokine receptor 2 by monocytes, promoting their recruitment to atherosclerotic lesions. (Arterioscler Thromb Vasc Biol. 2011;31:1283-1290.

Experiences of living with chronic back pain: The physical disabilities

Purpose. Back-related functional limitations are largely assessed using lists of activities, each scored on a yes/no basis and the scores then summed. This provides little information about how chronic back pain (CBP) patients live with their condition. This study describes the consequences of living day-to-day with CBP and documents the 'insider' accounts of its impact on daily life. Method. Unstructured interviews, using the 'Framework' approach with topic guide, were recorded and transcribed verbatim. Subjects were sampled for age, sex, ethnicity and occupation from new referrals with back pain to a rheumatology outpatient clinic. Eleven subjects (5 male, 6 female) were interviewed either in English (n = 9) or their preferred language (n = 2). Interviews were read in-depth twice to identify the topics. Data were extracted in phrases and sentences using thematic content analysis. Results. Four themes emerged: sleep/rest, mobility, independence and leisure. All subjects reported issues about sleep and rest, nine about mobility, seven about independence and six on leisure. Most descriptions concerned loss and limitation in daily life. Strategies for coping with sleep disruption and physical limitations were described. Conclusions. Subjects provided graphic 'in-depth' descriptions of experiences living with CBP every day; expressed regret at the loss of capabilities and distress at the functional consequences of those losses. Facilitating 'adjustment' to 'loss' may be more helpful than inferring the potential for a life free of pain as a result of therapeutic endeavours