Despite 2 decades of research, no clear function for annexin A1 (AnxA1) has been established. Using AnxA1-KO mice, we show that tumor growth and metastasis are significantly decreased, whereas rodent survival and tumor necrosis are greatly increased when tumors grow in AnxA1-KO mice. Systems analysis of gene expression in these tumors specifically implicates 2 related vascular functions, angiogenesis and wound healing, in this impairment. Both tumor vascular development and wound healing are greatly retarded in KO tissues. Aortic ring assays reveal induced AnxA1 expression on sprouting endothelial cells of normal mice whereas KO aortas exhibit impaired endothelial cell sprouting that is rescued by adenoviral expression of AnxA1. Key differences in specific gene regulation may define new molecular pathways mediating angiogenesis, including a reset profile of pro-versus anti-angiogenic factors, apparently distinct for physiological versus pathological angiogenesis. These studies establish novel pro-angiogenic functions for AnxA1 in vascular endothelial cell sprouting, wound healing, and tumor growth and metastasis, thereby uncovering a new functional target for repairing damaged tissue and treating diseases such as cancer. They also provide critical new evidence that the tumor stroma and its microenvironment can greatly affect tumor progression and metastasis.systems biology ͉ tumor vasculature ͉ tumor microenvironment ͉ cancer targets A nnexin A1 (AnxA1) was originally described as an antiphospholipase A2 and glucocorticoid-inducible 37-kDa protein (1) and later cloned and identified as a member of the annexin superfamily of calcium-dependent phospholipid binding proteins (2). Although the exact function of AnxA1 remains unknown, it likely plays an important role in inflammation, leukocyte migration and accumulation, and phagocytosis (3). Other functions have been suggested, including cell signaling, apoptosis, and membrane trafficking (3). Yet AnxA1-KO mice are born without apparent developmental abnormalities that would support any singular or predominant function (4).Recently, AnxA1 was discovered by subtractive proteomic mapping to be selectively expressed in vivo on the outer luminal surface of tumor but not normal vascular endothelial cells (ECs), where it can interact with specific antibodies injected intravenously to allow tumor-specific immuno-targeting and imaging (5). Targeted radioimmunotherapy greatly enhanced rat survival, even with advanced solid tumors (5). Immunohistochemistry confirms selective vascular expression in human tumors. Here, we hypothesize that tumor-induced vascular expression of AnxA1 is functionally important for tumor development. Using KO mice, we show that AnxA1 expression by host tissues can significantly influence tumor growth and metastasis in vivo. Inability to express AnxA1 disrupts EC function in angiogenesis and the expression of specific genes that define distinct molecular pathways mediating angiogenesis and wound healing. ResultsTo study the effects of AnxA1 on tumor ...
Mutations in the phosphotyrosine-binding domain protein ARH cause autosomal recessive hypercholesterolemia (ARH), an inherited form of hypercholesterolemia due to a tissue-specific defect in the removal of low density lipoproteins (LDL) from the circulation. LDL uptake by the LDL receptor (LDLR) is markedly reduced in the liver but is normal or only moderately impaired in cultured fibroblasts of ARH patients. To define the molecular mechanism underlying ARH we examined ARH mRNA and protein in fibroblasts and lymphocytes from six probands with different ARH mutations. None of the probands had detectable full-length ARH protein in fibroblasts or lymphoblasts. Five probands were homozygous for mutations that introduced premature termination codons. No relationship was apparent between the site of the mutation in ARH and the amount of mRNA. The only mutation identified in the remaining proband was a SINE VNTR Alu (SVA) retroposon insertion in intron 1, which was associated with no detectable ARH mRNA. (125)I-LDL degradation was normal in ARH fibroblasts, as previously reported. In contrast, LDLR function was markedly reduced in ARH lymphoblasts, despite a 2-fold increase in LDL cell surface binding in these cells. These data indicate that all ARH mutations characterized to date preclude the synthesis of full-length ARH and that ARH is required for normal LDLR function in lymphocytes and hepatocytes, but not in fibroblasts. Residual LDLR function in cells that do not require ARH may explain why ARH patients have lower plasma LDL levels than do patients with homozygous familial hypercholesterolemia who have no functional LDLRs.
Lower thermal conductivity of background tissues significantly increases temperatures within a defined ablation target. These findings provide insight into the 'oven effect' (i.e. increased heating efficacy for tumours surrounded by cirrhotic liver or fat) and highlight the importance of both the tumour and the surrounding tissue characteristics when contemplating RF ablation efficacy.
ObjectivesThis study aimed to identify factors that influence people’s willingness to volunteer and participation in emergency volunteering in northern China.Design/SettingThis study was conducted in Heilongjiang province in September and October 2014 using a mixed methods approach, which included a cross-sectional questionnaire survey on community residents and in–depth interviews with community residents and relevant organisational managers and officials in relation to emergency responses. A stratified cluster sampling strategy was employed to select questionnaire respondents.Participants2686 respondents completed the questionnaire survey; 19 key informants were interviewed.Primary and secondary outcome measuresWillingness to volunteer was the major concern of this study. Self-reported past experience of the participants in emergency volunteering served as a secondary outcome.Results65.7% of respondents were willing to volunteer in emergencies. 24.3% of respondents had participated in emergency actions. Higher levels of willingness to volunteer and participation in volunteering were found in those who resided in rural areas (OR=1.308 (1.064 to 1.608) for willingness; OR=1.518 (1.208 to 1.908) for participation), had stronger community attachment (OR=1.720 (1.429 to 2.069) for willingness; OR=1.547 (1.266 to 1.890) for participation), had higher recognition of responsibility (OR=1.981 (1.498 to 2.619) for willingness; OR=1.517 (1.177 to 1.955) for participation), demonstrated preparedness behaviour (OR=1.714 (1.424 to 2.064) for willingness; OR=1.391 (1.151 to 1.681) for participation) and were covered by injury insurance (OR=1.335 (1.102 to 1.619) for willingness; OR=1.822 (1.500 to 2.214) for participation). The in-depth interviews revealed that an inappropriate policy environment and poor volunteer organisational management were major barriers for converting willingness into actions.ConclusionA relatively high level of willingness to volunteer in emergencies in northern China is associated with a range of individual, community and institutional factors. Efforts should be made to translate willingness into effective contributions to the emergency response system. This can be done through improving policies, regulations, coordination mechanisms and volunteer training and support.
By coupling the asymmetric three-terminal mesoscopic dielectric system with a temperature probe, at low temperature, the ballistic heat flux flow through the other two asymmetric terminals in the nonlinear response regime is studied based on the Landauer formulation of transport theory. The thermal rectification is attained at the quantum regime. It is a purely quantum effect and is determined by the dependence of the ratio τ RC (ω)/τ RL (ω) on ω, the phonon's frequency. Where τ RC (ω) and τ RL (ω) are respectively the transmission coefficients from two asymmetric terminals to the temperature probe, which are determined by the inelastic scattering of ballistic phonons in the temperature probe. Our results are confirmed by extensive numerical simulations.
Laser-induced spin-wave dynamics in an in-plane magnetized FePt film is studied using all-optical pump-probe magneto-optical Kerr spectroscopy under different external fields and pump fluences. Uniform precession spin wave is observed. Nonlinear external field dependence of its frequency is found and well explained by the macrospin model of uniform precession. The effective damping shows a significant external-field dependence. Calculation taking account for magnetic inhomogeneity fits the external-field dependence well, revealing main magnetic inhomogeneity origin of the extrinsic damping. An intrinsic Gilbert damping parameter of <0.028 is inferred and shows potential applications of this film in magnonics.
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