A novel plant toxin, persin, with in vivo activity in the mammary gland, induces Bim-dependent apoptosis in human breast cancer cells

Phytochemicals have provided an abundant and effective source of therapeutics for the treatment of cancer. Here we describe the characterization of a novel plant toxin, persin, with in vivo activity in the mammary gland and a p53-, estrogen receptor-, and Bcl-2-independent mode of action. Persin was previously identified from avocado leaves as the toxic principle responsible for mammary gland-specific necrosis and apoptosis in lactating livestock. Here we used a lactating mouse model to confirm that persin has a similar cytotoxicity for the lactating mammary epithelium. Further in vitro studies in a panel of human breast cancer cell lines show that persin selectively induces a G(2)-M cell cycle arrest and caspase-dependent apoptosis in sensitive cells. The latter is dependent on expression of the BH3-only protein Bim. Bim is a sensor of cytoskeletal integrity, and there is evidence that unique structure of the compound, persin could represent a novel class of microtubule-targeting agent with potential specificity for breast cancers.

Physical activity and strength of the femoral neck during the adolescent growth spurt: A longitudinal analysis

Loading of the femoral neck (FN) is dominated by bending and compressive stresses. We hypothesize that adaptation of the FN to physical activity would be manifested in the cross-sectional area (CSA) and section modulus (Z) of bone, indices of axial and bending strength, respectively. We investigated the influence of physical activity on bone strength during adolescence using 7 years of longitudinal data from 109 boys and 121 girls from the Saskatchewan Paediatric Bone and Mineral Accrual Study (PBMAS). Physical activity data (PAC-Q physical activity inventory) and anthropometric measurements were taken every 6 months and DXA bone scans were measured annually (Hologic QDR2000, array mode). We applied hip structural analysis to derive strength and geometric indices of the femoral neck using DXA scans. To control for maturation, we determined a biological maturity age defined as years from age at peak height velocity (APHV). To account for the repeated measures within individual nature of longitudinal data, multilevel random effects regression analyses were used to analyze the data. When biological maturity age and body size (height and weight) were controlled, in both boys and girls, physical activity was a significant positive independent predictor of CSA and Z of the narrow region of the femoral neck (P < 0.05). There was no independent effect of physical activity on the subperiosteal width of the femoral neck. When leg length and leg lean mass were introduced into the random effects models to control for size and muscle mass of the leg (instead of height and weight), all significant effects of physical activity disappeared. Even among adolescents engaged in normal levels of physical activity, the statistically significant relationship between physical activity and indices of bone strength demonstrate that modifiable lifestyle factors like exercise play an important role in optimizing bone strength during the growing years. Physical activity differences were explained by the interdependence between activity and lean mass considerations. Physical activity is important for optimal development of bone strength. (c) 2005 Elsevier Inc. All rights reserved.

Size-corrected BMD decreases during peak linear growth: Implications for fracture incidence during adolescence

Peak adolescent fracture incidence at the distal end of the radius coincides with a decline in size-corrected BMD in both boys and girls. Peak gains in bone area preceded peak gains in BMC in a longitudinal sample of boys and girls, supporting the theory that the dissociation between skeletal expansion and skeletal mineralization results in a period of relative bone weakness. Introduction: The high incidence of fracture in adolescence may be related to a period of relative skeletal fragility resulting from dissociation between bone expansion and bone mineralization during the growing years. The aim of this study was to examine the relationship between changes in size-corrected BMD (BMDsc) and peak distal radius fracture incidence in boys and girls. Materials and Methods: Subjects were 41 boys and 46 girls measured annually (DXA; Hologic 2000) over the adolescent growth period and again in young adulthood. Ages of peak height velocity (PHV), peak BMC velocity (PBMCV), and peak bone area (BA) velocity (PBAV) were determined for each child. To control for maturational differences, subjects were aligned on PHV. BMDsc was calculated by first regressing the natural logarithms of BMC and BA. The power coefficient (pc) values from this analysis were used as follows: BMDsc = BMC/BA(pc). Results: BMDsc decreased significantly before the age of PHV and then increased until 4 years after PHV. The peak rates in radial fractures (reported from previous work) in both boys and girls coincided with the age of negative velocity in BMDsc; the age of peak BA velocity (PBAV) preceded the age of peak BMC velocity (PBMCV) by 0.5 years in both boys and girls. Conclusions: There is a clear dissociation between PBMCV and PBAV in boys and girls. BMDsc declines before age of PHV before rebounding after PHV. The timing of these events coincides directly with reported fracture rates of the distal end of the radius. Thus, the results support the theory that there is a period of relative skeletal weakness during the adolescent growth period caused, in part, by a draw on cortical bone to meet the mineral demands of the expanding skeleton resulting in a temporary increased fracture risk.

Brachial blood pressure but not carotid arterial waveforms predict cardiovascular events in elderly female hypertensives

Central arterial waveforms and related indices of large artery properties can be determined with relative ease. This would make them an attractive adjunct in the risk stratification for cardiovascular disease. Although they have been associated with some classical risk factors and the presence of coronary disease, their prospective value in predicting cardiovascular outcomes is unknown. The present study determined the relative predictive value for cardiovascular disease-free survival of large artery properties as compared with noninvasive brachial blood pressure alone in a population of elderly female hypertensive subjects. We measured systemic arterial compliance, central systolic pressure, and carotid augmentation index in a subset of female participants in the Second Australian National Blood Pressure Study ( untreated blood pressure 169/88 +/- 12/ 8 mm Hg). There were a total of 53 defined events during a median of 4.1 years of follow-up in 484 women with complete measurements. Although baseline blood pressures at the brachial artery predicted cardiovascular disease-free survival ( hazard ratio [HR], 2.3; 95% CI, 1.3 to 4.1 for pulse pressure >= 81 versus < 81 mm Hg; P = 0.01), no such relation was found for carotid augmentation index ( HR, 0.80; 95% CI, 0.44 to 1.44; P value not significant) or systemic arterial compliance ( HR, 1.25; 95% CI, 0.72 to 2.16; P value not significant). Blood pressure, but not noninvasively measured central arterial waveforms, predict outcome in the older female hypertensive patient. Thus, blood pressure measurement alone is superior to measurement of arterial waveforms in predicting outcome in this group.

Expression of the human cachexia-associated protein (HCAP) in prostate cancer and in a prostate cancer animal model of cachexia

Prostate cancer (CaP) patients with disseminated disease often suffer from severe cachexia, which contributes to mortality in advanced cancer. Human cachexia-associated protein (HCAP) was recently identified from a breast cancer library based on the available 20-amino acid sequence of proteolysis-inducing factor (PIF), which is a highly active cachectic factor isolated from mouse colon adenocarcinoma MAC16. Herein, we investigated the expression of HCAP in CaP and its potential involvement in CaP-associated cachexia. HCAP mRNA was detected in CaP cell lines, in primary CaP tissues and in its osseous metastases. In situ hybridization showed HCAP mRNA to be localized only in the epithelial cells in CaP tissues, in the metastatic foci in bone, liver and lymph node, but not in the stromal cells or in normal prostate tissues. HCAP protein was detected in 9 of 14 CaP metastases but not in normal prostate tissues from cadaveric donors or patients with organ-confined tumors. Our Western blot analysis revealed that HCAP was present in 9 of 19 urine specimens from cachectic CaP patients but not in 19 urine samples of noncachectic patients. HCAP mRNA and protein were also detected in LuCaP 35 and PC-3M xenografts from our cachectic animal models. Our results demonstrated that human CaP cells express HCAP and the expression of HCAP is associated with the progression of CaP and the development of CaP cachexia. © 2003 Wiley-Liss, Inc.

A legal perspective of integrated surface mining, solid waste landfill reclamation and land conservation

In the area of international environmental law this thesis proposes the formulation of one-step planning and permitting regulation for the integrated utilisation of new surface mines as depositories for municipal solid waste. Additionally, the utilisation of abandoned and currently operated surface mines is proposed as solid waste landfills as an integral step in their reclamation. Existing laws, litigation and issues in the United Kingdom, the U.S. and Canada are discussed because of their common legal system, language and heritage. The critical shortage of approved space for disposal of solid waste has caused an urgent and growing problem for both the waste disposal industry and society. Surface mining can serve three important environmental and societal functions inuring to the health and welfare of the public: (1) providing basic minerals for goods and construction; (20 sequentially, to provide critically needed, safe burial sites for society's wastes, and (3) to conserve land by dual purpose use and to restore derelict land to beneficial surface use. Currently, the first two functions are treated environmentally, and in regulation, as two different siting problems, yet they both are earth-disturbing and excavating industries requiring surface restoration. The processes are largely duplicative and should be combined for better efficiency, less earth disturbance, conservation of land, and for fuller and better reclamation of completed surface mines returning the surfaces to greater utility than present mined land reclamation procedures. While both industries are viewed by a developed society and its communities as "bad neighbours", they remain essential and critical for mankind's existence and welfare. The study offers successful examples of the integrated process in each country. The study argues that most non-fuel surface mine openings, if not already safe, can economically, through present containment technology, be made environmentally safe for use as solid waste landfills. Simultaneously, the procedure safeguards and monitors protection of ground and surface waters from landfill contamination.

EP4 prostanoid receptor-mediated vasodilatation of human middle cerebral arteries

1 Dilatation of the cerebral vasculature is recognised to be involved in the pathophysiology of migraine. Furthermore, elevated levels of prostaglandin E2 (PGE2) occur in the blood, plasma and saliva of migraineurs during an attack, suggestive of a contributory role. In the present study, we have characterised the prostanoid receptors involved in the relaxation and contraction of human middle cerebral arteries in vitro. 2 In the presence of indomethacin (3μM) and the TP receptor antagonist GR32191 (1 μM), PGE2 was found to relax phenylephrine precontracted cerebral arterial rings in a concentration-dependent manner (mean pEC50 8.0 ± 0.1, n = 5). 3 Establishment of a rank order of potency using the EP4 > EP2 agonist 11-deoxy PGE1, and the EP2 > EP4 agonist PGE1-OH (mean pEC 50 of 7.6 ± 0.1 (n = 6) and 6.4 ± 0.1 (n = 4), respectively), suggested the presence of functional EP4 receptors. Furthermore, the selective EP2 receptor agonist butaprost at concentrations < 1 μM failed to relax the tissues. 4 Blockade of EP 4 receptors with the EP4 receptor antagonists AH23848 and EP4A caused significant rightward displacements in PGE2 concentration-response curves, exhibiting pA2 and pKB values of 5.7 ± 0.1, n = 3, and 8.4, n = 3, respectively. 5 The IP receptor agonists iloprost and cicaprost relaxed phenylephrine precontracted cerebral arterial rings (mean pEC50 values 8.3 ± 0.1 (n = 4) and 8.1 ± 0.1 (n = 9), respectively). In contrast, the DP and FP receptor agonists PGD2 and PGFα2 failed to cause appreciable relaxation or contraction at concentrations of up to 30 μM. In the absence of phenylephrine contraction and GR32191, the TP receptor agonist U46619 caused concentration-dependent contraction of cerebral artery (mean pEC50 7.4 ± 0.3, n = 3). 6 These data demonstrate the presence of prostanoid EP4 receptors mediating PGE2 vasodilatation of human middle cerebral artery. IP receptors mediating relaxation and TP receptors mediating contraction were also functionally demonstrated.

Crack initiation in asphalt mixtures under external compressive loads

Crack initiation was studied for asphalt mixtures under external compressive loads. High tensile localized stresses e direction of the external loads. A quantitative crack initiation criterion the edges of compressed air voids lead to the growth of wing cracks in thon was derived using pseudostrain energy balance principle. Bond energy is determined and it increases with aging and loading rate while decreases with temperature. Cohesive and adhesive cracking occur simultaneously and a method was proposed to determine the individual percentage. The crack initiation criterion is simplified and validated through comparing the predicted and measured compressive strength of the asphalt mixtures.

Anisotropic characterization of crack growth in the tertiary flow of asphalt mixtures in compression

Asphalt mixtures exhibit primary, secondary, and tertiary stages in sequence during a rutting deterioration. Many field asphalt pavements are still in service even when the asphalt layer is in the tertiary stage, and rehabilitation is not performed until a significant amount of rutting accompanied by numerous macrocracks is observed. The objective of this study was to provide a mechanistic method to model the anisotropic cracking of the asphalt mixtures in compression during the tertiary stage of rutting. Laboratory tests including nondestructive and destructive tests were performed to obtain the viscoelastic and viscofracture properties of the asphalt mixtures. Each of the measured axial and radial total strains in the destructive tests were decomposed into elastic, plastic, viscoelastic, viscoplastic, and viscofracture strains using the pseudostrain method in an extended elastic-viscoelastic correspondence principle. The viscofracture strains are caused by the crack growth, which is primarily signaled by the increase of phase angle in the tertiary flow. The viscofracture properties are characterized using the anisotropic damage densities (i.e., the ratio of the lost area caused by cracks to the original total area in orthogonal directions). Using the decomposed axial and radial viscofracture strains, the axial and radial damage densities were determined by using a dissipated pseudostrain energy balance principle and a geometric analysis of the cracks, respectively. Anisotropic pseudo J-integral Paris' laws in terms of damage densities were used to characterize the evolution of the cracks in compression. The material constants in the Paris' law are determined and found to be highly correlated. These tests, analysis, and modeling were performed on different asphalt mixtures with two binders, two air void contents, and three aging periods. Consistent results were obtained; for instance, a stiffer asphalt mixture is demonstrated to have a higher modulus, a lower phase angle, a greater flow number, and a larger n1 value (exponent of Paris' law). The calculation of the orientation of cracks demonstrates that the asphalt mixture with 4% air voids has a brittle fracture and a splitting crack mode, whereas the asphalt mixture with 7% air voids tends to have a ductile fracture and a diagonal sliding crack mode. Cracks of the asphalt mixtures in compression are inclined to propagate along the direction of the external compressive load. © 2014 American Society of Civil Engineers.

Mechanistic modeling of fracture in asphalt mixtures under compressive loading

When an asphalt mixture is subjected to a destructive compressive load, it experiences a sequence of three deformation stages, as follows: the (1) primary, (2) secondary, and (3) tertiary stages. Most literature research focuses on plastic deformation in the primary and secondary stages, such as prediction of the flow number, which is in fact the initiation of the tertiary stage. However, little research effort has been reported on the mechanistic modeling of the damage that occurs in the tertiary stage. The main objective of this paper is to provide a mechanistic characterizing method for the damage modeling of asphalt mixtures in the tertiary stage. The preliminary study conducted by the writers illustrates that deformation during the tertiary flow of the asphalt mixtures is principally caused by the formation and propagation of cracks, which was signaled by the increase of the phase angle in the tertiary phase. The strain caused by the growth of cracks is the viscofracture strain, which can be obtained by conducting the strain decomposition of the measured total strain in the destructive compressive test. The viscofracture strain is employed in the research reported in this paper to mechanistically characterize the time-dependent fracture (viscofracture) of asphalt mixtures in compression. By using the dissipated pseudostrain energy-balance principle, the damage density and true stress are determined and both are demonstrated to increase with load cycles in the tertiary stage. The increased true stress yields extra viscoplastic strain, which is the reason why the permanent deformation is accelerated by the occurrence of cracks. To characterize the evolution of the viscofracture in the asphalt mixtures in compression, a pseudo J-integral Paris' law in terms of damage density is proposed and the material constants in the Paris' law are determined, which can be employed to predict the fracture of asphalt mixtures in compression. © 2013 American Society of Civil Engineers.

Characterization of viscoplastic yielding of asphalt concrete

A temperature and strain rate dependent yield surface model was proposed to characterize the viscoplastic yielding of asphalt concrete. Laboratory tests were conducted on specimens that have two binders, two air void contents, and three aging periods. Strain decomposition was performed to obtain viscoplastic strain and stress-pseudostrain curves were constructed to determine the model parameters accurately and efficiently. Results indicate that a stiffer asphalt concrete has greater cohesion and strain hardening amplitude, both of which decline as temperature increases or strain rate decreases. The temperature and strain rate factors of the yield surface can be accurately determined solely by the peak stress of the strength tests. © 2013 Elsevier Ltd. All rights reserved.

Characterizing permanent deformation and fracture of asphalt mixtures by using compressive dynamic modulus tests

Permanent deformation and fracture may develop simultaneously when an asphalt mixture is subjected to a compressive load. The objective of this research is to separate viscoplasticity and viscofracture from viscoelasticity so that the permanent deformation and fracture of the asphalt mixtures can be individually and accurately characterized without the influence of viscoelasticity. The undamaged properties of 16 asphalt mixtures that have two binder types, two air void contents, and two aging conditions are first obtained by conducting nondestructive creep tests and nondestructive dynamic modulus tests. Testing results are analyzed by using the linear viscoelastic theory in which the creep compliance and the relaxation modulus are modeled by the Prony model. The dynamic modulus and phase angle of the undamaged asphalt mixtures remained constant with the load cycles. The undamaged asphalt mixtures are then used to perform the destructive dynamic modulus tests in which the dynamic modulus and phase angle of the damaged asphalt mixtures vary with load cycles. This indicates plastic evolution and crack propagation. The growth of cracks is signaled principally by the increase of the phase angle, which occurs only in the tertiary stage. The measured total strain is successfully decomposed into elastic strain, viscoelastic strain, plastic strain, viscoplastic strain, and viscofracture strain by employing the pseudostrain concept and the extended elastic-viscoelastic correspondence principle. The separated viscoplastic strain uses a predictive model to characterize the permanent deformation. The separated viscofracture strain uses a fracture strain model to characterize the fracture of the asphalt mixtures in which the flow number is determined and a crack speed index is proposed. Comparisons of the 16 samples show that aged asphalt mixtures with a low air void content have a better performance, resisting permanent deformation and fracture. © 2012 American Society of Civil Engineers.

Microstructure-based inherent anisotropy of asphalt mixtures

Asphalt mixtures have been demonstrated to be anisotropic materials in both laboratory and field tests. The anisotropy of asphalt mixtures consists of inherent anisotropy and stress-induced anisotropy. In previous work, the inherent anisotropy of asphalt mixtures was quantified by using only the inclination angles of the coarse aggregate particles in the asphalt mixtures. However, the inclination of fine aggregates also has a contribution to the inherent anisotropy. Moreover, the contribution to the inherent anisotropy of each aggregate may not be the same as in the previous work but will depend on the size, orientation, and sphericity of the aggregate particle. This paper quantifies the internal microstructure of the aggregates in asphalt mixtures by using an aggregate-related geometric parameter, the vector magnitude. The original formulation of the vector magnitude, which addresses only the orientation of coarse aggregates, is modified to account for not only the coarse aggregate orientation, but also the size, orientation, and sphericity of coarse and fine aggregates. This formulation is applied to cylindrical lab-mixed lab-compacted asphalt mixture specimens varying in asphalt binder type, air void content, and aging period. The vertical modulus and the horizontal modulus are also measured by using nondestructive tests. A relationship between the modified vector magnitude and the modulus ratio of the vertical modulus to the horizontal modulus is developed to quantify the influence of the inherent microstructure of the aggregates on the anisotropy of the mixtures. The modulus ratio is found to depend solely on the aggregate characteristics including the inclination angle, size, and sphericity, and it is independent of the asphalt binder type, air void content, and aging period. The inclination angle, itself, proves to be insufficient to quantify the inherent anisotropy of the asphalt mixtures. © 2011 American Society of Civil Engineers.

Anisotropic viscoelastic properties of undamaged asphalt mixtures

A test protocol and a data analysis method are developed in this paper on the basis of linear viscoelastic theory to characterize the anisotropic viscoelastic properties of undamaged asphalt mixtures. The test protocol includes three nondestructive tests: (1) uniaxial compressive creep test, (2) indirect tensile creep test, and (3) the uniaxial tensile creep test. All three tests are conducted on asphalt mixture specimens at three temperatures (10, 20, and 30°C) to determine the tensile and compressive properties at each temperature and then to construct the master curve of each property. The determined properties include magnitude and phase angle of the compressive complex modulus in the vertical direction, magnitude and phase angle of the tensile complex modulus, and the magnitude and phase angle of the compressive complex modulus in the horizontal plane. The test results indicate that all tested asphalt mixtures have significantly different tensile properties from compressive properties. The peak value of the master curve of the tensile complex modulus phase angle is within a range from 65 to 85°, whereas the peak value of the compressive moduli phase angle in both directions ranges from 35 to 55°. In addition, the undamaged asphalt mixtures exhibit distinctively anisotropic properties in compression. The magnitude of the compressive modulus in the vertical direction is approximately 1.2 to ̃2 times of the magnitude of the compressive modulus in the horizontal plane. Dynamic modulus tests are performed to verify the results of the proposed test protocol. The test results from the proposed test protocol match well with those from the dynamic tests. © 2012 American Society of Civil Engineers.