bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Failure Effect Analysis of Composite High-Speed Flywheel Rotors
Authors: Fischer G , Grothaus R , Hufenbach W
Published: April 2008

Due to their high specific strength and the possibility of creating a load-adapted property profile, composite materials are ideally suited for the design of high-speed flywheel rotors. The rotors are exposed to extreme loading conditions by high centrifugal forces, partially superposed by elevated temperatures due to an integrated electrical machine, bearings or air friction.

A sophisticated fail-safe design of composite flywheel rotors has been applied here, which allows the rotor to fail catastrophically. To withstand the manifold burst behavior safely the exact loading of the containment must be known within a simultaneous engineering approach of rotor and containment. Therefore, adapted rotor rigs and devices for measuring the burst effects in the axial, radial and circumferential direction have been designed and successfully tested. Experimental failure studies on the fiber composite flywheel rims prove the manifold burst behavior and containment interactions. Extreme axial shock waves due to the composite fragment movement have been measured experimentally, which are principally not known for isotropic rotor failure.
Assessment of Composite Containment Loadings by an Adapted Failure Effect Analysis
Authors: Hufenbach W , Grothaus R
Published: April 2008

Principal different rotor failure modes require adapted design approaches for the design of composite containments. The Hagg/Shankey approach considers the brittle fracture of isotropic rotors and the subsequent impact of large fragments in containment rings. Other approaches are based on multi-fragmentation, which is typical for rotors made of composite materials. This failure mode assumes a composite dust rather than large fragments. The physical model is more complex and only first semi-empirical ideas have been formulated to describe the post-failure effects on the containment.

The composite dust has the potential to cause a carbon dust explosion but rather often also results in a composite particle flow. This latter effect has already been observed in practical applications. Due to recent advances in experimental composite rotor failure assessment, this manifold burst behavior with axial shock waves not known for metallic rotors, could be proved principally.

Two different theories to analyze these “dust” failure effects are theoretically analyzed concerning their physical plausibility. A comparison with experimental data is presented and the general assessment of these semi-empirical approaches is used to estimate containment loading limits.
Long-Term Strain-Corrosion Behavior in RPM Sewer Pipes
Authors: Hopkins SW , Duffner DH , Johnston PR , McGarry FJ
Published: April 2008

The mechanical properties of reinforced plastic mortar (RPM) pipe material are typically measured prior to production in order to establish design properties, and during production to ensure quality of the pipe material. Seldom does the opportunity become available to measure the mechanical properties of service-aged (conditioned) components. In this paper, the short-term properties of the service-aged pipes are compared with the original production specifications. The long-term, strain-corrosion cracking properties have also been measured during the past 10 years on these service-aged pipes. Some laboratory specimens still have not failed after 10 years under test.

Reinforced plastic mortar (RPM) pipes were excavated from the ground after about 15 years of sewer service, and material coupons from these pipes were subjected to various mechanical tests. Axial-direction tensile tests, hoop-direction stiffness, and acid strain-corrosion testing were performed. The acid strain corrosion tests were monitored as a function of time until failure. The resulting lifetimes were related to the initial surface strains and showed a decreasing logarithmic relationship for both concentrations of the sulfuric acid solutions. Some pipe samples have been under test for 10 years, and prior to this testing were buried in the ground, and used as sewer pipes for 15 years.

The failed laboratory specimens were compared by fractographic examination with those from in-service failures. Laboratory specimens that failed in shorter times appeared to be overload in nature and exhibited little, if any, time-dependent fracture surface features. In-service failures indicate that the crack had been present for a significant time. Comparisons are also made between the observed fractographic appearance of the fibers and the laboratory failure time for both pH values.
Experimental and Computational Characterization of the High Strain Rate Tensile Response of Polymer Matrix Composites
Authors: Goldberg RK , Gilat A
Published: April 2008

A research program is underway to experimentally characterize the strain rate dependent deformation and failure response of polymer matrix composites subject to high strain rate impact loads and to develop strain rate dependent deformation and failure models for the analysis of these types of materials. State variable constitutive equations based on a viscoplasticity approach have been developed to model the deformation of the polymer matrix. The constitutive equations are then combined with a mechanics of materials based micromechanics model which utilizes fiber substructuring to predict the effective mechanical and thermal response of the composite. Tensile stress-strain curves for a representative composite are obtained experimentally for strain rates ranging from quasi-static to several hundred per second. The developed numerical procedure is also used to compute the deformation response. The predictions compare favorably to the experimentally obtained values both qualitatively and quantitatively. Effective elastic and thermal constants are predicted for another composite, and compared to finite element results.
Computational Simulation of Composite Fracture Toughness Parameters
Authors: Zhang H , Minnetyan L , Chamis CC
Published: April 2008

Energy release rate G and critical value of stress intensity factor K are usually suggested as two types of parameters for characterizing material toughness. Computational prediction of energy release rate is based on composite mechanics with micro-stress level damage assessment, finite element structural analysis and damage progression tracking modules. In this paper, Mode I interlaminar and intralaminar fracture toughness GIC of composites are examined by computational simulation. Results show that computational simulation has a good predictive capability for monitoring damage progression in composites. Computational simulation enables assessment of the damage initiation and propagation loads. Because fracture toughness tests on composites are time consuming, difficult and expensive, computational simulation can be used prior to testing. Through simulation, sensitive parameters affecting fracture toughness are identified, which significantly enhance the accuracy and productivity of experiments. Simulation results are compared with test data.
Tensile, Compressive, and Shear Response of a Particulate Reinforced Aluminum Composite
Authors: Lei X , Lissenden CJ
Published: April 2008

The effect that various loads have on a 6092/SiC/17.5p-T6 particulate reinforced aluminum composite is determined. In addition to the mechanical response from tensile, compressive, and shear loading, yield loci in the axial-shear stress plane are constructed using axial-torsional loading of a thin-walled tube. Yield loci are determined by multiple yield probes of a single specimen using a 40 × 10-6 equivalent offset strain definition of yielding. Cyclic tensile straining to increasingly higher amplitudes indicated a modulus reduction of 16% prior to fracture, strongly suggesting accumulation of internal damage, but no change in the elastic Poisson's ratio was observed. Cyclic compressive loading resulted in no observable change in modulus. Cyclic shear loading led to a minimal shear modulus reduction of approximately 6%. The initial yield locus in the axial-shear stress plane had an eccentricity in the compressive stress direction that is known as a strength differential. The strength-differential was measured to be 55% and is believed to be associated with thermal residual stresses from heat treatment. After shear prestraining subsequent yield loci were constructed. Hardening was observed to be primarily kinematic.
A Range of Practical Failure Criteria for Laminated Composites
Authors: Rousseau CQ
Published: April 2008

The purpose of this paper is to clarify when and where various composite failure criteria are most appropriate, and why, based on structural requirements and the physics of failure. Structural requirements and the structural criticality of a given part determine the level of analysis detail appropriate in product development. Similar practical considerations suggest the level of analysis detail in phases such as predesign technology development and failure analysis. The level of analysis detail drives the choice of failure criterion. A modern understanding of the physics of laminated composite structural failure is provided as a basis for discussing the merits of various failure criteria. A wide range of failure criteria is cited (from physically and computationally simple to complex), and their advantages and disadvantages briefly discussed. Finally, decision trees are presented for the appropriate choice of a criterion, given various structural design scenarios.
A Criterion to Control Nonlinear Error in the Mixed-Mode Bending Test
Authors: Reeder JR
Published: April 2008

The mixed-mode bending test has been widely used to measure delamination toughness and was recently standardized by ASTM as Standard Test Method D6671-01. This simple test is a combination of the standard Mode I (opening) test and a Mode II (sliding) test. This test uses a unidirectional composite test specimen with an artificial delamination subjected to bending loads to characterize when a delamination will extend. When the displacements become large, the linear theory used to analyze the results of the test yields errors in the calculated toughness values. The current standard places no limit on the specimen loading and therefore test data can be created using the standard that are significantly in error. A method of limiting the error that can be incurred in the calculated toughness values is needed. In this paper, nonlinear models of the MMB test are refined. One cf the nonlinear models is then used to develop a simple criterion for prescribing conditions where the nonlinear error will remain below 5%.
Observational Study on Fall Trends in Snowboarders
Authors: Cooper N , Greenwald RM
Published: April 2008

Snowboarding has distinctly different injury patterns compared with traditional alpine skiing. Injuries occur more frequently in the upper extremity and less frequently in the knees compared to alpine skiing. Snowboarding continues to evolve as a sport, with active participation at all age and experience levels, and on different terrain including slopes, pipes, and terrain parks. An observational study of snowboarders at one U.S. and one Austrian ski resort was conducted during the 2004–05 season to investigate fall trends in a snowboarding population. The purpose of the study was to quantify the incidence of falling, what anatomical structure impacted during a fall, fall direction, and helmet usage as a function of age, gender, ability level, and terrain. Two categories of terrain were identified; standard slopes and terrain parks including half-pipes. Children and adults fall twice as often as youths and young adults. Beginners fall approximately six times more often than advanced snowboarders, and average more than one fall per beginner per run. Runs in the pipe and in a terrain park resulted in a fall 34 and 20 % of the time, respectively. Terrain and experience dictated which body part impacted the snow surface. For beginners, 72 % of all falls were onto the hands. For more experienced participants in the half-pipe or in a terrain park, 50 % of falls were onto the boarder's back or bottom. Helmet use for snowboarders was slightly greater than 50 %. Children were most likely to use a helmet (>90 %), while less than 40 % of young adults used helmets. These observational data will be expanded and combined with injury data to quantify injury risk in the sport of snowboarding as a function of key demographics and environmental variables.
On Piste Fatalities in Recreational Snow Sports in the U.S.
Authors: Shealy JE , Johnson RJ , Ettlinger CF
Published: April 2008

This study documents fatalities and risk factors in alpine winter sports. The authors have tracked all known fatalities (n=854) occurring to recreational skiers and snowboarders within the boundaries of ski resorts in the United States since January 1978 through the winter of 2004/05. Data are limited to trauma deaths. Medical emergency deaths, deaths to employees, and deaths involving uphill lift facilities were excluded. Fatality data came from three sources: the U.S. Consumer Product Safety Commission (CPSC), the National Ski Areas Association (NSAA), and public news sources. Information concerning the accident, the injury, and the equipment used, were recorded. Data on skier and snowboarder resort utilization and demographic variables were obtained from NSAA annual reports. This particular analysis covers the 14 seasons 1991/92 through 2004/05. Five hundred sixty-two deaths were recorded; 97 to snowboarders and 465 to skiers during 761 million resort visits. During that time, helmet utilization went from essentially zero to 33.2 % for the general at-risk population. The fatality rate for skiers was 0.75 deaths per million visits (D/MV), and the snowboarder rate was 0.53 D/MV. These rates have not changed significantly over time. Most fatalities occurred to experienced males between the ages of 18 to 43. The most common scenario is a severe head injury resulting from high speed impact with a tree on or beside an intermediate trail. During the three most recent seasons, the known average prevalence of helmet utilization was 38.7 % among the fatally injured. Helmet utilization does not appear to affect fatality incidence, but it does shift primary cause of death patterns, from mostly head injuries for those not using a helmet to mostly chest and torso for those wearing a helmet. The fatality rate for alpine skiers remained significantly higher than for snowboarders. The demographic profile of the fatally injured remained unchanged from previous research.
Lisfranc Ligament Injuries in Windsurfers
Authors: Mitani G , Hirose H , Nakamura Y , Shimpuku E , Minezaki T , Mochida J
Published: April 2008

Recently, due to evolution of equipment and techniques, ordinary-level windsurfers can attempt acrobatic activities that previously only high-level windsurfers could perform in stormy conditions. Moreover, many difficult aerial tricks have been developed by high-level windsurfers. Synchronously, “foot strap injuries” have increased, which affect the knee, ankle, and foot by twisting loads because the foot is unable to be released from the foot strap. Here we report three Lisfranc ligament injuries in windsurfers that had not been diagnosed appropriately at another medical institution. The cases of two professional, and one amateur windsurfer, all of whom sustained a sprain to the anterior foot when they failed to land properly following an aerial trick or during wave riding, are reported in this publication. Weightbearing anterior to posterior (AP) view radiographs were an important tool for the diagnosis of these Lisfranc ligament injuries which can easily be missed on nonweightbearing films. Surgical treatment was chosen for two cases and conservative treatment was chosen for the other. To allow the windsurfers to return successfully to competition, we devised a special cork insole inside a marine boot called the “Ninja.” Lisfranc Ligament injuries should be suspected as there are frequent foot injuries in windsurfers, and adequate treatment can enable the patients to return to competition successfully.
Experimental Measurement of Selected Snowboard Mechanical Properties
Authors: Grewal D , Lund C , Rossetter E
Published: April 2008

Snowboard manufacturers attempt to design boards with mechanical properties that provide desirable ride and handling characteristics, adequate strength, and low manufacturing costs. Snowboards are typically a sandwich composite of several individual layers that vary significantly in geometry and composition. To better understand the influence of core materials and construction on a board's stiffness, ultimate failure load, and stored energy, several commercially available snowboards were tested to failure in three point bending. A series of representative boards were tested with three different core materials: foam, wood, and honeycomb. The results show that stiffness and ultimate failure load are most strongly influenced by the core wrap thickness, while the energy storage is most strongly influenced by the core material and construction method used.
Transplantation of Bone Marrow-Derived Very Small Embryonic-Like Stem Cells Attenuates Left Ventricular Dysfunction and Remodeling After Myocardial Infarction
Authors: Dawn Buddhadeb , Tiwari Sumit , Kucia Magdalena J. , Zuba-Surma Ewa K. , Guo Yiru , SanganalMath Santosh K. , Abdel-Latif Ahmed , Hunt Greg , Vincent Robert J. , Taher Hisham , Reed Nathan J. , Ratajczak Mariusz Z. , Bolli Roberto
Published: April 2008

Adult bone marrow (BM) contains Sca-1+/Lin−/CD45− very small embryonic-like stem cells (VSELs) that express markers of several lineages, including cardiac markers, and differentiate into cardiomyocytes in vitro. We examined whether BM-derived VSELs promote myocardial repair after a reperfused myocardial infarction (MI). Mice underwent a 30-minute coronary occlusion followed by reperfusion and received intramyocardial injection of vehicle (n= 11), 1 × 105 Sca-1+/Lin−/CD45+ enhanced green fluorescent protein (EGFP)-labeled hematopoietic stem cells (n= 13 [cell control group]), or 1 × 104 Sca-1+/Lin−/CD45− EGFP-labeled cells (n= 14 [VSEL-treated group]) at 48 hours after MI. At 35 days after MI, VSEL-treated mice exhibited improved global and regional left ventricular (LV) systolic function (echocardiography) and attenuated myocyte hypertrophy in surviving tissue (histology and echocardiography) compared with vehicle-treated controls. In contrast, transplantation of Sca-1+/Lin−/CD45+ cells failed to confer any functional or structural benefits. Scattered EGFP+ myocytes and capillaries were present in the infarct region in VSEL-treated mice, but their numbers were very small. These results indicate that transplantation of a relatively small number of CD45− VSELs is sufficient to improve LV function and alleviate myocyte hypertrophy after MI, supporting the potential therapeutic utility of these cells for cardiac repair.

Disclosure of potential conflicts of interest is found at the end of this article.
Transforming Growth Factor β Cooperates with Persephin for Dopaminergic Phenotype Induction
Authors: Roussa Eleni , Oehlke Oliver , Rahhal Belal , Heermann Stephan , Heidrich Stefanie , Wiehle Michael , Krieglstein Kerstin
Published: April 2008

The aim of the present study was to investigate the putative cooperative effects of transforming growth factor β (TGF-β) and glial cell line-derived neurotrophic factor (GDNF) family ligands in the differentiation of midbrain progenitors toward a dopaminergic phenotype. Therefore, a mouse midbrain embryonic day (E) 12 neurospheres culture was used as an experimental model. We show that neurturin and persephin (PSPN), but not GDNF, are capable of transient induction of dopaminergic neurons in vitro. This process, however, requires the presence of endogenous TGF-β. In contrast, after 8 days in vitro GDNF rescued the TGF-β neutralization-dependent loss of the TH-positive cells. In vivo, at E14.5, no apparent phenotype concerning dopaminergic neurons was observed in Tgf-β2−/−/gdnf−/− double mutant mice. In vitro, combined TGF-β/PSPN treatment achieved a yield of approximately 20% TH-positive cells that were less vulnerable against 1-methyl-4-phenyl pyridinium ion toxicity. The underlying TGF-β/PSPN differentiation signaling is receptor-mediated, involving p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways. These results indicate that phenotype induction and survival of fully differentiated neurons are accomplished through distinct pathways and individual factor requirement. TGF-β is required for the induction of dopaminergic neurons, whereas GDNF is required for regulating and/or maintaining a differentiated neuronal phenotype. Moreover, this study suggests that the combination of TGF-β with PSPN is a potent inductive cocktail for the generation of dopaminergic neurons that should be considered in tissue engineering and cell replacement therapies for Parkinson's disease.

Disclosure of potential conflicts of interest is found at the end of this article.
Novel Cardiac Precursor-Like Cells from Human Menstrual Blood-Derived Mesenchymal Cells
Authors: Hida Naoko , Nishiyama Nobuhiro , Miyoshi Shunichiro , Kira Shinichiro , Segawa Kaoru , Uyama Taro , Mori Taisuke , Miyado Kenji , Ikegami Yukinori , Cui ChangHao , Kiyono Tohru , Kyo Satoru , Shimizu Tatsuya , Okano Teruo , Sakamoto Michiie , Ogawa Satoshi , Umezawa Akihiro
Published: April 2008

Stem cell therapy can help repair damaged heart tissue. Yet many of the suitable cells currently identified for human use are difficult to obtain and involve invasive procedures. In our search for novel stem cells with a higher cardiomyogenic potential than those available from bone marrow, we discovered that potent cardiac precursor-like cells can be harvested from human menstrual blood. This represents a new, noninvasive, and potent source of cardiac stem cell therapeutic material. We demonstrate that menstrual blood-derived mesenchymal cells (MMCs) began beating spontaneously after induction, exhibiting cardiomyocyte-specific action potentials. Cardiac troponin-I-positive cardiomyocytes accounted for 27%–32% of the MMCs in vitro. The MMCs proliferated, on average, 28 generations without affecting cardiomyogenic transdifferentiation ability, and expressed mRNA of GATA-4 before cardiomyogenic induction. Hypothesizing that the majority of cardiomyogenic cells in MMCs originated from detached uterine endometrial glands, we established monoclonal endometrial gland-derived mesenchymal cells (EMCs), 76%–97% of which transdifferentiated into cardiac cells in vitro. Both EMCs and MMCs were positive for CD29, CD105 and negative for CD34, CD45. EMCs engrafted onto a recipient's heart using a novel 3-dimensional EMC cell sheet manipulation transdifferentiated into cardiac tissue layer in vivo. Transplanted MMCs also significantly restored impaired cardiac function, decreasing the myocardial infarction (MI) area in the nude rat model, with tissue of MMC-derived cardiomyocytes observed in the MI area in vivo. Thus, MMCs appear to be a potential novel, easily accessible source of material for cardiac stem cell-based therapy.

Disclosure of potential conflicts of interest is found at the end of this article.
Lineage Selection of Functional and Cryopreservable Human Embryonic Stem Cell-Derived Neurons
Authors: Ladewig Julia , Koch Philipp , Endl Elmar , Meiners Banu , Opitz Thoralf , Couillard-Despres Sebastien , Aigner Ludwig , Brüstle Oliver
Published: April 2008

A major prerequisite for the biomedical application of human embryonic stem cells (hESC) is the derivation of defined and homogeneous somatic cell types. Here we present a human doublecortin (DCX) promoter-based lineage-selection strategy for the generation of purified hESC-derived immature neurons. After transfection of hESC-derived neural precursors with a DCX-enhanced green fluorescent protein construct, fluorescence-activated cell sorting enables the enrichment of immature human neurons at purities of up to 95%. Selected neurons undergo functional maturation and are able to establish synaptic connections. Considering that the applicability of purified hESC-derived neurons would largely benefit from an efficient cryopreservation technique, we set out to devise defined freezing conditions involving caspase inhibition, which yield post-thaw recovery rates of up to 83%. Combined with our lineage-selection procedure this cryopreservation technique enables the generation of human neurons in a ready-to-use format for a large variety of biomedical applications.

Disclosure of potential conflicts of interest is found at the end of this article.
Modeling the environmental fate of perfluorooctanoate and its precursors from global fluorotelomer acrylate polymer use
Authors: van Zelm Rosalie , Huijbregts Mark A.J , Russell Mark H , Jager Tjalling , van de Meent Dik
Published: April 2008

The environment contains various direct and indirect sources of perfluorooctanoic acid (PFOA). The present study uses a dynamic multispecies environmental fate model to analyze the potential formation of perfluorooctanoate (PFO), the anion of PFOA, in the environment from fluorotelomer acrylate polymer (FTacrylate) emitted to landfills and wastewater, residual fluorotelomer alcohol (8:2 FTOH) in FTacrylate, and residual PFOA in FTacrylate. A multispecies version of the SimpleBox model, which is capable of determining the fate of a chemical and its degradation products, was developed for this purpose. An uncertainty analysis on the chemical-specific input parameters was performed to examine for uncertainty in modeled concentrations. In 2005, residual 8:2 FTOH made up 80% of the total contribution of FTacrylate use to PFO concentrations in global oceans, and residual PFOA in FTacrylate contributed 15% to PFO concentrations from FTacrylate use in global oceans. After hundreds of years, however, the main source of PFO from total historical FTacrylate production is predicted to be FTacrylate degrading in soil following land application of sludge from sewage treatment plants, followed by FTacrylate still present in landfills. Uncertainty in modeled PFO concentrations was up to a factor of 3.3. Current FTacrylate use contributes less than 1% of the PFO in seawater, but because direct PFOA emission sources are reduced and PFOA continues to be formed from FTacrylate in soil and in landfills, this fraction grows over time.
The Lean Profile: A Step Change in Drilling Performance
Authors: Calderoni A. , Ligrone A. , Molaschi C.
Published: April 2008

With the conventional drilling technique, a general rule-of-thumb establishes that the surface and intermediate casing strings are to be run in holes with a diameter of up to 6-7 in. larger than the casing.

This rule is based on the fact that: it is difficult to drill a straight vertical well withconventional technologies;the larger the casing diameter the stiffer the casingstring.

The clearance between casing and open hole is then reduced to about 1" for the deeper sections, because of the higher flexibility of the casing strings.

This paper presents the "Lean Profile", an innovative drilling technique which aims at maintaining 1" clearance throughout the whole casing program, leading to a slimmer well profile but keeping the same size for the production casing string. To achieve this it is mandatory to adopt suitable drilling technologies that will be deeply discussed in the paper.

The "Lean Profile" has been successfully applied to some wells drilled from on-shore clusters with parallel vertical sections long as much as 2,000 meters. The drilling environment is challenging with problems such as formations' tendency to deviate from the vertical trajectory, wellbore instability and circulation losses.

In this operating scenario the "Lean Profile" provided for dramatic time and cost reduction. In fact, the halving of the rock volume involved in the drilling process resulted in an outstanding drilling performance (-40% on drilling time with respect to standard technology), less material consumption and less waste production.

The Lean Profile is part of the drilling strategy for some 30 wells in the Val d'Agri, southern Italy, with interesting cost saving opportunities.

This paper summarizes experiences and results from the field along with engineering considerations.
Mono‐(2‐ethylhexyl) Phthalate Increases Spermatocyte Mitochondrial Peroxiredoxin 3 and Cyclooxygenase 2
Authors: Onorato Thomas M. , Brown Petrice W. , Morris Patricia L.
Published: April 2008

ABSTRACT: Mono‐(2‐ethylhexyl) phthalate (MEHP), the biologically active metabolite of the plasticizer di‐(2‐ethylhexyl) phthalate, is a member of a class of chemical compounds with known adverse effects on the male reproductive system. Recent studies showed that oxidative stress and mitochondrial dysfunction in germ cells may contribute to phthalate‐induced disruption of spermatogenesis. To determine whether the redox‐protein mitochondrial thioredoxin‐dependent peroxidase, peroxiredoxin 3 (Prx3), may be a component of germ cell homeostasis mechanisms, this study first examined the physiologic relevance of Prx3 in the rodent testis by determining its cell‐specific expression. Our findings show that prx3 mRNA is expressed in a developmental, cell‐specific manner in rat Leydig cells, Sertoli cells, and germ cells; among mouse germ cells, prx3 expression was highest in spermatocytes, findings consistent with those in rat. In mouse meiotic spermatocytes, Prx3 was strikingly localized at the nuclear perimeter and cytoplasm, findings suggestive of a direct role for Prx3 in determining spermatocyte response to toxicants. To better define the mechanisms involved in male germ cell dysfunction following phthalate exposure, an immortalized mouse spermatocyte‐derived germ cell line, GC‐2spd(ts), was exposed to MEHP (24 hours; 100 and 200 μM). We determined whether Prx3 and cyclooxygenase‐2 (COX‐2), pivotal proteins involved in oxidative stress responses in spatially restricted subcellular domains, were affected. Mitochondrial Prx3 and mitochondrial and cytosolic COX‐2 significantly increased following 200 μM MEHP treatment; proliferation was inhibited without inducing cell death. Using this germ cell model, the data suggest that changes in cellular oxidation‐reduction (redox) homeostasis in the germline can accompany MEHP exposure, disrupting mitochondrial antioxidant defenses, despite absence of phthalate‐induced apoptosis.
Phosphorylation of Mitogen‐Activated Protein Kinase 8 (MAPK8) Is Associated With Germ Cell Apoptosis and Redistribution of the Bcl2‐Modifying Factor (BMF)
Authors: Show Matthew D. , Hill Christine M. , Anway Matthew D. , Wright William W. , Zirkin Barry R.
Published: April 2008

ABSTRACT: Successful spermatogenesis requires that germ cells remain in physical contact with Sertoli cells until spermiation. Previous studies have shown that the Bcl2‐modifying factor (BMF) is a proapoptotic protein found in many epithelial cells which, when phosphorylated by the active form of mitogen‐activated protein kinase 8 (p‐MAPK8), initiates apoptosis in response to loss of adhesion of the cells to their basal lamina. Based on this, we hypothesized that p‐MAPK8 and BMF may play important roles in the apoptotic death of testicular germ cells in response to their detachment from Sertoli cells. Immunohistochemical analysis of the normal rat testis revealed p‐MAPK8 expression in spermatocytes and elongated spermatids but not in round spermatids. This localization was opposite to that of BMF, which is expressed in round spermatids but not in spermatocytes or elongated spermatids. When freshly isolated germ cells were cultured in the absence of Sertoli cells, a condition in which there was widespread germ cell apoptosis, an increase in p‐MAPK8 relative to overall MAPK8 protein, was seen by Western blot analysis. Additionally, immunocytochemical analysis showed an increase in immunoreactive p‐MAPK8 in round spermatids and spermatocytes in association with BMF expression. From these correlative data, we propose that the activation of MAPK8 and redistribution of BMF may be integrally involved in the mechanism by which specific germ cells undergo programmed cell death in response to their detachment from Sertoli cells.
Beta‐Microseminoprotein in Serum Correlates With the Levels in Seminal Plasma of Young, Healthy Males
Authors: Valtonen‐André Camilla , Sävblom Charlotta , Fernlund Per , Lilja Hans , Giwercman Aleksander , Lundwall Åke
Published: April 2008

ABSTRACT: Beta‐microseminoprotein (MSP) is one of the most abundant proteins secreted by the prostate gland. Because MSP is also synthesized in nonreproductive organs, the establishment of a solid relationship between the levels of MSP in serum and semen is crucial for future studies connecting MSP with aging or diseases of the prostate gland. We developed a specific, competitive, europium‐based immunoassay to measure MSP in serum and seminal plasma. We also produced recombinant MSP in insect cells using baculo virus and purified it to homogeneity by a novel approach with ethanol extraction and gel filtration. The median values of MSP in 205 young men were 12 μg/L (2.5–97.5 percentile, 4.9–26 μg/L) in serum and 0.53 g/L (2.5–97.5 percentile, 0.13–2.0 g/L) or 1.8 mg (2.5–97.5 percentile, 0.32–6.6 mg) in seminal plasma. MSP in serum showed significant correlation to MSP in seminal plasma (r = .50, P < .001). Significant correlations were also found in seminal plasma between MSP and prostate‐specific antigen (PSA) (r = .65, P < .001) and between MSP and Zn2+ (r = .54, P < .001). The yield of recombinant MSP in culture medium was 35 mg/L or higher, and recovery following ethanol extraction was 80%–90%. MSP in serum reflects the prostate secretion of MSP, and correlations were also found in seminal plasma between MSP and PSA and Zn2+. This suggests that MSP in serum can be used as a marker of prostate secretion, despite the contribution from extra prostatic tissues.
Inhibition of 11β‐Hydroxysteroid Dehydrogenase Enzymatic Activities by Glycyrrhetinic Acid In Vivo Supports Direct Glucocorticoid‐Mediated Suppression of Steroidogenesis in Leydig Cells
Authors: Hu Guo‐Xin , Lin Han , Sottas Chantal M. , Morris David J. , Hardy Matthew P. , Ge Ren‐Shan
Published: April 2008

ABSTRACT: Previous studies have suggested that glucocorticoid (GC) can directly affect testicular testosterone (T) biosynthesis by Leydig cells through a receptor‐mediated mechanism. Interconversion of corticosterone (CORT), the active form in rodents, and 11‐dehydroCORT, the biologically inert 11‐keto form, is catalyzed by 11βHSD1. This enzyme thus controls the intracellular concentration of active GC. We have postulated that elevated CORT levels resulting from stress exceed the Leydig cell's capacity for metabolic inactivation of CORT, resulting in suppressed T production. The present study tested whether inhibition of 11βHSD1 in vivo, by the administration of glycyrrhetinic acid (GA), increases intracellular active GC concentration and thereby affects serum T concentration and Leydig cell T production. Adult Sprague‐Dawley rats were treated with vehicle (corn oil), CORT, GA, or GA + CORT. Serum luteinizing hormone (LH), CORT, and T levels were measured, as were the steroidogenic capacities of purified Leydig cells. Twofold elevations of CORT were achieved by the administration of either CORT or GA alone, but in both cases there was no effect on serum T levels. However, when CORT and GA were administered in combination, serum CORT levels increased 3.5‐fold (to 420 ± 34 ng/mL) and serum T levels were reduced significantly (to 0.72 ± 0.07 ng/mL; control, 2.12 ± 0.23 ng/mL). Serum levels of LH were not affected by CORT, GA, or GA + CORT. Consistent with the reduced serum T levels following GA + CORT, steroidogenic enzyme expression and capacities were significantly reduced compared to control. These data support a role for 11βHSD1 in modulating intracellular CORT concentrations and, in turn, for a direct effect of GC on Leydig cells in response to stress.
Mechanisms of Cancer Prevention by Green and Black Tea Polyphenols
Authors: Ann Beltz Lisa , Kay Bayer Diana , Lynn Moss Amber , Mitchell Simet Ira
Published: April 2008

Drinking green tea is associated with decreased frequency of cancer development. This review outlines the wide range of mechanisms by which epigallocatechin gallate (ECGC) and other green and black tea polyphenols inhibit cancer cell survival. EGCG suppressed androgen receptor expression and signalling via several growth factor receptors. Cell cycle arrest or apoptosis involved caspase activation and altered Bcl-2 family member expression. EGCG inhibited telomerase activity and led to telomere fragmentation. While at high concentrations polyphenols had pro-oxidative activities, at much lower levels, anti-oxidative effects occurred. Nitric oxide production was reduced by EGCG and black tea theaflavins by suppressing inducible nitric oxide synthase via blocking nuclear translocation of the transcription factor nuclear factor-κB as a result of decreased IκB kinase activity. Polyphenols up- or down-regulated activity of a number of key enzymes, including mitogen-activated protein kinases and protein kinase C, and increased or decreased protein/ mRNA levels, including that of cyclins, oncogenes, and tumor suppressor genes. Metastasis was inhibited via effects on urokinase and matrix metalloproteinases. Polyphenols reduced angiogenesis, in part by decreasing vascular endothelial growth factor production and receptor phosphorylation. Recent work demonstrated that EGCG reduced dihydrofolate reductase activity, which would affect nucleic acid and protein synthesis. It also acted as an aryl hydrocarbon receptor antagonist by directly binding the receptors molecular chaperone, heat shock protein 90. In conclusion, green and black tea polyphenols act at numerous points regulating cancer cell growth, survival, and metastasis, including effects at the DNA, RNA, and protein levels.
Potential Deployment of Angiotensin I Converting Enzyme Inhibitors and of Angiotensin II Type 1 and Type 2 Receptor Blockers in Cancer Chemotherapy
Authors: Molteni Agostino , Heffelfinger Sue , Moulder John E. , Uhal Bruce , Castellani William J.
Published: April 2008

There is significant evidence that both angiotensin I converting enzyme inhibitors (ACEI) and type 1 and type 2 angiotensin 2 (A2) receptor blockers may inhibit tumor growth. The finding is supported by many reports where these two classes of drugs showed cytostatic effects on the cultures of several lines of both normal and neoplastic cells. These drugs often transformed the cellular biochemical structures, especially in neoplastic cell lines. The same drugs also delayed the growth of different types of tumors in a variety of experimental animals (breast and lung carcinoma in mice; sarcomas, squamous cell carcinomas and hepatocellular carcinomas in rats), and there are a few reports of successful treatment of a limited number of cases of Kaposi sarcoma and gliomas with these drugs. Retrospective studies in hypertensive subjects treated with ACEI or A2 receptor blockers also seem to indicate that the incidence and growth of different neoplasms was delayed when these patients were compared to hypertensive patients receiving alternate medications. There is strong indication that the pharmacologic effect of these drugs may be exerted by reduction or inhibition of the synthesis of angiotensin 2. A2 is a powerful mitogen and its effect on cellular growth is exerted through stimulation of many factors, including transforming growth factor β (TGFβ), epidermal growth factor (EGF), smooth muscle actin (SMA), and tyrosine kinase. A2 also regulates apoptotic mechanisms and angiogenesis. The pharmacologic action of most of these drugs, however, is not necessarily limited to downregulaton of A2. Many ACEI, especially those containing the sulfhydryl (SH group), possess antioxidant or metalloprotease inhibitory properties per se. These experimental and retrospective data justify clinical testing of these drugs in appropriate randomized trials. Several such trials are currently in process. If these trials confirm the experimental and retrospective studies, these agents will provide a significant contribution to the therapeutic treatment of many malignancies in humans.
Anti-Angiogenic Cancer Therapy Based on Integrin αvβ3 Antagonism
Authors: Cai Weibo , Chen Xiaoyuan
Published: April 2008

Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a fundamental process during cancer progression. Anti-angiogenic strategies have been pursued for cancer treatment and prevention of cancer recurrence and metastasis. Integrins are a family of cell adhesion molecules consisting of two non-covalently bound transmembrane subunits (α3 and β). Much research has demonstrated that integrin signaling plays a key role in tumor angiogenesis and metastasis. Integrin αvβ3 is highly expressed on activated endothelial cells and tumor cells but is not present in resting endothelial cells and most normal organ systems, which makes it a suitable target for anti-angiogenic cancer therapy. In this review we will focus on cancer therapy targeting integrin αvβ3 while other integrins (such as α5β1, αIIbβ3, αvβ5, α6β4) will only be briefly mentioned when relevant. MEDI-522 (a humanized anti-human integrin avb3 monoclonal antibody) and Cilengitide (cyclic peptidic integrin αvβ3 /αvβ5 antagonist) are currently in clinical trials for anti-angiogenic cancer therapy. Small interfering RNA (siRNA) that specifically silences integrin αv and/or β3 was reported to cause tumor shrinkage in preclinical xenograft models. Combination of anti-integrin αvβ3 therapy and other therapeutic approaches (such as chemotherapy, radiotherapy and gene therapy) has also been applied for cancer treatment. Mounting evidence suggests that there is potentially synergistic effect of combined therapeutic approaches over single modality alone. Lastly, integrin targeted delivery (drugs, genes, and radioisotopes) and imaging (optical, MRI, ultrasound, SPECT, and PET) is discussed in detail.
Tumor Physiology and Delivery of Nanopharmaceuticals
Authors: Campbell Robert B.
Published: April 2008

Over the past few decades significant advances have been made in the development of nanopharmaceuticals (including phospholipid and polymer-based therapeutics) against cancer. There is still, however, room for improvement. Today, many researchers are focusing on the development of innovative approaches to selectively deliver drugs to solid tumors, while minimizing insult to healthy tissues. Unfortunately, the majority of these efforts are confronted by physiological barriers that reduce the clinical dose required to effectively manage the disease state. In an effort to develop promising nanopharmaceutical products of the future, we review the most important problems facing drug delivery experts today. We discuss here, the physiological role of solid tumors in delivery and transport of nanopharmaceutical products. The nature of tumors in terms of their unique anatomical structure and functions is also discussed. Finally, an overview of ways to overcome physiological barrier functions and exploit tumor pathogenesis for therapeutic gain is provided.
The Role of Anticoagulation in Cancer Patients: Facts and Figures
Authors: De Lorenzo Ferruccio , Dotsenko Olena , Scully Michael F. , Tymoshchuk Myroslava
Published: April 2008

Thromboembolic events contribute significantly to the morbidity and mortality in cancer. Effective and safe anticoagulation - mainstay in prevention and treatment of thrombosis - remains very challenging clinical task in oncology patients - population of high rate of treatment failure, bleeding complications and thromboembolic events recurrences. Prospective randomized clinical studies have documented that with advent of low molecular weight heparins new possibilities for thrombosis treatment and long-term prevention with more convenient and safe anticoagulation have emerged. Considerable advances have been achieved at present time in our understanding of the pathobiology of thrombogenesis in human malignancies, particularly of the interactions between coagulation cascade reactions and processes of tumor growth and dissemination. This builds up a new challenge for modern oncology - appreciation of the hypothesis of antimalignant effects of anticoagulants, which could influence the outcome of human cancer. Antineoplastic effects of antithrombotic drugs have been reported in various experimental models. Heparins have been the most extensively studied and have been shown to reduce the primary tumour growth and its metastatic spread. Joint evidence from fundamental research and from several randomized clinical trials, observing beneficial impact of low molecular weight heparins therapy on cancer patients survival, dictate the need for further scientific steps to confirm biological effects of heparins in human malignancies. The evidence is started to accumulate, that clinically approved heparins have different abilities to influence some processes of metastasis spread. The experimental work towards development of heparin derivates with low anticoagulant activity, but with potential inhibitory effects on tumor cells migration is in progress.
Pharmacokinetics and Pharmacodynamics of Lipidic Nano-Particles in Cancer
Authors: Allen Theresa M. , K. Cheng Wilson W. , Hare Jennifer I. , Laginha Kimberley M.
Published: April 2008

Nanoscale drug delivery systems (DDS) are used to circumvent some of the non-ideal properties of conventional anticancer chemotherapy drugs. Manipulation of the physical properties of DDS provides improved control over the pharmacokinetics (PK) and pharmacodynamics (PD) of the encapsulated drugs relative to free drugs. Liposomes are the archetypical nanoscale DDS and the first of these received clinical approval in 1990. DOXIL®, liposomal doxorubicin, was the first commercially available liposomal anticancer drug (1995). It has an enhanced circulation half-life compared to the free drug because of its surface-grafted polyethylene glycol coating. DOXIL® passively targets solid tumors, and once the liposomes localize in the tumor interstitial space, the cytotoxic drug is slowly released within the tumor. Liposomes can act as sustained release delivery system and manipulation of properties such as, liposome diameter, drug release rate, bioavailability and dosing schedule can significantly impact the therapeutic outcome of the liposomal drugs. This review will focus on how alteration of these properties can impact the therapeutic efficacy and side effect profiles of DDS.
Nucleic Acid Based Therapeutics for Tumor Therapy
Authors: Ogris Manfred
Published: April 2008

Although being a heterogeneous disease, cancer has certain characteristic features which can be utilized for treatment with novel macromolecular therapeutics. The active cycling status of tumor cells, proliferating tumor endothelium and a leaky vasculature allow the targeted delivery of therapeutically active nucleic acids into tumor tissue. We and others have developed polycationic gene carriers forming so called polyplexes with nucleic acids. Cellular aspects like binding, internalization and intracellular fate were enlightened. Additionally, virus like domains were incorporated into the polyplex. Hydrophilic shielding domains protect the polyplex from unspecific interaction with blood components, targeting ligands allow cell specific binding and internalization into target cells, and membrane active peptides have a favorable influence on intracellular trafficking. Physical targeting of polyplexes, like locoregional hyperthermia and photochemical internalization (PCI) have been further used to enhance the efficiency of nucleic acid transfer. Therapeutic concepts were carried out in different tumor models in mice. Local application of synthetic, double stranded RNA led to eradication of intracranial glioblastoma. A gene directed enzyme prodrug approach utilizing site directed activation of cyclophosphamide with cytochrome P450 gave first, promising results.