bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Arsenic on Maternal and Fetal Health
Authors: Vahter Marie
Published: July 2009

Arsenic, which is commonly found in drinking water, is a potent toxicant, but little is known about its effects on maternal health. Arsenic's modes of action include enzyme inhibition and oxidative stress as well as immune, endocrine, and epigenetic effects. A couple of studies reported increased blood pressure and anemia during pregnancy. Susceptibility to arsenic is dependent on the biomethylation, which occurs via one-carbon metabolism. Methylarsonic acid and dimethylarsinic acid are main metabolites in urine, and elevated methylarsonic acid is considered a general risk factor. Arsenic easily passes the placenta, and a few human studies indicate a moderately increased risk of impaired fetal growth and increased fetal and infant mortality. The fetus and infant are probably partly protected by the increased methylation of arsenic during pregnancy and lactation; the infant is also protected by low arsenic excretion in breast milk. Early-life exposure may induce changes that will become apparent much later in life.
Sialic Acid Is an Essential Nutrient for Brain Development and Cognition
Authors: Wang Bing
Published: July 2009

The rapid growth of infant brains places an exceptionally high demand on the supply of nutrients from the diet, particularly for preterm infants. Sialic acid (Sia) is an essential component of brain gangliosides and the polysialic acid (polySia) chains that modify neural cell adhesion molecules (NCAM). Sia levels are high in human breast milk, predominately as N-acetylneuraminic acid (Neu5Ac). In contrast, infant formulas contain a low level of Sia consisting of both Neu5Ac and N-glycolylneuraminic acid (Neu5Gc). Neu5Gc is implicated in some human inflammatory diseases. Brain gangliosides and polysialylated NCAM play crucial roles in cell-to-cell interactions, neuronal outgrowth, modifying synaptic connectivity, and memory formation. In piglets, a diet rich in Sia increases the level of brain Sia and the expression of two learning-related genes and enhances learning and memory. The purpose of this review is to summarize the evidence showing the importance of dietary Sia as an essential nutrient for brain development and cognition.
ERp46 is reduced by high glucose and regulates insulin content in pancreatic β-cells
Authors: Alberti Avra , Karamessinis Panagiotis , Peroulis Michalis , Kypreou Katerina , Kavvadas Panagiotis , Pagakis Stamatis , Politis Panagiotis K. , Charonis Aristidis
Published: July 2009

Our studies focus on ERp46, an endoplasmic reticulum (ER) component, and analyze its involvement in glucose toxicity and in insulin production. Differences in pancreatic β-TC-6 cell proteome under conditions of low vs. high glucose were examined by proteomic approaches, including two-dimensional gel electrophoresis, image analysis, and mass spectrometry. Among differentially expressed proteins, ERp46, a novel endoplasmic reticulum component, was examined further. The expression of ERp46 in pancreatic sections was analyzed by immunocytochemistry, and high glucose-induced alterations of expression were evaluated in cultured β-cells, in isolated pancreatic islets, and in the pancreas of db/db diabetic animals. Inhibition of ERp46 expression by siRNA was performed to study its role in insulin production, in secretion, and in ER stress. Proteomic analysis led to identification of 46 differentially expressed spots corresponding to 23 proteins. Since ERp46 is a novel protein with a possible crucial role in secretory cells, we further analyzed its role in β-cell function. ERp46 expression is reduced in high glucose concentration in β-TC-6 cells and in isolated murine islets. Further analysis revealed high expression of ERp46 in pancreatic islets compared with exocrine tissue. Interestingly, a marked decrease in ERp46 expression was found in the pancreatic islets of db/db mice. Most importantly, siRNA-mediated knockdown of ERp46 in cultured β-cells led to a significant decrease in the insulin content; however, no alterations in insulin mRNA levels were observed under these conditions. In addition, reduced expression of ERp46 by siRNA increased the expression of CHOP and peIF2a, indicating development of ER stress. We conclude that ERp46 may be an important component in the phenomenon of “glucose toxicity” involved in insulin production at the posttranslational level.
The effects of amino acids on glucose metabolism of isolated rat skeletal muscle are independent of insulin and the mTOR/S6K pathway
Authors: Stadlbauer Karin , Brunmair Barbara , Szöcs Zsuzsanna , Krebs Michael , Luger Anton , Fürnsinn Clemens
Published: July 2009

Two mechanisms have been proposed for the modulation of skeletal muscle glucose metabolism by amino acids. Whereas studies on humans and cultured cells suggested acute insulin desensitization via mammalian target of rapamycin (mTOR) and its downstream target p70 S6 kinase (S6K), investigations using native specimens of rat muscle hinted at impairment of glucose oxidation by competition for mitochondrial oxidation. To better understand these seemingly contradictory findings, we explored the effects of high concentrations of mixed amino acids on fuel metabolism and S6K activity in freshly isolated specimens of rat skeletal muscle. In this setting, increasing concentrations of amino acids dose-dependently reduced the insulin-stimulated rates of CO2production from glucose and palmitate (decrease in glucose oxidation induced by addition of 5.5, 11, 22, and 44 mmol/l amino acids: −16 ± 3, −25 ± 7, −44 ± 4, −62 ± 4%; P < 0.02 each). This effect could not be attributed to insulin desensitization, because it was not accompanied by any reduction of insulin-stimulated glucose transport [+12 ± 16, +17 ± 22, +21 ± 33, +13 ± 12%; all nonsignificant (NS)] or glycogen synthesis (+1 ± 6, −5 ± 6, −9 ± 8, +6 ± 5%; all NS) and because it persisted without insulin stimulation. Abrogation of S6K activity by the mTOR blocker rapamycin failed to counteract amino acid-induced inhibition of glucose and palmitate oxidation, which therefore was obviously independent of mTOR/S6K signaling (decrease in glucose oxidation by addition of 44 mmol/l amino acids: without rapamycin, −60 ± 4%; with rapamycin, −50 ± 13%; NS). We conclude that amino acids can directly affect muscle glucose metabolism via two mechanisms, mTOR/S6K-mediated insulin desensitization and mitochondrial substrate competition, with the latter predominating in isolated rat muscle.
Inflammation and impaired adipogenesis in hypertrophic obesity in man
Authors: Gustafson Birgit , Gogg Silvia , Hedjazifar Shahram , Jenndahl Lachmi , Hammarstedt Ann , Smith Ulf
Published: July 2009

Obesity is associated mainly with adipose cell enlargement in adult man (hypertrophic obesity), whereas the formation of new fat cells (hyperplastic obesity) predominates in the prepubertal age. Adipose cell size, independent of body mass index, is negatively correlated with whole body insulin sensitivity. Here, we review recent findings linking hypertrophic obesity with inflammation and a dysregulated adipose tissue, including local cellular insulin resistance with reduced IRS-1 and GLUT4 protein content. In addition, the number of preadipocytes in the abdominal subcutaneous adipose tissue capable of undergoing differentiation to adipose cells is reduced in hypertrophic obesity. This is likely to promote ectopic lipid accumulation, a well-known finding in these individuals and one that promotes insulin resistance and cardiometabolic risk. We also review recent results showing that TNFα, but not MCP-1, resistin, or IL-6, completely prevents normal adipogenesis in preadipocytes, activates Wnt signaling, and induces a macrophage-like phenotype in the preadipocytes. In fact, activated preadipocytes, rather than macrophages, may completely account for the increased release of chemokines and cytokines by the adipose tissue in obesity. Understanding the molecular mechanisms for the impaired preadipocyte differentiation in the subcutaneous adipose tissue in hypertrophic obesity is a priority since it may lead to new ways of treating obesity and its associated metabolic complications.
Dietary palmitate and linoleate oxidations, oxidative stress, and DNA damage differ according to season in mouse lemurs exposed to a chronic food deprivation
Authors: Giroud Sylvain , Perret Martine , Gilbert Caroline , Zahariev Alexandre , Goudable Joëlle , Le Maho Yvon , Oudart Hugues , Momken Iman , Aujard Fabienne , Blanc Stéphane
Published: July 2009

This study investigated the extent to which the increase in torpor expression in the grey mouse lemur, due to graded food restriction, is modulated by a trade-off between a whole body sparing of polyunsaturated dietary fatty acids and the related oxidative stress generated during daily torpor. We measured changes in torpor frequency, total energy expenditure (TEE), linoleate (polyunsaturated fatty acid) and palmitate (saturated fatty acid) oxidation, hexanoyl-lysine (HEL; the product of linoleate peroxidation), and 8-hydroxydeoxyguanosine (8OHdG; a marker of DNA damage). Animals under summer-acclimated long days (LD) or winter-acclimated short days (SD) were exposed to a 40% (LD40 and SD40) and 80% (LD80 and SD80) 35-day calorie restriction (CR). During CR, all groups reduced their body mass, but LD80 animals reached survival-threatened levels at day 22 and were then excluded from the CR trial. Only SD mouse lemurs increased their torpor frequency with CR and displayed a decrease in their TEE adjusted for fat-free mass. After CR, SD40 mouse lemurs shifted the dietary fatty acid oxidation toward palmitate and spared linoleate. Such a shift was not observed in LD animals and during severe CR, during which oxidation of both dietary fatty acids was increased. Concomitantly, HEL increased in both LD40 and SD80 groups, whereas DNA damage was only seen in SD80 food-restricted animals. HEL correlated positively with linoleate oxidation confirming in vivo the substrate/product relationship demonstrated in vitro, and negatively with TEE adjusted for fat-free mass, suggesting higher oxidative stress associated with increased torpor expression. This suggests a seasonal-dependant, cost-benefit trade-off between maximizing torpor propensity and minimizing oxidative stress that is associated with a shift toward sparing of dietary polyunsaturated fatty acids that is dependent upon the expression of a winter phenotype.
Carbohydrate refeeding after a high-fat diet rapidly reverses the adaptive increase in human skeletal muscle PDH kinase activity
Authors: Bigrigg J. Kent , Heigenhauser George J. F. , Inglis J. Greig , LeBlanc Paul J. , Peters Sandra J.
Published: July 2009

Pyruvate dehydrogenase (PDH) regulates oxidative carbohydrate disposal in skeletal muscle and is downregulated by reversible phosphorylation catalyzed by PDH kinase (PDK). Previous work has demonstrated increased PDK activity and PDK4 expression in human skeletal muscle following a high-fat low-carbohydrate (HF) diet, which leads to decreased PDH in the active form (PDHa activity) and carbohydrate oxidation. The purpose of this study was to examine the time course of changes in PDK and PDHa activities with refeeding of carbohydrates after an HF diet in human skeletal muscle. Healthy male volunteers ( n = 8) consumed a standardized 3-day Pre-diet with the same energy content as their habitual diet, followed by a eucaloric 6-day HF diet (Pre-diet: 50:30:20%; HF diet: 5:75:20%; carbohydrate/fat/protein). Muscle biopsies were taken before and after the HF diet and at 45 min and 3 h after carbohydrate refeeding with a single high-glycemic index carbohydrate meal (88:5:7% carbohydrate/fat/protein) representing approximately one third of the individual subject's habitual energy intake. PDK activity increased from 0.08 ± 0.01 Pre- to 0.25 ± 0.02 min ( P < 0.001) Post-HF diet, and decreased with carbohydrate refeeding to 0.17 ± 0.05 ( P = 0.014) and 0.11 ± 0.01 min ( P = 0.006) at 45 min and 3 h, respectively. PDHa decreased from 0.89 ± 0.20 to 0.32 ± 0.05 ( P = 0.007) mmol·min−1·kg wet wt−1 following the HF diet, and was increased transiently with refeeding at 45 min, but returned to lower values by 3 h ( P = 0.025 compared with Pre). The potential mechanism(s) for this attenuation of PDHa activity remains unclear. These data demonstrate that in human skeletal muscle, the adaptive increase in PDK activity following an HF diet is rapidly reversed to Pre-diet activity levels within 45 min to 3 h, and this is accompanied by a short-term increase in PDHa activity.
Real-time measurement of renal blood flow in healthy subjects using contrast-enhanced ultrasound
Authors: Kalantarinia Kambiz , Belcik J. Todd , Patrie James T. , Wei Kevin
Published: July 2009

Current methods for measuring renal blood flow (RBF) are time consuming and not widely available. Contrast-enhanced ultrasound (CEU) is a safe and noninvasive imaging technique suitable for assessment of tissue blood flow, which has been used clinically to assess myocardial blood flow. We tested the utility of CEU in monitoring changes in RBF in healthy volunteers. We utilized CEU to monitor the expected increase in RBF following a high protein meal in healthy adults. Renal cortical perfusion was assessed by CEU using low mechanical index (MI) power modulation Angio during continuous infusions of Definity. Following destruction of tissue microbubbles using ultrasound at a MI of 1.0, the rate of tissue replenishment with microbubbles and the plateau acoustic intensity (AI) were used to estimate the RBF velocity and cortical blood volume, respectively. Healthy adults ( n = 19, mean age 26.6 yr) were enrolled. The A.β parameter of CEU, representing mean RBF increased by 42.8%from a baseline of 17.05 ± 6.23 to 23.60 ± 6.76 dB/s 2 h after the ingestion of the high-protein meal ( P = 0.002). Similarly, there was a 37.3%increase in the β parameter, representing the geometric mean of blood velocity after the high protein meal ( P < 0.001). The change in cortical blood volume was not significant ( P = 0.89). Infusion time of Definity was 6.3 ± 2.0 min. The ultrasound contrast agent was tolerated well with no serious adverse events. CEU is a fast, noninvasive, and practical imaging technique that may be useful for monitoring renal blood velocity, volume, and flow.
Excitation of Mouse Superficial Dorsal Horn Neurons by Histamine and/or PAR-2 Agonist: Potential Role in Itch
Authors: Akiyama Tasuku , Carstens Mirela Iodi , Carstens E.
Published: July 2009

Recent studies have suggested the existence of separate transduction mechanisms and sensory pathways for histamine and nonhistaminergic types of itch. We studied whether histamine and an agonist of the protease-activated receptor (PAR)-2, associated with nonhistaminergic itch, excite murine dorsal horn neurons. Single units were recorded in superficial lumbar dorsal horn of adult ICR mice anesthetized with pentobarbital. Unit activity was searched using a small intradermal hindpaw injection of histamine or the PAR-2 agonist SLIGRL-NH2. Isolated units were subsequently challenged with intradermal histamine followed by SLIGRL-NH2 (each 50 μg/1 μl) or reverse order, followed by mechanical, thermal, and algogenic stimuli. Forty-three units were classified as wide dynamic range (62%), nociceptive specific (22%), or mechano insensitive (16%). Twenty units gave prolonged (mean, 10 min) discharges to intradermal injection of histamine; 76% responded to subsequent SLIGRL-NH2, often more briefly. Units additionally responded to noxious heat (63%), cooling (43%), topical mustard oil (53%), and intradermal capsaicin (67%). Twenty-two other units gave prolonged (mean, 5 min) responses to initial intradermal injection of SLIGRL-NH2; 85% responded to subsequent intradermal histamine. They also responded to noxious heat (75%), mustard oil (93%), capsaicin (63%), and one to cooling. Most superficial dorsal horn neurons were excited by both histamine and the PAR-2 agonist, suggesting overlapping pathways for histamine- and non–histamine-mediated itch. Because the large majority of pruritogen-responsive neurons also responded to noxious stimuli, itch may be signaled at least partly by a population code.
Meta-analysis of gene expression in human pancreatic islets after in vitro expansion
Authors: Kutlu B. , Kayali A. G. , Jung S. , Parnaud G. , Baxter D. , Glusman G. , Goodman N. , Behie L. A. , Hayek A. , Hood L.
Published: July 2009

Pancreatic islet transplantation as a potential cure for type 1 diabetes (T1D) cannot be scaled up due to a scarcity of human pancreas donors. In vitro expansion of β-cells from mature human pancreatic islets provides an alternative source of insulin-producing cells. The exact nature of the expanded cells produced by diverse expansion protocols and their potential for differentiation into functional β-cells remain elusive. We performed a large-scale meta-analysis of gene expression in human pancreatic islet cells, which were processed using three different previously described protocols for expansion and for which redifferentiation was attempted. All three expansion protocols induced dramatic changes in the expression profiles of pancreatic islets; many of these changes are shared among the three protocols. Attempts at redifferentiation of expanded cells induce a limited number of gene expression changes. Nevertheless, these fail to restore a pancreatic islet-like gene expression pattern. Comparison with a collection of public microarray datasets confirmed that expanded cells are highly comparable to mesenchymal stem cells. Genes induced in expanded cells are also enriched for targets of transcription factors important for pluripotency induction. The present data increase our understanding of the active pathways in expanded and redifferentiated islets. Knowledge of the mesenchymal stem cell potential may help development of drug therapeutics to restore β-cell mass in T1D patients.
p,p′‐DDE Induces Apoptosis of Rat Sertoli Cells via a FasL‐Dependent Pathway
Authors: Shi Yuqin , Song Yang , Wang Yinan , Liang Xianmin , Hu Yafei , Guan Xia , Cheng Jin , Yang Kedi
Published: July 2009

One,1‐dichloro‐2,2 bis(p‐chlorophenyl) ethylene (p,p′‐DDE), the major metabolite of 2,2‐bis(4‐Chlorophenyl)‐1,1,1‐trichloroethane (DDT), is a known persistent organic pollutant and male reproductive toxicant. It has antiandrogenic effect. However, the mechanism by which p,p′‐DDE exposure causes male reproductive
toxicity remains unknown. In the present study, rat Sertoli cells were used to investigate the molecular mechanism involved in p,p′‐DDE‐induced toxicity in male reproductive system. The results indicated that p,p′‐DDE exposure at over 30 μM showed the induction of apoptotic cell death. p,p′‐DDE could induce increases in FasL mRNA and protein, which could be blocked by an antioxidant agent, N‐acetyl‐l‐cysteine (NAC). In addition, caspase‐3 and ‐8 were activated by p,p′‐DDE treatment in these cells. The activation of NF‐κB was enhanced with the increase of p,p′‐DDE dose. Taken together, these results suggested that exposure to p,p′‐DDE might induce apoptosis of rat Sertoli cells through a FasL‐dependent pathway.
A Wavelet‐Based Multiresolution Reconstruction Method for Fluorescent Molecular Tomography
Authors: Zou Wei , Wang Jiajun , Wu Kongpei , Feng David Dagan
Published: July 2009

Image reconstruction of fluorescent molecular tomography (FMT) often involves repeatedly solving large‐dimensional matrix equations, which are computationally expensive, especially for the case where there are large deviations in the optical properties between the target and the reference medium. In this paper, a wavelet‐based multiresolution reconstruction approach is proposed for the FMT reconstruction in combination with a parallel forward computing strategy, in which both the forward and the inverse problems of FMT are solved in the wavelet domain. Simulation results demonstrate that the proposed approach can significantly speed up the reconstruction process and improve the image quality of FMT.
Association of MCP-1 -2518 A/G Single Nucleotide Polymorphism with the Serum Level of CRP in Slovak Patients with Ischemic Heart Disease, Angina Pectoris, and Hypertension
Authors: Bucova Maria , Lietava Jan , Penz Peter , Mrazek Frantisek , Petrkova Jana , Bernadic Marian , Petrek Martin
Published: July 2009

The aim of our work was to find if MCP-1 -2518 (A/G) single nucleotide polymorphism (SNP) influences somehow the serum concentrations of high-sensitive CRP (hsCRP) both in patients suffering from ischemic heart disease (IHD), myocardial infarction (MI), angina pectoris (AP), and hypertension (HT) and in control group of healthy subjects. Totally, 263 patients with the diagnosis of IHD, out of them 89 with MI, 145 with AP, 205 with HT, and also 67 healthy subjects were included in the study. First, we estimated the serum levels of hsCRP. We found that patients with AP had significantly higher serum level of hsCRP than both control group of healthy subjects (P=.043) and IHD patients without AP (P=.026). The presence of the mutant G allele statistically significantly correlated with the higher serum levels of hsCRP in patients with IHD (P=.016), AP (P=.004), and HT (P=.013). Higher correlations were found in men (AP:P=.019; HT:P=.047). In all cases the highest levels of hsCRP were found both in patients and healthy controls with homozygous GG genotype.
Newton‐Krylov Type Algorithm for Solving Nonlinear Least Squares Problems
Authors: Abdel-Aziz Mohammedi R. , El-Alem Mahmoud M.
Published: July 2009

The minimization of a quadratic function within an ellipsoidal trust region is an important
subproblem for many nonlinear programming algorithms. When the number of variables is large,
one of the most widely used strategies is to project the original problem into a small dimensional
subspace. In this paper, we introduce an algorithm for solving nonlinear least squares problems.
This algorithm is based on constructing a basis for the Krylov subspace in conjunction with a
model trust region technique to choose the step. The computational step on the small dimensional
subspace lies inside the trust region. The Krylov subspace is terminated such that the termination
condition allows the gradient to be decreased on it. A convergence theory of this algorithm is
presented. It is shown that this algorithm is globally convergent.
Temperature‐Change‐Based Thermal Tomography
Authors: Xu Yong , Wei Xiangyu , Wang Ge
Published: July 2009

Thermal properties of biological tissues play a critical role in the study of tumor angiogenesis and the design and monitoring of thermal therapies. To map thermal parameters noninvasively, we propose temperature‐change‐based thermal tomography (TTT) that relies on relative temperature mapping using magnetic resonance imaging (MRI). Our approach is unique in two aspects: (1) the steady‐state body temperature in thermal equilibrium is not restricted to be spatially invariant, and (2) absolute temperature mapping is not required. These two features are physiologically realistic and technically convenient. Our numerical simulation indicates that a (9 mm) 3 tumor inside a breast phantom can be reliably depicted, assuming moderate temperature mapping accuracy of 0.5∘C.
An Iterative Method for Generalized Equilibrium Problems, Fixed Point Problems and Variational Inequality Problems
Authors: Liu Qing-you , Zeng Wei-you , Huang Nan-jing
Published: July 2009

We introduce an iterative scheme by the viscosity approximation method for finding a common element of the set of solutions of generalized equilibrium problems, the set of common fixed points of infinitely many nonexpansive mappings, and the set of solutions of the variational inequality for "Equation missing"-inverse-strongly monotone mappings in Hilbert spaces. We give some strong-convergence theorems under mild assumptions on parameters. The results presented in this paper improve and generalize the main result of Yao et al. (2007).
Charge Transport Mechanism in Thin Cuticles Holding Nandi Flame Seeds
Authors: Kipnusu Wycliffe K. , Katana Gabriel , Migwi Charles M. , Rathore I. V. S. , Sangoro Joshua R.
Published: July 2009

Metal‐sample‐metal sandwich configuration has been used to investigate DC conductivity in 4 μm thick Nandi flame [Spathodea campanulata P. Beauv.] seed cuticles. J‐V characteristics showed ohmic conduction at low fields and space charge limited current at high fields. Charge mobility in ohmic region was 4.06 × 10−5  (m2V−1s−1). Temperature‐dependent conductivity measurements have been carried out in the temperature range 320 K  450 K. Activation energy within a temperature of 320 K–440 K was about 0.86 eV. Variable range hopping (VRH) is the main current transport mechanism at the range of 330–440 K. The VRH mechanism was analyzed based on Mott theory and the Mott parameters: density of localized states near the Fermi‐level N(EF) ≈ 9.04 × 1019  (eV−1cm−3) and hopping distance R ≈ 1.44 × 10−7 cm, while the hopping energy (W) was in the range of 0.72 eV–0.98 eV.
The Differential Gene Expression Pattern ofMycobacterium tuberculosisin Response to Capreomycin and PA-824 versus First-Line TB Drugs Reveals Stress- and PE/PPE-Related Drug Targets
Authors: Fu Li M. , Tai Shu C.
Published: July 2009

Tuberculosis is a leading infectious disease causing millions of deaths each year. How to eradicate mycobacterial persistence has become a central research focus for developing next-generation TB drugs. Yet, the knowledge in this area is fundamentally limited and only a few drugs, notably capreomycin and PA-824, have been shown to be active against non-replicating persistent TB bacilli. In this study, we performed a new bioinformatics analysis on microarray-based gene expression data obtained from the public domain to explore genes that were differentially induced by drugs between the group of capreomycin and PA-824 and the group of mainly the first-line TB drugs. Our study has identified 42 genes specifically induced by capreomycin and PA-824. Many of these genes are related to stress responses. In terms of the distribution of identified genes in a specific category relative to the whole genome, only the categories of PE/PPE and conserved hypotheticals have statistical significance. Six among the 42 genes identified in this study are on the list of the top 100 persistence targets selected by the TB Structural Genomics Consortium. Further biological elucidation of their roles in mycobacterial persistence is warranted.
Laser Beam Welding of AA5052, AA5083, and AA6061 Aluminum Alloys
Authors: El-Batahgy A. , Kutsuna M.
Published: July 2009

The present investigation was mainly concerned with characteristics of autogeneous laser butt welding of 2 mm thickness nonheat treatableAA5052‐H12,AA5083‐H12 and 2 mm, 3 mm
thickness heat treatableAA6061‐T6aluminum alloys. The effect of laser welding parameters,
surface cleaning, filler wire addition, and backing strip on quality of laser welded joints was clarified
using 5 kW CO2 laser machine.
It was found that all the investigated alloys showed tendencies for porosity and solidification cracking,
particularly, at high welding speed (≥4 m/min). Porosity was prevented by accurate cleaning of the
base metal prior to welding and optimizing the flow rate of argon shielding gas. Solidification cracking
was avoided through two different approaches. The first one is based on the addition of filler metal
as reported in other research works. The other new approach is concerned with autogeneous
welding using a backing strip from the same base metal, and this could be applicable in production.
Preventing solidification cracking in both cases was related mainly to a considerable decrease in the
stress concentration at the weld metal center as a result of improving the fusion zone profile.
The implementation of the new approach could help in producing weldments with a better quality due
to the absence of the filler metal, which is known as a source for hydrogen‐related porosity. It can
also have a positive economic aspect concerning the manufacturing cost since welding is done
without the addition of filler metal. Not only quality and economic positive aspects could be
achieved, but also high productivity is another feature since high quality autogeneous weldments were
produced with high welding speed, 6 m/min. Hardness measurements and tensile test of AA6061 alloy welds indicated a remarkable softening of the fusion zone due to dissolution of the strengthening precipitates, and this was recovered by aging treatment after welding. For alloys AA5052 and AA5083, softening of the fusion zone due to the
loss of its work‐hardened condition was much less in comparison with AA6061 alloy.
The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by Progastrin in Human Colorectal Cancer Cells
Authors: Pannequin Julie , Bonnans Caroline , Delaunay Nathalie , Ryan Joanne , Bourgaux Jean-François , Joubert Dominique , Hollande Frédéric
Published: July 2009

The Wnt and Notch signaling pathways are both abnormally activated in colorectal cancer (CRC). We recently showed that progastrin depletion inhibited Wnt signaling and increased goblet cell differentiation of CRC cells. Here, we show that progastrin down-regulation restores the expression by CRC cells of the early secretory lineage marker Math-1/Hath-1 due to an inhibition of Notch signaling. This effect is mediated by a decreased transcription of the Notch ligand Jagged-1, downstream of β-catenin/Tcf-4. Accordingly, recombinant progastrin sequentially activated the transcription of Wnt and Notch target genes in progastrin-depleted cells. In addition, restoration of Jagged-1 levels in these cells is sufficient to activate Tcf-4 activity, demonstrating the occurrence of a feedback regulation from Notch toward Wnt signaling. These results suggest that progastrin could be instrumental in maintaining the concomitant activation of Wnt and Notch pathways in CRC cells, further highlighting the interest of progastrin targeting for the clinical management of CRC. [Cancer Res 2009;69(15):6065–73]
Comparison of Human and Rat Uterine Leiomyomata: Identification of a Dysregulated Mammalian Target of Rapamycin Pathway
Authors: Crabtree Judy S. , Jelinsky Scott A. , Harris Heather A. , Choe Sung E. , Cotreau Monette M. , Kimberland Michelle L. , Wilson Ewa , Saraf Kathryn A. , Liu Wei , McCampbell Adrienne S. , Dave Bhuvanesh , Broaddus Russell R. , Brown Eugene L. , Kao Wenling , Skotnicki Jerauld S. , Abou-Gharbia Magid , Winneker Richard C. , Walker Cheryl L.
Published: July 2009

Uterine leiomyomata, or fibroids, are benign tumors of the uterine myometrium that significantly affect up to 30% of reproductive-age women. Despite being the primary cause of hysterectomy in the United States, accounting for up to 200,000 procedures annually, the etiology of leiomyoma remains largely unknown. As a basis for understanding leiomyoma pathogenesis and identifying targets for pharmacotherapy, we conducted transcriptional profiling of leiomyoma and unaffected myometrium from humans and Eker rats, the best characterized preclinical model of leiomyomata. A global comparison of mRNA from leiomyoma versus myometrium in human and rat identified a highly significant overlap of dysregulated gene expression in leiomyomata. An unbiased pathway analysis using a method of gene-set enrichment based on the sigPathway algorithm detected the mammalian target of rapamycin (mTOR) pathway as one of the most highly up-regulated pathways in both human and rat tumors. To validate this pathway as a therapeutic target for uterine leiomyomata, preclinical studies were conducted in Eker rats. These rats develop uterine leiomyomata as a consequence of loss of Tsc2 function and up-regulation of mTOR signaling. Inhibition of mTOR in female Eker rats with the rapamycin analogue WAY-129327 for 2 weeks decreased mTOR signaling and cell proliferation in tumors, and treatment for 4 months significantly decreased tumor incidence, multiplicity, and size. These results identify dysregulated mTOR signaling as a component of leiomyoma etiology across species and directly show the dependence of uterine leiomyomata with activated mTOR on this signaling pathway for growth. [Cancer Res 2009;69(15):6171–8]
CTLA4Variants, UV-Induced Tolerance, and Risk of Non-Melanoma Skin Cancer
Authors: Welsh Marleen M. , Applebaum Katie M. , Spencer Steven K. , Perry Ann E. , Karagas Margaret R. , Nelson Heather H.
Published: July 2009

Although skin tumors are highly immunogenic, exposure to UV radiation is known to suppress immune responses via regulatory T cells. Specifically, the activity of cytotoxic lymphocyte-associated antigen-4 (CTLA-4) is integral in regulating the development of UV-induced tolerance and, concomitantly, skin cancers. Due to the inverse relationship between tumor surveillance and autoimmunity, we hypothesize that the same genetic variant in the CTLA4 locus that increases risk for autoimmune diseases is associated with decreased risk of non-melanoma skin cancer (NMSC). We analyzed whether the polymorphism CT60 or haplotypes of CTLA4 influence odds of developing the major types of NMSC, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), in a population-based case-control study of Caucasians in New Hampshire (849 controls, 930 BCC, and 713 SCC). The CTLA4 CT60 GG genotype was associated with decreased odds for BCC and SCC, controlling for age, sex, lifetime number of severe sunburns, and skin type [BCC: odds ratio (OR), 0.7; 95% confidence interval (95% CI), 0.5-0.9; SCC: OR, 0.7; 95% CI, 0.5-1.0]. For BCC, this decrease was apparent largely among those with a higher lifetime number of severe sunburns (Pinteraction = 0.0074). There were significantly decreased odds of disease associated with two haplotypes, which possess the CT60 G allele. Additionally, lifetime number of severe sunburns modestly altered the effects of the CTLA4 haplotypes in BCC, and the association seemed driven by the CT60 single nucleotide polymorphism. In conclusion, genetic variation at the CTLA4 locus may be etiologically important in NMSC, the most prevalent malignancy in the United States. [Cancer Res 2009;69(15):6158–63]
Complete Regression of Advanced Primary and Metastatic Mouse Melanomas following Combination Chemoimmunotherapy
Authors: Kohlmeyer Judith , Cron Mira , Landsberg Jennifer , Bald Tobias , Renn Marcel , Mikus Sandra , Bondong Sandra , Wikasari Diana , Gaffal Evelyn , Hartmann Gunther , Tüting Thomas
Published: July 2009

The development of therapeutic strategies which induce effective cellular antitumor immunity represents an important goal in cancer immunology. Here, we used the unique features of the genetically engineered Hgf-Cdk4R24C mouse model to identify a combination chemoimmunotherapy for melanoma. These mice develop primary cutaneous melanomas which grow progressively and metastasize in the absence of immunogenic foreign proteins such as oncogenes or antigens. Primary and metastatic tumors evade innate and adaptive immune defenses, although they naturally express melanocytic antigens which can be recognized by antigen-specific T cells. We found that primary melanomas continued to grow despite infiltration with adoptively transferred, in vivo–activated, tumor-specific CD8+ T cells. To promote tumor immune defense, we developed a treatment protocol consisting of four complementary components: (a) chemotherapeutic preconditioning prior to (b) adoptive lymphocyte transfer and (c) viral vaccination followed by (d) adjuvant peritumoral injections of immunostimulatory nucleic acids. Lymphocyte ablation and innate antiviral immune stimulation cooperatively enhanced the expansion and the effector cell differentiation of adoptively transferred lymphocytes. The efficacy of the different treatment approaches converged in the tumor microenvironment and induced a strong cytotoxic inflammatory response enabling preferential recognition and destruction of melanoma cells. This combination chemoimmunotherapy caused complete regression of advanced primary melanomas in the skin and metastases in the lung with minimal autoimmune side effects. Our results in a clinically highly relevant experimental model provide a scientific rationale to evaluate similar strategies which unleash the power of innate and adaptive immune defense in future clinical trials. [Cancer Res 2009;69(15):6265–74]
Dynamic Contrast-enhanced Magnetic Resonance Imaging as a Predictor of Clinical Outcome in Canine Spontaneous Soft Tissue Sarcomas Treated with Thermoradiotherapy
Authors: Viglianti Benjamin L. , Lora-Michiels Michael , Poulson Jeanie M. , Lan Lan , Yu Dahio , Sanders Linda , Craciunescu Oana , Vujaskovic Zeljko , Thrall Donald E. , MacFall James , Charles Cecil H. , Wong Terence , Dewhirst Mark W.
Published: July 2009

Purpose: This study tests whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters obtained from canine patients with soft tissue sarcomas, treated with hyperthermia and radiotherapy, are predictive of therapeutic outcome.

Experimental Design: Thirty-seven dogs with soft tissue sarcomas had DCE-MRI done before and following the first hyperthermia. Signal enhancement for tumor and reference muscle were fitted empirically, yielding a washin/washout rate for the contrast agent and tumor area under the signal enhancement curve (AUC) calculated from 0 to 60 seconds, 90 seconds, and the time of maximal enhancement in the reference muscle. These parameters were then compared with local tumor control, metastasis-free survival, and overall survival.

Results: Pretherapy rate of contrast agent washout was positively predictive of improved overall and metastasis-free survival with hazard ratio of 0.67 (P = 0.015) and 0.68 (P = 0.012), respectively. After the first hyperthermia washin rate, AUC60, AUC90, and AUCt-max were predictive of improved overall and metastasis-free survival with hazard ratio ranging from 0.46 to 0.53 (P < 0.002) and 0.44 to 0.55 (P < 0.004), respectively. DCE-MRI parameters were compared with extracellular pH and 31P MR spectroscopy results (previously published) in the same patients showing a correlation. This suggested that an increase in perfusion after therapy was effective in eliminating excess acid from the tumor.

Conclusions: This study shows that DCE-MRI has utility predicting overall and metastasis-free survival in canine patients with soft tissue sarcomas. To our knowledge, this is the first time that DCE-MRI parameters are predictive of clinical outcome for soft tissue sarcomas.
HER Family Receptor Abnormalities in Lung Cancer Brain Metastases and Corresponding Primary Tumors
Authors: Sun Menghong , Behrens Carmen , Feng Lei , Ozburn Natalie , Tang Ximing , Yin Guosheng , Komaki Ritsuko , Varella-Garcia Marileila , Hong Waun Ki , Aldape Kenneth D. , Wistuba Ignacio I.
Published: July 2009

Purpose: To compare the characteristics of deregulation of HER receptors and their ligands between primary tumor and corresponding brain metastases of non–small cell lung carcinoma (NSCLC).

Experimental Design: Fifty-five NSCLC primary tumors and corresponding brain metastases specimens were examined for the immunohistochemical expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, Her2, Her3, and phosphorylated Her3, and their ligands EGF, transforming growth factor-α, amphiregulin, epiregulin, betacellulin, heparin-binding EGFR-like growth factor, neuregulin (NRG) 1, and NRG2. Analysis of EGFR copy number using fluorescence in situ hybridization and mutation by PCR-based sequencing was also done.

Results: Metastases showed significantly higher immunohistochemical expression of EGF (membrane: brain metastases 66.0 versus primary tumors 48.5; P = 0.027; nucleus: brain metastases 92.2 versus 67.4; P = 0.008), amphiregulin (nucleus: brain metastases 53.7 versus primary tumors 33.7; P = 0.019), phosphorylated EGFR (membrane: brain metastases 161.5 versus primary tumors 76.0; P < 0.0001; cytoplasm: brain metastases 101.5 versus primary tumors 55.9; P = 0.014), and phosphorylated Her3 (membrane: brain metastases 25.0 versus primary tumors 3.7; P = 0.001) than primary tumors did. Primary tumors showed significantly higher expression of cytoplasmic transforming growth factor-α(primary tumors 149.8 versus brain metastases 111.3; P = 0.008) and NRG1 (primary tumors 158.5 versus brain metastases 122.8; P = 0.006). In adenocarcinomas, a similar high frequency of EGFR copy number gain (high polysomy and amplification) was detected in primary (65%) and brain metastasis (63%) sites. However, adenocarcinoma metastases (30%) showed higher frequency of EGFR amplification than corresponding primary tumors (10%). Patients whose primary tumors showed EGFR amplification tended to develop brain metastases at an earlier time point.

Conclusions: Our findings suggest that NSCLC brain metastases have some significant differences in HER family receptor–related abnormalities from primary lung tumors.
Differential Genetic and Functional Markers of Second Neoplasias in Hodgkin's Disease Patients
Authors: Lorenzo Yolanda , Provencio Mariano , Lombardía Luís , Díaz Raquel , Silva Javier , Herrera Mercedes , García Jose M. , Peña Cristina , García Vanesa , Romero Jesús , Domínguez Gemma , Bonilla Félix
Published: July 2009

Purpose: The mechanisms involved in the appearance of a second neoplasia in patients with Hodgkin's disease (HD) are probably related to the genomic damage induced by the treatments administered and its repair. Here, we searched for some constitutive molecular mechanisms that in a basal manner may influence the behavior of HD patients.

Experimental Design: We aimed to evaluate with the Comet Assay whether baseline, induced, and unrepaired DNA damage differ between HD patients who did not develop a second neoplasia (HD-NST), HD patients who developed a second tumor (HD-ST), and healthy individuals; and to identify, through cDNA microarray hybridization, an expression signature of genes that could discriminate between the three groups.

Results: Baseline, induced, and unrepaired DNA damage was higher in HD-ST than in HD-NST and higher in the second group than in healthy donors. The genomic approach revealed two sets of genes that discriminated between healthy subjects and patients and between the three sets of individuals. Hsp40, RAD50, TPMT, Rap2a, E2F2, EPHX2, TBX21, and BATF were validated by reverse transcription-PCR.

Conclusions: Functional and genomic techniques revealed that alterations in cell cycle, repair, detoxification, and stress response pathways could be involved in the development of HD and in the occurrence of a primary second neoplasia in these patients. Both approaches may be useful as biological markers in the clinical setting.
Clinical and Immunologic Effects of Intranodal Autologous Tumor Lysate-Dendritic Cell Vaccine with Aldesleukin (Interleukin 2) and IFN-α2a Therapy in Metastatic Renal Cell Carcinoma Patients
Authors: Schwaab Thomas , Schwarzer Adrian , Wolf Benita , Crocenzi Todd S. , Seigne John D. , Crosby Nancy A. , Cole Bernard F. , Fisher Jan L. , Uhlenhake Jill C. , Mellinger Diane , Foster Cathy , Szczepiorkowski Zbigniew M. , Webber Susan M. , Schned Alan R. , Harris Robert D. , Barth Richard J. , Heaney John A. , Noelle Randolph J. , Ernstoff Marc S.
Published: July 2009

Purpose: To evaluate the clinical and immunologic outcomes of DC (dendritic cell) vaccine with interleukin (IL)-2 and IFN-α 2a in metastatic renal cell carcinoma patients.

Experimental Design: Eighteen consented and eligible patients were treated. Peripheral blood monocytes were cultured ex vivo into mature DCs and loaded with autologous tumor lysate. Treatment consisted of five cycles of intranodal vaccination of DCs (1 × 107 cells/1 mL Lactated Ringer's solution), 5-day continuous i.v. infusion of IL-2 (18MiU/m2), and three s.c. injections of IFN-α 2a (6MiU) every other day. Response Evaluation Criteria in Solid Tumors criteria were used for disease assessment. Correlative immunologic end points included peripheral blood lymphocyte cell phenotype and function as well as peripheral blood anti–renal cell carcinoma antibody and cytokine levels.

Results: All patients received between two and five treatment cycles. Toxicities consisted of known and expected cytokine side effects. Overall objective clinical response rate was 50% with three complete responses. Median time to progression for all patients was 8 months, and median survival has not been reached (median follow up of 37+ months). Treatment-related changes in correlative immunologic end points were noted and the level of circulating CD4+ T regulatory cells had a strong association with outcome. Pre–IP-10 serum levels approached significance for predicting outcome.

Conclusions: The clinical and immunologic responses observed in this trial suggest an interaction between DC vaccination and cytokine therapy. Our data support the hypothesis that modulation of inflammatory, regulatory, and angiogenic pathways are necessary to optimize therapeutic benefit in renal cell carcinoma patients. Further exploration of this approach is warranted.
Growth Inhibition of Human Multiple Myeloma Cells by an Oncolytic Adenovirus Carrying the CD40 Ligand Transgene
Authors: Fernandes Margret S. , Gomes Erica M. , Butcher Lindsay D. , Hernandez-Alcoceba Reuben , Chang Dongkun , Kansopon Joe , Newman Joseph , Stone Marvin J. , Tong Alex W.
Published: July 2009

Purpose: The growth-inhibitory activity of recombinant CD40 ligand (CD40L) is well documented in human multiple myeloma (MM). We examined MM-targeted delivery of CD40L by a conditional replicative oncolytic adenovirus, AdEHCD40L.

Experimental Design: The growth-regulatory activity of AdEHCD40L was determined in vitro and in vivo. Differential analysis with AdEHCD40L and parental virus (AdEHNull)–infected cultures allowed the identification of cellular and molecular pathways modulated by the CD40L transgene.

Results: Conditional expression of viral E1A and CD40L transgene was shown in human MM lines RPMI 8226 [interleukin (IL)-6 independent] and Kas-6/1 (IL-6 dependent) under hypoxic conditions commonly found in MM in situ. AdEHCD40L inhibited MM cell growth more effectively than AdEHNull. This enhanced growth-inhibitory activity was abrogated by cotreatment with a CD40L antibody. Chemoresistant MM lines (MR20 and LR5) were similarly susceptible to AdEHCD40L treatment. AdEHCD40L induced apoptosis and S-phase cell cycle blockade while uniquely up-regulating the previously described proapoptotic elements tumor necrosis factor–related apoptosis-inducing ligand, Fas, and IL-8. Intratumoral injections of AdEHCD40L reduced the growth of severe combined immunodeficient/hu RPMI 8226 xenografts by >50% compared with 28% reduction by AdEHNull. Adenoviral hexon and CD40L were detected in AdEHCD40L-treated tumors at day 35 after infection primarily in necrotic areas, suggesting viral replicative activity.

Conclusions: These findings show that CD40L acts in concert with viral oncolysis to produce MM growth inhibition through activation of cellular apoptosis. The direct growth-inhibitory activity of AdEHCD40L, together with the well-known immune-potentiating features of CD40L, may be clinically applicable for the experimental treatment of MM or plasma cell leukemia.