bluuebunny/crossref_metadata_2025 huggingface dataset:
Subversion of Protein Kinase Cα Signaling in Hematopoietic Progenitor Cells Results in the Generation of a B-Cell Chronic Lymphocytic Leukemia–Like Population In vivo
Authors: Nakagawa Rinako , Soh Jae Won , Michie Alison M.
Published: January 2006

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of long-lived mature B cells with the distinctive phenotype CD19hi CD5+ CD23+ IgMlo, which are refractory to apoptosis. An increased level of apoptosis has been observed on treatment of human B-CLL cells with protein kinase C (PKC) inhibitors, suggesting that this family of protein kinases mediate survival signals within B-CLL cells. Therefore, to investigate the ability of individual PKC isoforms to transform developing B cells, we stably expressed plasmids encoding PKC mutants in fetal liver–derived hematopoietic progenitor cells (HPC) from wild-type mice and then cultured them in B-cell generation systems in vitro and in vivo. Surprisingly, we noted that expression of a plasmid-encoding dominant-negative PKCα (PKCα-KR) in HPCs and subsequent culture both in vitro and in vivo resulted in the generation of a population of cells that displayed an enhanced proliferative capacity over untransfected cells and phenotypically resemble human B-CLL cells. In the absence of growth factors and stroma, these B-CLL-like cells undergo cell cycle arrest and, consistent with their ability to escape growth factor withdrawal-induced apoptosis, exhibited elevated levels of Bcl-2 expression. These studies therefore identify a unique oncogenic trigger for the development of a B-CLL-like disease resulting from the subversion of PKCα signaling. Our findings uncover novel avenues not only for the study of the induction of leukemic B cells but also for the development of therapeutic drugs to combat PKCα-regulated transformation events. (Cancer Res 2006; 66(1): 527-34)
Protease-Activated Receptor-2 Is Essential for Factor VIIa and Xa–Induced Signaling, Migration, and Invasion of Breast Cancer Cells
Authors: Morris Dionne R. , Ding Yu , Ricks Tiffany K. , Gullapalli Anuradha , Wolfe Breann L. , Trejo JoAnn
Published: January 2006

Protease-activated receptors (PAR) are G protein–coupled receptors that function as cell-surface sensors for coagulant proteases, as well as other proteases associated with the tumor microenvironment. PAR1 is activated by thrombin whereas the upstream coagulant protease VIIa bound to tissue factor and Xa can activate both PAR1 and PAR2. PAR1 has been implicated in tumor cell growth, migration, and invasion whereas the function of PAR2 in these processes is largely unknown. Towards defining the functional importance of PAR2 in cancer cells, we used small interfering RNAs to deplete highly invasive breast cancer cells of endogenous PAR proteins. Our findings strongly suggest that PAR2 is critical for MDA-MB-231 and BT549 breast cancer cell migration and invasion towards NIH 3T3 fibroblast conditioned medium. To define the relative importance of PAR1 versus PAR2 in mediating factor VIIa and Xa responses, we assessed signaling in cancer cells lacking either endogenous PAR1 or PAR2 proteins. Strikingly, in MDA-MB-231 cells depleted of PAR2, we observed a marked inhibition of VIIa and Xa signaling to phosphoinositide hydrolysis and extracellular signal–regulated kinase 1/2 activation whereas signaling by VIIa and Xa remained intact in PAR1-deficient cells. Factor VIIa and Xa–induced cellular migration was also impaired in MDA-MB-231 cells deficient in PAR2 but not in cells lacking PAR1. Together, these studies reveal the novel findings that PAR2, a second protease-activated G protein–coupled receptor, has a critical role in breast cancer cell migration and invasion and functions as the endogenous receptor for coagulant proteases VIIa and Xa in these cells. (Cancer Res 2006; 66(1): 307-14)
Influence of Insulin-like Growth Factors on the Strength of the Relation of Vitamin D and Calcium Intakes to Mammographic Breast Density
Authors: Diorio Caroline , Bérubé Sylvie , Byrne Celia , Mâsse Benoît , Hébert-Croteau Nicole , Yaffe Martin , Coté Gary , Pollak Michael , Brisson Jacques
Published: January 2006

Diets with higher vitamin D and calcium contents were found associated with lower mammographic breast density and breast cancer risk in premenopausal women. Because laboratory studies suggest that the actions of vitamin D, calcium, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 (IGFBP-3) on human breast cancer cells are interrelated, we examined whether IGF-I and IGFBP-3 levels could affect the strength of the association of vitamin D and calcium intakes with breast density. Among 771 premenopausal women, breast density was measured by a computer-assisted method, vitamin D and calcium intakes by a food frequency questionnaire, and levels of plasma IGF-I and IGFBP-3 by ELISA methods. Multivariate linear regression models were used to examine the associations and the interactions. The negative associations of vitamin D or calcium intakes with breast density were stronger among women with IGF-I levels above the median (β = −2.8, P = 0.002 and β = −2.5, P = 0.002, respectively) compared with those with IGF-I levels below or equal to the median (β = −0.8, P = 0.38 and β = −1.1, P = 0.21; Pinteraction = 0.09 and 0.16, respectively). Similar results were observed within levels of IGFBP-3 (Pinteraction = 0.06 and 0.03, respectively). This is the first study to report that the negative relation of vitamin D and calcium intakes with breast density may be seen primarily among women with high IGF-I or high IGFBP-3 levels. Our findings suggest that the IGF axis should be taken into account when the effects of vitamin D and calcium on breast density (and perhaps breast cancer risk) are examined at least among premenopausal women. (Cancer Res 2006; 66(1): 588-97)
Doxazosin Induces Apoptosis of Benign and Malignant Prostate Cells via a Death Receptor–Mediated Pathway
Authors: Garrison Jason B. , Kyprianou Natasha
Published: January 2006

Quinazoline-based α1-adrenoceptor antagonists such as doxazosin and terazosin have been previously shown to induce apoptosis in prostate cancer cells via an α1-adrenoceptor–independent pathway, involving activation of transforming growth factor-β1 (TGF-β1) signaling. In this study, the molecular events initiating this apoptotic effect were further investigated in vitro using the human androgen-independent prostate cancer cells PC-3 and the human benign prostate epithelial cells BPH-1. Quantitative microarray assays were done in PC-3 and BPH-1 cells after treatment with doxazosin (25 μmol/L, 6 and 24 hours) to identify the early gene changes. Transient changes in the expression of several apoptosis regulators were identified, including up-regulation of Bax and Fas/CD95 and down-regulation of Bcl-xL and TRAMP/Apo3. Moreover, there were significant changes in the expression pattern of signaling components of the extracellular matrix such as integrins α2, αV, β1, and β8. Western blot analysis revealed activation of caspase-8 and caspase-3 within the first 6 to 12 hours of treatment with doxazosin in both PC-3 and BPH-1 cells. Doxazosin-induced apoptosis was blocked by specific caspase-8 inhibitors, supporting the functional involvement of caspase-8 in doxazosin-induced apoptosis. The effect of doxazosin on recruitment of Fas-associated death domain (FADD) and procaspase-8 to the Fas receptor was examined via analysis of death-inducing signaling complex formation. Doxazosin increased FADD recruitment and subsequent caspase-8 activation, implicating Fas-mediated apoptosis as the underlying mechanism of the effect of doxazosin in prostate cells. These results show that doxazosin exerts its apoptotic effects against benign and malignant prostate cells via a death receptor–mediated mechanism with a potential integrin contribution towards cell survival outcomes. (Cancer Res 2006; 66(1): 464-72)
Pathology of Genetically Engineered Mouse Models of Pancreatic Exocrine Cancer: Consensus Report and Recommendations
Authors: Hruban Ralph H. , Adsay N. Volkan , Albores-Saavedra Jorge , Anver Miriam R. , Biankin Andrew V. , Boivin Gregory P. , Furth Emma E. , Furukawa Toru , Klein Alison , Klimstra David S. , Klőppel Gűnter , Lauwers Gregory Y. , Longnecker Daniel S. , Lűttges Jutta , Maitra Anirban , Offerhaus G. Johan A. , Pérez-Gallego Lucía , Redston Mark , Tuveson David A.
Published: January 2006

Several diverse genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These mouse models have a spectrum of pathologic changes; however, until now, there has been no uniform nomenclature to characterize these changes. An international workshop, sponsored by The National Cancer Institute and the University of Pennsylvania, was held from December 1 to 3, 2004 with the goal of establishing an internationally accepted uniform nomenclature for the pathology of genetically engineered mouse models of pancreatic exocrine neoplasia. The pancreatic pathology in 12 existing mouse models of pancreatic neoplasia was reviewed at this workshop, and a standardized nomenclature with definitions and associated images was developed. It is our intention that this nomenclature will standardize the reporting of genetically engineered mouse models of pancreatic exocrine neoplasia, that it will facilitate comparisons between genetically engineered mouse models and human pancreatic disease, and that it will be broad enough to accommodate newly emerging mouse models of pancreatic neoplasia. (Cancer Res 2006; 66(1): 95-106)
Mist1-KrasG12D Knock-In Mice Develop Mixed Differentiation Metastatic Exocrine Pancreatic Carcinoma and Hepatocellular Carcinoma
Authors: Tuveson David A. , Zhu Liqin , Gopinathan Aarthi , Willis Nicholas A. , Kachatrian Leili , Grochow Rebecca , Pin Christopher L. , Mitin Natalia Y. , Taparowsky Elizabeth J. , Gimotty Phyllis A. , Hruban Ralph H. , Jacks Tyler , Konieczny Stephen F.
Published: January 2006

Despite the prevalence of oncogenic Kras mutations in the earliest stages of pancreatic ductal adenocarcinoma, the cellular compartment in which oncogenic Kras initiates tumorigenesis remains unknown. To address this, we have gene targeted KrasG12D into the open reading frame of Mist1, a basic helix-loop-helix transcription factor that is expressed during pancreatic development and required for proper pancreatic acinar organization. Although the pancreata of Mist1KrasG12D/+ mutant mice predictably exhibited acinar metaplasia and dysplasia, the frequent death of these mice from invasive and metastatic pancreatic cancer with mixed histologic characteristics, including acinar, cystic, and ductal features, was unexpected and in contrast to previously described mutant mice that ectopically expressed the Kras oncogene in either acinar or ductal compartments. Interestingly, many of the mutant mice developed hepatocellular carcinoma, implicating Mist1KrasG12D/+ cells in both pancreatic and hepatic neoplasia. Concomitant Trp53+/− mutation cooperated with Mist1KrasG12D/+ to accelerate lethality and was associated with advanced histopathologic findings, including parenchymal liver metastasis. These findings suggest that Mist1-expressing cells represent a permissive compartment for transformation by oncogenic Kras in pancreatic tumorigenesis. (Cancer Res 2006; 66(1): 242-7)
Genetically Induced Pancreatic Adenocarcinoma Is Highly Immunogenic and Causes Spontaneous Tumor-Specific Immune Responses
Authors: Garbe Annette I. , Vermeer Benjamin , Gamrekelashvili Jaba , Wasielewski Reinhard von , Greten Florian R. , Westendorf Astrid M. , Buer Jan , Schmid Roland M. , Manns Michael P. , Korangy Firouzeh , Greten Tim F.
Published: January 2006

Treatment options for pancreatic cancer are limited and often ineffective. Immunotherapeutic approaches are one possible option that needs to be evaluated in appropriate animal models. The aim of the present study was to analyze tumor-specific immune responses in a mouse model of pancreatic cancer, which mimics the human disease closely. C57BL/6 EL-TGF-α × Trp53−/− mice, which develop spontaneous ductal pancreatic carcinoma, were generated. EL-TGF-α × Trp53−/− mice developed spontaneous pancreatic tumors with pathomorphologic features close to the human disease. Tumor-specific CD8+ T-cell responses and IgG responses were analyzed in EL-TGF-α × Trp53−/− mice during tumor development and compared with mice with s.c. growing pancreatic tumors. In contrast to spontaneous pancreatic tumors, cell lines generated from these tumors were rejected after s.c. injection into wild-type mice but not in nude or RAG knockout mice. Direct comparison of spontaneous and s.c. injected tumors revealed an impaired infiltration of CD8+ T cells in spontaneous pancreatic tumors, which was also evident after adoptive transfer of tumor-specific T cells. Intratumoral cytokine secretion of tumor necrosis factor-α, IFN-γ, IL-6, and MCP-1 was lower in spontaneous tumors as well as the number of adoptively transferred tumor-specific T cells. Our data provide clear evidence for tumor-specific immune responses in a genetic mouse model for pancreatic carcinoma. Comparative analysis of s.c. injected tumors and spontaneous tumors showed significant differences in tumor-specific immune responses, which will help in improving current immune-based cancer therapies against adenocarcinoma of the pancreas. (Cancer Res 2006; 66(1): 508-16)
Breast Cancer DNA Methylation Profiles in Cancer Cells and Tumor Stroma: Association with HER-2/neu Status in Primary Breast Cancer
Authors: Fiegl Heidi , Millinger Simone , Goebel Georg , Müller-Holzner Elisabeth , Marth Christian , Laird Peter W. , Widschwendter Martin
Published: January 2006

The HER-2/neu gene is amplified and overexpressed in 20% to 30% of invasive breast carcinomas and is associated with increased metastatic potential and less tamoxifen sensitivity. We generated the DNA methylation profiles of 143 human breast tumors and found significant differences in HER-2/neu expression and DNA methylation of five genes. For three of these five genes [PGR (coding for the progesterone receptor), HSD17B4 (coding for type 4 17-β-hydroxysteroid dehydrogenase, an enzyme that mainly degrades active 17-β-estradiol into inactive metabolites), and CDH13 (coding for H-cadherin)] a higher prevalence of DNA methylation in HER-2/neu-positive cancers was confirmed in an independent set of microdissected primary breast cancers. DNA methylation was not only present in cancer cells but also in the tumor stroma fraction. Of the isolated fractions in HER-2/neu-positive versus -negative cancers, 27.1% versus 10.5%, respectively, showed DNA methylation of the five genes (P = 0.011, Fisher's exact test). In Her-2++/+++ breast cancers, HSD17B4 mRNA expression was inversely associated with HSD17B4 methylation (P = 0.04). These data support the view that in addition to HER-2/neu-associated signaling, epigenetic changes in cancer as well as in tumor stroma cells might attribute to the specific biological features of HER-2/neu-positive cancers. (Cancer Res 2006; 66(1): 29-33)
Loss of DNA Polymerase ζ Causes Chromosomal Instability in Mammalian Cells
Authors: Wittschieben John P. , Reshmi Shalini C. , Gollin Susanne M. , Wood Richard D.
Published: January 2006

Rev3L encodes the catalytic subunit of DNA polymerase ζ (pol ζ) in mammalian cells. In yeast, pol ζ helps cells bypass sites of DNA damage that can block replication enzymes. Targeted disruption of the mouse Rev3L gene causes lethality midway through embryonic gestation, and Rev3L−/− mouse embryonic fibroblasts (MEFs) remain in a quiescent state in culture. This suggests that pol ζ may be necessary for tolerance of endogenous DNA damage during normal cell growth. We report the generation of mitotically active Rev3L−/− MEFs on a p53−/− genetic background. Rev3L null MEFs exhibited striking chromosomal instability, with a large increase in translocation frequency. Many complex genetic aberrations were found only in Rev3L null cells. Rev3L null cells had increased chromosome numbers, most commonly near pentaploid, and double minute chromosomes were frequently found. This chromosomal instability associated with loss of a DNA polymerase activity in mammalian cells is similar to the instability associated with loss of homologous recombination capacity. Rev3L null MEFs were also moderately sensitive to mitomycin C, methyl methanesulfonate, and UV and γ-radiation, indicating that mammalian pol ζ helps cells tolerate diverse types of DNA damage. The increased occurrence of chromosomal translocations in Rev3L−/− MEFs suggests that loss of Rev3L expression could contribute to genome instability during neoplastic transformation and progression. (Cancer Res 2006; 66(1): 134-42)
Mutant SOD1 Instability: Implications for Toxicity in Amyotrophic Lateral Sclerosis
Authors: Tiwari Ashutosh , Hayward Lawrence J.
Published: January 2006

The biological basis of preferential motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remains incompletely understood, and effective therapies to prevent the lethal consequences of this disorder are not yet available. Since 1993, more than 100 mutant variants of the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1) have been identified in familial ALS. Many studies have sought to distinguish abnormal properties shared by these proteins that may contribute to their toxic effects and cause age-dependent motor neuron loss. Complex networks of cellular interactions and changes associated with aging may link mutant SOD1s and other stresses to motor neuron death in ALS. Our laboratory and collaborators have compared physicochemical properties of biologically metallated wild-type and mutant SOD1 proteins to discern specific vulnerabilities that may be relevant to the mutant toxicity in vivo. X-ray crystal structures obtained from metallated ‘wild-type-like’ (WTL) SOD1 mutants, which retain the ability to bind copper and zinc and exhibit normal specific activity, indicate a native-like structure with only subtle changes to the backbone fold. In contrast, a group of ‘metal-binding region’ (MBR) SOD1 mutants that are deficient in copper and zinc exhibit severe thermal destabilization and structural disorder of conserved loops near the metal-binding sites. A growing body of evidence highlights specific stresses in vivo that may perturb well-folded, metallated SOD1 variants and thereby favor an increased burden of partially unfolded, metal-deficient species. For example, WTL SOD1 mutants are more susceptible than wild-type SOD1 to reduction of the intrasubunit disulfide bond between Cys-57 and Cys-146 at physiological pH and temperature. This bond anchors the disulfide loop to the SOD1 β-barrel and helps to maintain the dimeric configuration of the protein. Cleavage of the disulfide linkage renders the well-folded WTL mutants vulnerable to metal loss and monomerization such that they may resemble the destabilized and locally misfolded MBR mutant species. SOD1 proteins with disordered loops or monomeric structure are expected to be more susceptible to aberrant self-association or detrimental interactions with other cellular constituents. The challenge for future investigations is to relate these abnormal properties of partially unfolded SOD1 to specific mechanisms of toxicity in motor neurons, supporting cells, or target tissues.
Inter- and Intracellular Signaling in Amyotrophic Lateral Sclerosis: Role of p38 Mitogen-Activated Protein Kinase
Authors: Bendotti C. , Bao Cutrona M. , Cheroni C. , Grignaschi G. , Lo Coco D. , Peviani M. , Tortarolo M. , Veglianese P. , Zennaro E.
Published: January 2006

The pathogenetic processes underlying the selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) are complex and still not completely understood even in the cases of inherited disease caused by mutations in the Cu/Zn superoxide dismutase-dependent (SOD1) gene. Recent evidence supports the view that ALS is not a cell-autonomous disease and that glial-neuron cross-talk, throughout cytokines and other toxic factors like the nitric oxide and superoxide, is a crucial determinant for the induction of motor neuron death. This cell-cell interaction may determine the progression of the disease through processes that are likely independent of the initial trigger and that may converge on the activation of intracellular death pathways in the motor neurons. In this review we provide support to the hypothesis that aberrant expression and activity of p38 mitogen protein-activated kinases cascade (p38MAPK) in motor neurons and glial cells may play a role in the development and progression of ALS. Increased activation of p38MAPK may phosphorylate neuron-specific substrates altering their physiological properties and it may turn on responsive genes leading to neurotoxicity.
Preclinical Trials – An Update on Translational Research in ALS
Authors: Ludolph Albert C. , Sperfeld A.-D.
Published: January 2006

Translational research has become a strategy which describes the steps from in vitro experimental therapy, its translation into experimental animals and finally to humans. However, this translation of hypotheses from one of these levels to another faces a number of difficulties which are currently of major interest for the development of therapeutics. In particular, in the previously untreatable motor neuron diseases, the steps from genes to transgenic animals and finally to the patient have proven difficult. High expectations have not met with the transfer of numerous therapies from experimental animals to men; there are many in- and outside the field which already question the value of animal models. It is the opinion of the authors that we should not dismiss the models before we have not defined generally accepted standards of protocols for therapeutic studies in experimental animals. Only if a generally agreed standardized and validated methodology in mice cannot predict the human response to therapeutics, an animal model should be abandoned. In contrast, the value of translating genetic findings to experimental animals and men is currently shown for motor proteins; in particular the functional impact of dynactin and dynein for the integrity of motor neurons of rodents and men are in the center of interest.
Presbyopia: The First Stage of Nuclear Cataract?
Authors: McGinty S.J. , Truscott R.J.W.
Published: January 2006

Presbyopia, the inability to accommodate, affects almost everyone at middle age. Recently, it has been shown that there is a massive increase in the stiffness1 of the lens with age and, since the shape of the lens must change during accommodation, this could provide an explanation for presbyopia. In this review, we propose that presbyopia may be the earliest observable symptom of age-related nuclear (ARN) cataract. ARN cataract is a major cause of world blindness. The genesis of ARN cataract can be traced to the onset of a barrier within the lens at middle age. This barrier restricts the ability of small molecules, such as antioxidants, to penetrate into the centre of the lens leaving the proteins in this region susceptible to oxidation and post-translational modification. Major protein oxidation and colouration are the hallmarks of ARN cataract. We postulate that the onset of the barrier, and the hardening of the nucleus, are intimately linked. Specifically, we propose that progressive age-dependent hardening of the lens nucleus may be responsible for both presbyopia and ARN cataract.
The 5-HT2A –1438 A/G and 5-HTTLPR Polymorphisms and Personality Dimensions in Adolescent Anorexia Nervosa: Association Study
Authors: Rybakowski Filip , Slopien Agnieszka , Dmitrzak-Weglarz Monika , Czerski Piotr , Rajewski Andrzej , Hauser Joanna
Published: January 2006

Disturbances of serotonergic neurotransmission and temperamental vulnerability have both been implicated in the pathogenesis of anorexia nervosa (AN). We genotyped the –1438 A/G polymorphism in the 5-HT2A receptor gene and serotonin transporter linked-polymorphic region (5-HTTLPR) in 132 adolescent subjects with AN and in 93 healthy controls. Personality dimensions in AN patients were assessed with the Temperament and Character Inventory. In a case-control model, we tested the hypothesis that these genetic variants confer susceptibility to AN. We also analyzed whether two polymorphisms show association with temperamental and character traits. No significant difference was found in the 5-HTTLPR frequency between AN patients and controls; however, there was a statistical trend towards a higher frequency of the A allele of the –1438 A/G polymorphism in patients than in controls (64.9 vs. 56.7%, χ2 test, p = 0.08). We also found a significant association between the A allele of this polymorphism and two temperamental traits. Patients homozygous for the A allele showed lower reward dependence than G/G homozygotes, and A/A homozygotes showed lower harm avoidance than heterozygotes. Low reward dependence and harm avoidance were more characteristic of the restrictive-type AN than of other subtypes of the disorder. No association of 5-HTTLPR with personality dimensions in AN patients was observed. Our results may suggest that the A allele of the –1438 A/G polymorphism confers some genetic risk for adolescent AN patients, especially in those with personality traits, which are typical of the restrictive-type AN.
Effect of Amiodarone on Phospholipid Content and Composition in Heart, Lung, Kidney and Skeletal Muscle: Relationship to Alteration of Thyroid Function
Authors: Rabkin Simon W.
Published: January 2006

To investigate the effect of chronic amiodarone treatment on tissue phospholipids, a marker of amiodarone-induced toxicity, and to test the hypothesis that tissue phospholipids changes are related to amiodarone-induced effects on thyroid function, male Wistar rats were treated with amiodarone and tissue phospholipid content and fractions were assessed. Twenty-six animals were allocated to 4 groups: (i) group 1 received amiodarone, 20 mg/kg per day, for 3 weeks (n = 6); (ii) group 2 received amiodarone for 5 weeks (n = 6); (iii) group 3 received drug for 6 weeks (n = 6), and (iv) group 4 (control group) received the diluent for 6 weeks (n = 8). Total phospholipid content of lung, kidney and skeletal muscle but not heart was increased after 3 weeks of amiodarone treatment. With longer durations of treatment, the phospholipid content was significantly (p < 0.05) reduced in all four organs. The proportion of phospholipids in different classes was modified by amiodarone treatment with the most consistent changes across different tissues being reductions in phosphatidylethanolamine and increases in phosphatidylserine. Serum thyroxine concentration was significantly (p < 0.05) reduced at 5 weeks of treatment and thereafter. There was a significant correlation between serum thyroxine and total phospholipid concentration in heart (r = 0.555; p < 0.05) and lung (r = 0.502; p < 0.05). For heart, there was a significant correlation between serum thyroxine and the distribution of phospholipid classes, mainly for phosphatidylserine even after considering amiodarone dose. The same was found in the lung. In the kidney and skeletal muscle, there was a significant (p < 0.05) correlation between serum thyroxine and the proportion of phospholipids in phosphatidylcholine and sphingomyelin. In conclusion, this study presents the novel finding of a biphasic tissue phospholipid response to amiodarone characterized by a short term increase in phospholipids in lung, kidney and skeletal muscle but not the heart followed by a long term decline in phospholipids in all four organs that is likely due to a direct action of amiodarone on phospholipid metabolism and potentially the result of amiodarone-induced reduction in thyroid function.
Measuring Eco‐efficiency of Production with Data Envelopment Analysis
Authors: Kuosmanen Timo , Kortelainen Mika
Published: January 2006

Aggregation of environmental pressures into a single environmental damage index is a major challenge of eco‐efficiency measurement. This article examines how the data envelopment analysis (DEA) method can be adapted for this purpose. DEA accounts for substitution possibilities between different natural resources and emissions and does not require subjective judgment about the weights. Although DEA does not require subjective or normative judgment, soft weight restrictions can be incorporated into the framework. The proposed approach is illustrated by an application to assessing ecoefficiency of road transportation in the three largest towns of eastern Finland.
Assessing the Eco‐efficiency of End‐of‐Pipe Technologies with the Environmental Cost Efficiency Indicator
Authors: Hellweg Stefanie , Doka Gabor , Finnveden Göran , Hungerbühler Konrad
Published: January 2006

The concept of eco‐efficiency is increasingly being applied to judge the combined environmental and economic performance of product systems, processes, and/or companies. Ecoefficiency is often defined as the ratio of economic value added to environmental impact added. This definition is not appropriate for end‐of‐pipe treatment technologies because these technologies aim at improving the environmental performance of technical processes at the cost of financial expense. Therefore, an indicator for the assessment of end‐of‐pipe technologies has been proposed. This indicator, called environmental cost efficiency (ECE), is defined as the ratio of net environmental benefits to the difference in costs. ECE is applied to four end‐of‐pipe technologies for the treatment of municipal solid waste: sanitary landfill, mechanical‐biological treatment, modern grate incineration, and a staged thermal process (pyrolysis and gasification). A life‐cycle assessment was performed on these processes to quantify the net environmental benefit. Moreover, the approximate net costs (costs minus benefits) were quantified. The results show that, relative to grate incineration, sanitary landfills and mechanical‐biological treatment are less costly but environmentally more harmful. We calculated the ECE for all combinations of technologies. The results indicate that the staged thermal process may be the most environmentally cost‐efficient alternative to all other treatment technologies in the long run, followed by mechanical‐biological treatment and grate incineration.
A Framework for Quantified Eco‐efficiency Analysis
Authors: Huppes Gjalt , Ishikawa Masanobu
Published: January 2006

Eco‐efficiency is an instrument for sustainability analysis, indicating an empirical relation in economic activities between environmental cost or value and environmental impact. This empirical relation can be matched against normative considerations as to how much environmental quality or improvement society would like to offer in exchange for economic welfare, or what the trade‐off between the economy and the environment should be if society is to realize a certain level of environmental quality. Its relevance lies in the fact that relations between economy and environment are not self‐evident, not at a micro level and not at the macro level resulting from micro‐level decisions for society as a whole. Clarifying the why and what of eco‐efficiency is a first step toward decision support on these two aspects of sustainability. With the main analytic framework established, filling in the actual economic and environmental relations requires further choices in modeling. Also, the integration of different environmental effects into a single score requires a clear definition of approach, because several partly overlapping methods exist. Some scaling problems accompany the specification of numerator and denominator, which need a solution and some standardization before eco‐efficiency analysis can become more widely used. With a method established, the final decision is how to embed it in practical decision making. In getting the details of eco‐efficiency better specified, its strengths, but also its weaknesses and limitations, need to be indicated more clearly.
The Cost of Sustainability Capital and the Creation of Sustainable Value by Companies
Authors: Figge Frank , Hahn Tobias
Published: January 2006

We develop and apply a valuation methodology to calculate the cost of sustainability capital, and, eventually, sustainable value creation of companies. Sustainable development posits that decisions must take into account all forms of capital rather than just economic capital. We develop a methodology that allows calculation of the costs that are associated with the use of different forms of capital. Our methodology borrows the idea from financial economics that the return on capital has to cover the cost of capital. Capital costs are determined as opportunity costs, that is, the forgone returns that would have been created by alternative investments. We apply and extend the logic of opportunity costs to the valuation not only of economic capital but also of other forms of capital. This allows (a) integrated analysis of use of different forms of capital based on a value‐based aggregation of different forms of capital, (b) determination of the opportunity cost of a bundle of different forms of capital used in a company, called cost of sustainability capital, (c) calculation of sustainability efficiency of companies, and (d) calculation of sustainable value creation, that is, the value above the cost of sustainability capital. By expanding the well‐established logic of the valuation of economic capital in financial markets to cover other forms of capital, we provide a methodology that allows determination of the most efficient allocation of sustainability capital for sustainable value creation in companies. We demonstrate the practicability of the methodology by the valuation of the sustainability performance of British Petroleum (BP).
Calculating Cost‐effectiveness for Activities with Multiple Environmental Effects Using the Maximum Abatement Cost Method
Authors: Oka Tosihiro , Ishikawa Masanobu , Fujii Yoshifumi , Huppes Gjalt
Published: January 2006

A maximum abatement cost (MAC) method is proposed as a means of assessing preferential purchasing of products with multiple environmental effects. Using the MAC method, cost‐effectiveness of the introduction of a product with less emissions of some substances than conventional products can be assessed. In the MAC method, the reduction of a pollutant is multiplied by the MAC, the maximum unit cost of the measures taken elsewhere in society aiming to reduce the pollutant, and is added up over the relevant pollutants. The total sum, called avoidable abatement cost (AAC), is compared with the additional private cost of the product for the purchaser. When the additional private cost is smaller than the AAC, the product is regarded as relatively eco‐efficient. The MAC method is illustrated with an assessment of industrial pumps. The advantages and limitations of the method are discussed.
Integrated Environmental and Economic Assessment of Products and Processes
Authors: Rüdenauer Ina , Gensch Carl‐Otto , Grießhammer Rainer , Bunke Dirk
Published: January 2006

The eco‐efficiency analysis method developed and used by the Öko‐Institut analyzes different alternatives that fulfill a defined consumer need, from an environmental as well as an economic perspective.

Like life‐cycle assessment (LCA), eco‐efficiency analysis makes possible the setting of priorities in purchasing decisions or can be used to show optimization potentials in product development processes.

Eco‐efficiency analysis builds upon two methods: LCA, according to ISO 14040 ff. (to assess the environmental aspects of products and processes), and life‐cycle costing. Life‐cycle costing results in a single figure—the total costs of ownership to one or several actors. The environmental impacts can be evaluated and aggregated as a single score or the impact category indicator results can be kept separate. In either case two single scores can be compared: the total environmental burden or the impact category indicator results, and the total costs of ownership of the alternatives under consideration.

The results can then be plotted in two‐dimensional graphs that show the effectiveness of certain measures in environmental and economic terms. The efficiency is expressed as a numerical ratio of environmental savings to difference in costs.

Together with furnishing more detailed results and a discussion of additional benefits or potential barriers, eco‐efficiency analysis broadens the basis for decision‐making processes.
Estimation of Oceanic Precipitation Efficiency in Cloud Models
Authors: Sui Chung-Hsiung , Li Xiaofan , Yang Ming-Jen , Huang Hsiao-Ling
Published: January 2006

Precipitation efficiency is estimated based on vertically integrated budgets of water vapor and clouds using hourly data from both two-dimensional (2D) and three-dimensional (3D) cloud-resolving simulations. The 2D cloud-resolving model is forced by the vertical velocity derived from the Tropical Ocean Global Atmosphere Coupled Ocean–Atmosphere Response Experiment (TOGA COARE). The 3D cloud-resolving modeling is based on the fifth-generation Pennsylvania State University–National Center for Atmospheric Research (PSU–NCAR) Mesoscale Model (MM5) simulation of Typhoon Nari (in 2001). The analysis of the hourly moisture and cloud budgets of the 2D simulation shows that the total moisture source (surface evaporation and vertically integrated moisture convergence) is converted into hydrometeors through vapor condensation and deposition rates regardless of the area size where the average is taken. This leads to the conclusion that the large-scale and cloud-microphysics precipitation efficiencies are statistically equivalent. Results further show that convergence (divergence) of hydrometeors would make precipitation efficiency larger (smaller). The precipitation efficiency tends to be larger (even >100%) in light rain conditions as a result of hydrometeor convergence from the neighboring atmospheric columns. Analysis of the hourly moisture and cloud budgets of the 3D results from the simulation of a typhoon system with heavy rainfall generally supports that of 2D results from the simulation of the tropical convective system with moderate rainfall intensity.
The 29 June 2000 Supercell Observed during STEPS. Part II: Lightning and Charge Structure
Authors: Wiens Kyle C. , Rutledge Steven A. , Tessendorf Sarah A.
Published: January 2006

This second part of a two-part study examines the lightning and charge structure evolution of the 29 June 2000 tornadic supercell observed during the Severe Thunderstorm Electrification and Precipitation Study (STEPS). Data from the National Lightning Detection Network and the New Mexico Tech Lightning Mapping Array (LMA) are used to quantify the total and cloud-to-ground (CG) flash rates. Additionally, the LMA data are used to infer gross charge structure and to determine the origin locations and charge regions involved in the CG flashes. The total flash rate reached nearly 300 min−1 and was well correlated with radar-inferred updraft and graupel echo volumes. Intracloud flashes accounted for 95%–100% of the total lightning activity during any given minute. Nearly 90% of the CG flashes delivered a positive charge to ground (+CGs). The charge structure during the first 20 min of this storm consisted of a midlevel negative charge overlying lower positive charge with no evidence of an upper positive charge. The charge structure in the later (severe) phase was more complex but maintained what could be roughly described as an inverted tripole, dominated by a deep midlevel (5–9 km MSL) region of positive charge. The storm produced only two CG flashes (both positive) in the first 2 h of lightning activity, both of which occurred during a brief surge in updraft and hail production. Frequent +CG flashes began nearly coincident with dramatic increases in storm updraft, hail production, total flash rate, and the formation of an F1 tornado. The +CG flashes tended to cluster in or just downwind of the heaviest precipitation, which usually contained hail. The +CG flashes all originated between 5 and 9 km MSL, centered at 6.8 km (−10°C), and tapped LMA-inferred positive charge both in the precipitation core and (more often) in weaker reflectivity extending downwind. All but one of the −CG flashes originated from >9 km MSL and tended to strike near the precipitation core.
Constraints on Wave Drag Parameterization Schemes for Simulating the Quasi-Biennial Oscillation. Part II: Combined Effects of Gravity Waves and Equatorial Planetary Waves
Authors: Campbell Lucy J. , Shepherd Theodore G.
Published: January 2006

This study examines the effect of combining equatorial planetary wave drag and gravity wave drag in a one-dimensional zonal mean model of the quasi-biennial oscillation (QBO). Several different combinations of planetary wave and gravity wave drag schemes are considered in the investigations, with the aim being to assess which aspects of the different schemes affect the nature of the modeled QBO. Results show that it is possible to generate a realistic-looking QBO with various combinations of drag from the two types of waves, but there are some constraints on the wave input spectra and amplitudes. For example, if the phase speeds of the gravity waves in the input spectrum are large relative to those of the equatorial planetary waves, critical level absorption of the equatorial planetary waves may occur. The resulting mean-wind oscillation, in that case, is driven almost exclusively by the gravity wave drag, with only a small contribution from the planetary waves at low levels. With an appropriate choice of wave input parameters, it is possible to obtain a QBO with a realistic period and to which both types of waves contribute. This is the regime in which the terrestrial QBO appears to reside. There may also be constraints on the initial strength of the wind shear, and these are similar to the constraints that apply when gravity wave drag is used without any planetary wave drag.

In recent years, it has been observed that, in order to simulate the QBO accurately, general circulation models require parameterized gravity wave drag, in addition to the drag from resolved planetary-scale waves, and that even if the planetary wave amplitudes are incorrect, the gravity wave drag can be adjusted to compensate. This study provides a basis for knowing that such a compensation is possible.
The Response Time of the Temperature of the Equatorial Troposphere to ENSO Heating
Authors: Clarke Allan J. , Kim Kwang-Y.
Published: January 2006

Air temperature anomalies, averaged over the troposphere to 200 mb and around the earth from 10°S to 10°N, lag the similarly averaged El Niño–Southern Oscillation (ENSO) atmospheric latent heating anomalies by about one month. Most of the latent heating is balanced by vertical adiabatic cooling although the zonally averaged imbalance is larger than is typical locally in the Tropics. The excess latent heating heats the atmosphere and generates a temperature anomaly. As the temperature anomaly rises, the atmosphere loses heat until the residual heating is balanced by anomalous cooling. By then the temperature anomaly is typically about 0.4°C. Analysis of the thermodynamic energy equation shows that the ENSO heat loss is highly linearly correlated with the air temperature anomaly averaged over the equatorial troposphere; that is, the adjustment to the residual anomalous heating (or cooling) is Newtonian. Consistent with the observed one-month lag, the Newtonian e-folding time is about 35 days. Similar results apply for latitude bands 5°S–5°N and 15°S–15°N (Newtonian cooling times of 29 and 46 days, respectively). The heat loss is mainly through meridional sensible heat flux rather than radiation. Much of the anomalous cooling is due to the mean meridional flow that diverges more temperature anomaly aloft than it converges near the surface.
An Overview of the Pharmacokinetics and Pharmacodynamics of Efalizumab: A Monoclonal Antibody Approved for Use in Psoriasis
Authors: Joshi Amita , Bauer Robert , Kuebler Peter , White Mark , Leddy Cecelia , Compton Peter , Garovoy Marvin , Kwon Paul , Walicke Patricia , Dedrick Russell
Published: January 2006

Efalizumab is a recombinant humanized monoclonal IgG1 antibody shown to be efficacious for the treatment of moderate to severe chronic plaque psoriasis. Efalizumab, a targeted inhibitor of T cell interactions, binds to the CD11a subunit of lymphocyte function—associated antigen 1 (LFA‐1), thereby preventing LFA‐1 binding to intercellular adhesion molecule 1 (ICAM‐1). The authors review the pharmacokinetic and pharmacodynamic data from the efalizumab clinical development program and discuss how these data led to selection of the optimal weekly subcutaneous (SC) dose of efalizumab (1.0 mg/kg) in adults. Efalizumab SC dosages of 1.0 mg/kg/wk or greater exerted maximal pharmacodynamic effects for CD11a expression and available CD11a binding sites on T lymphocytes. Dosages greater than 1.0 mg/kg/wk SC did not provide additional benefits; moreover, higher doses did not alter the safety profile. During long‐term administration of efalizumab, serum levels were generally stable and pharmacodynamic markers remained maximally affected.
The Effect of Oral Pleconaril on Hepatic Cytochrome P450 3A Activity in Healthy Adults Using Intravenous Midazolam as a Probe
Authors: Ma Joseph D. , Nafziger Anne N. , Rhodes Gerry , Liu Siyu , Gartung Anne M. , Bertino Joseph S.
Published: January 2006

Pleconaril is a viral capsid inhibitor under evaluation for treatment of infections caused by rhinoviruses and enteroviruses. This study evaluated the effect of pleconaril on hepatic cytochrome P450 (CYP) 3A activity as assessed by intravenous (IV) midazolam. Healthy adults received oral pleconaril 400 mg 3 times daily for 16 doses. Single‐dose, IV midazolam 0.025 mg/kg was administered before and during pleconaril administration. Midazolam and pleconaril plasma concentrations were assayed by LC/MS/MS. Bioequivalence was assessed by least squares geometric mean ratios (LS‐GMR) with 90% confidence intervals (90% CIs) for the measured midazolam pharmacokinetic parameters. Sixteen subjects were enrolled, and 14 subjects completed the study. Pleconaril decreased midazolam AUC0‐∞ 28% and increased systemic clearance 39%. LS‐GMR (90% CI) were 0.718 (0.674–0.765) and 1.392 (1.307–1.483), respectively. Plasma pleconaril concentrations steadily increased over time. Observed changes in midazolam AUC0‐∞ and systemic clearance suggest that oral pleconaril increased hepatic CYP3A activity in healthy adults.
Plasmapheresis reverses all side-effects of a cisplatin overdose – a case report and treatment recommendation
Authors: Hofmann Guenter , Bauernhofer Thomas , Krippl Peter , Lang-Loidolt Doris , Horn Sabine , Goessler Walter , Schippinger Walter , Ploner Ferdinand , Stoeger Herbert , Samonigg Hellmut
Published: January 2006

Background

Cisplatin is widely used as an antineoplastic agent since it is effective against a broad spectrum of different tumours. Nevertheless, it has several potential side effects affecting different organ systems and an overdose may lead to life-threatening complications and even death.

Case presentation

We report on a 46-year old woman with non-small cell lung cancer who accidentally received 225 mg/m2 of cisplatin, which was threefold the dose as scheduled, within a 3-day period. Two days later, the patient presented with hearing loss, severe nausea and vomiting, acute renal failure as well as elevated liver enzymes. In addition, she developed a severe myelodepression. After plasmapheresis on two consecutive days and vigorous supportive treatment, the toxicity-related symptoms improved and the patient recovered without any sequelae.

Conclusion

To date, no general accepted guidelines for the treatment of cisplatin overdoses are available. Along with the experience from other published cases, our report shows that plasmapheresis is capable of lowering cisplatin plasma and serum levels efficiently. Therefore, plasma exchange performed as soon as possible can ameliorate all side effects of a cisplatin overdose and be a potential tool for clinicians for treatment. However, additional intensive supportive treatment-modalities are necessary to control all occurring side effects.