bluuebunny/crossref_metadata_2025_split huggingface dataset:
TFE3 Fusions Activate MET Signaling by Transcriptional Up-regulation, Defining Another Class of Tumors as Candidates for Therapeutic MET Inhibition
Authors: Tsuda Masumi , Davis Ian J. , Argani Pedram , Shukla Neerav , McGill Gael G. , Nagai Makoto , Saito Tsuyoshi , Laé Marick , Fisher David E. , Ladanyi Marc 
Published: February 2007

Abstract
Specific chromosomal translocations encoding chimeric transcription factors are considered to play crucial oncogenic roles in a variety of human cancers but the fusion proteins themselves seldom represent suitable therapeutic targets. Oncogenic TFE3 fusion proteins define a subset of pediatric renal adenocarcinomas and one fusion (ASPL-TFE3) is also characteristic of alveolar soft part sarcoma (ASPS). By expression profiling, we identified the MET receptor tyrosine kinase gene as significantly overexpressed in ASPS relative to four other types of primitive sarcomas. We therefore examined MET as a direct transcriptional target of ASPL-TFE3. ASPL-TFE3 binds to the MET promoter and strongly activates it. Likewise, PSF-TFE3 and NONO-TFE3 also bind this promoter. Induction of MET by ASPL-TFE3 results in strong MET autophosphorylation and activation of downstream signaling in the presence of hepatocyte growth factor (HGF). In cancer cell lines containing endogenous TFE3 fusion proteins, inhibiting MET by RNA interference or by the inhibitor PHA665752 abolishes HGF-dependent MET activation, causing decreased cell growth and loss of HGF-dependent phenotypes. MET is thus a potential therapeutic target in these cancers. Aberrant transcriptional up-regulation of MET by oncogenic TFE3 fusion proteins represents another mechanism by which certain cancers become dependent on MET signaling. The identification of kinase signaling pathways transcriptionally up-regulated by oncogenic fusion proteins may reveal more accessible therapeutic targets in this class of human cancers. [Cancer Res 2007;67(3):919–29]
5-Fluorouracil Incorporated into DNA Is Excised by the Smug1 DNA Glycosylase to Reduce Drug Cytotoxicity
Authors: An Qian , Robins Peter , Lindahl Tomas , Barnes Deborah E. 
Published: February 2007

Abstract5-Fluorouracil (FU) has been widely used for more than four decades in the treatment of a range of common cancers. The fluorine-substituted uracila analogue is converted to several active metabolites but the mechanism of cytotoxicity has remained unclear. In a widely cited but unsubstantiated model, FU is thought to kill cells via the inhibition of thymidylate synthase and increased use of dUTP in place of TTP during DNA replication, with subsequent excision of high levels of uracil causing the fragmentation of newly synthesized DNA. Using gene-targeted cell lines defective in one or both of the two mammalian uracil-DNA glycosylase repair enzymes, we were able to test this model of FU cytotoxicity. Here, we show that incorporation of FU itself into DNA has been previously underestimated and is a predominant cause of cytotoxicity. FU readily becomes incorporated into the DNA of drug-treated cells, and accumulation of FU in the genome, rather than uracil excision, is correlated with FU cytotoxicity in mammalian cells. Furthermore, the Smug1, but not the Ung, uracil-DNA glycosylase excises FU from DNA and protects against cell killing. The data provides a clearer understanding of the action of FU, suggesting predictive biomarkers of drug response and a mechanism for acquired resistance in tumors. [Cancer Res 2007;67(3):940–5]
Methylation-Independent Silencing of the Tumor Suppressor INK4b (p15) by CBFβ-SMMHC in Acute Myelogenous Leukemia with inv(16)
Authors: Markus Jan , Garin Matthew T. , Bies Juraj , Galili Naomi , Raza Azra , Thirman Michael J. , Le Beau Michelle M. , Rowley Janet D. , Liu P. Paul , Wolff Linda 
Published: February 2007

Abstract
The tumor suppressor gene INK4b (p15) is silenced by CpG island hypermethylation in most acute myelogenous leukemias (AML), and this epigenetic phenomenon can be reversed by treatment with hypomethylating agents. Thus far, it was not investigated whether INK4b is hypermethylated in all cytogenetic subtypes of AML. A comparison of levels of INK4b methylation in AML with the three most common cytogenetic alterations, inv(16), t(8;21), and t(15;17), revealed a strikingly low level of methylation in all leukemias with inv(16) compared with the other types. Surprisingly, the expression level of INK4b in inv(16)+ AML samples was low and comparable with that of the other subtypes. An investigation into an alternative mechanism of INK4b silencing determined that the loss of INK4b expression was caused by inv(16)-encoded core binding factor β-smooth muscle myosin heavy chain (CBFβ-SMMHC). The silencing was manifested in an inability to activate the normal expression of INK4b RNA as shown in vitamin D3–treated U937 cells expressing CBFβ-SMMHC. CBFβ-SMMHC was shown to displace RUNX1 from a newly determined CBF site in the promoter of INK4b. Importantly, this study (a) establishes that the gene encoding the tumor suppressor p15INK4b is a target of CBFβ-SMMHC, a finding relevant to the leukemogenesis process, and (b) indicates that, in patients with inv(16)-containing AML, reexpression from the INK4b locus in the leukemia would not be predicted to occur using hypomethylating drugs. [Cancer Res 2007;67(3):992–1000]
Low-Dose Irradiation of Nontransformed Cells Stimulates the Selective Removal of Precancerous Cells via Intercellular Induction of Apoptosis
Authors: Portess Daniel I. , Bauer Georg , Hill Mark A. , O'Neill Peter 
Published: February 2007

Abstract
An important stage in tumorigenesis is the ability of a precancerous cell to escape natural anticancer signals imposed on it by neighboring cells and its microenvironment. We have previously characterized a system of intercellular induction of apoptosis whereby nontransformed cells selectively remove transformed cells from coculture via cytokine and reactive oxygen/nitrogen species (ROS/RNS) signaling. We report that irradiation of nontransformed cells with low doses of either high linear energy transfer (LET) α-particles or low-LET γ-rays leads to stimulation of intercellular induction of apoptosis. The use of scavengers and inhibitors confirms the involvement of ROS/RNS signaling and of the importance of transformed cell NADPH oxidase in the selectivity of the system. Doses as low as 2-mGy γ-rays and 0.29-mGy α-particles were sufficient to produce an observable increase in transformed cell apoptosis. This radiation-stimulated effect saturates at very low doses (50 mGy for γ-rays and 25 mGy for α-particles). The use of transforming growth factor-β (TGF-β) neutralizing antibody confirms a role for the cytokine in the radiation-induced signaling. The system may represent a natural anticancer mechanism stimulated by extremely low doses of ionizing radiation. [Cancer Res 2007;67(3):1246–53]
Endogenous Cytosine Damage Products Alter the Site Selectivity of Human DNA Maintenance Methyltransferase DNMT1
Authors: Valinluck Victoria , Sowers Lawrence C. 
Published: February 2007

Abstract
Alterations in cytosine methylation patterns are usually observed in human tumors. The consequences of altered cytosine methylation patterns include both inappropriate activation of transforming genes and silencing of tumor suppressor genes. Despite the biological effect of methylation changes, little is known about how such changes are caused. The heritability of cytosine methylation patterns from parent to progeny cells is attributed to the fidelity of the methylation-sensitive human maintenance methyltransferase DNMT1, which methylates with high specificity the unmethylated strand of a hemimethylated CpG sequence following DNA replication. We have been studying DNA damage that might alter the specificity of DNMT1, either inhibiting the methylation of hemimethylated sites or triggering the inappropriate methylation of previously unmethylated sites. Here, we show that known forms of endogenous DNA damage can cause either hypermethylation or hypomethylation. Inflammation-induced 5-halogenated cytosine damage products, including 5-chlorocytosine, mimic 5-methylcytosine and induce inappropriate DNMT1 methylation within a CpG sequence. In contrast, oxidation damage of the methyl group of 5-methylcytosine, with the formation of 5-hydroxymethylcytosine, prevents DNMT1 methylation of the target cytosine. We propose that reduced DNMT1 selectivity resulting from DNA damage could cause heritable changes in cytosine methylation patterns, resulting in human tumor formation. These data may provide a mechanistic link for the associations documented between inflammation and cancer. [Cancer Res 2007;67(3):946–50]
Peptide Vaccine Given with a Toll-Like Receptor Agonist Is Effective for the Treatment and Prevention of Spontaneous Breast Tumors
Authors: Nava-Parada Pilar , Forni Guido , Knutson Keith L. , Pease Larry R. , Celis Esteban 
Published: February 2007

AbstractOur goal is to develop peptide vaccines that stimulate tumor antigen–specific T-cell responses against frequently found cancers. Previous work has shown that to generate effective T-cell responses, peptides have to be administered in combination with strong adjuvants such as Toll-like receptor agonists. However, most animal tumor model systems used to study peptide vaccines were not truly representative of malignant diseases in humans because they solely used transplantable tumor lines, and instead of true tumor antigens, they used highly immunogenic foreign proteins. Here, we describe a peptide vaccination strategy, which is highly effective in delaying or preventing the occurrence of spontaneous breast tumors. Transgenic female BALB-neuT mice that carry the activated rat HER-2/neu oncogene were vaccinated with a synthetic peptide from the rat HER-2/neu gene product, which represents an epitope for CTLs in combination with a Toll-like receptor agonist adjuvant. Our results show that to obtain tumor antigen-specific CTL responses and antitumor effects, the vaccine had to be administered repetitively, or the function of CD4/CD25 T regulatory cells had to be blocked with anti-CD25 antibody therapy. Mice that were vaccinated with this approach remained tumor-free or were able to control spontaneous tumor growth and exhibited long-lasting CTL responses, not only against the immunizing peptide but also against other peptides derived from rat HER-2/neu product (i.e., epitope spreading). These results suggest that similar strategies should be followed for conducting clinical studies in patients. [Cancer Res 2007;67(3):1326–34]
HIV Protease Inhibitor Nelfinavir Inhibits Growth of Human Melanoma Cells by Induction of Cell Cycle Arrest
Authors: Jiang Wei , Mikochik Peter J. , Ra Jin H. , Lei Hanqin , Flaherty Keith T. , Winkler Jeffrey D. , Spitz Francis R. 
Published: February 2007

Abstract
HIV protease inhibitors (HIV PI) are a class of antiretroviral drugs that are designed to target the viral protease. Unexpectedly, this class of drugs is also reported to have antitumor activity. In this study, we have evaluated the in vitro activity of nelfinavir, a HIV PI, against human melanoma cells. Nelfinavir inhibits the growth of melanoma cell lines at low micromolar concentrations that are clinically attainable. Nelfinavir promotes apoptosis and arrests cell cycle at G1 phase. Cell cycle arrest is attributed to inhibition of cyclin-dependent kinase 2 (CDK2) and concomitant dephosphorylation of retinoblastoma tumor suppressor. We further show that nelfinavir inhibits CDK2 through proteasome-dependent degradation of Cdc25A phosphatase. Our results suggest that nelfinavir is a promising candidate chemotherapeutic agent for advanced melanoma, for which novel and effective therapies are urgently needed. [Cancer Res 2007;67(3):1221–7]
Targeted and Nontargeted Effects of Low-Dose Ionizing Radiation on Delayed Genomic Instability in Human Cells
Authors: Huang Lei , Kim Perry M. , Nickoloff Jac A. , Morgan William F. 
Published: February 2007

Abstract
All humans receive some radiation exposure and the risk for radiation-induced cancer at low doses is based on the assumption that there is a linear non-threshold relationship between dose and subsequent effect. Consequently, risk is extrapolated linearly from high radiation doses to very low doses. However, adaptive responses, bystander effects, and death-inducing effect may influence health effects associated with low-dose radiation exposure. Adaptive response is the phenomenon by which cells irradiated with a sublethal radiation dose can become less susceptible to subsequent high-dose radiation exposure. Bystander effects are nontargeted effects observed in cells that were not irradiated but were either in contact with or received soluble signals from irradiated cells. These non-hit bystander cells can exhibit damage typically associated with direct radiation exposure. Death-inducing effect is a phenomenon whereby medium from human-hamster hybrid cells displaying radiation-induced chromosomal instability is toxic to unirradiated parental cells. In this study, we show that human RKO cells do not exhibit adaptive response, bystander effect, or death-inducing effect, as measured by cell killing, or delayed genomic instability in a stably transfected plasmid–based green fluorescent protein assay measuring homologous recombination and delayed mutation/deletion events. However, growth medium conditioned by some chromosomally unstable RKO derivatives induced genomic instability, indicating that these cells can secrete factor(s) that elicit responses in nonirradiated cells. Furthermore, low radiation doses suppressed the induction of delayed genomic instability by a subsequent high dose, indicative of an adaptive response for radiation-induced genomic instability. These results highlight the inherent variability in cellular responses to low-dose radiation exposure and add to the uncertainties associated with evaluating potential hazards at these low doses. [Cancer Res 2007;67(3):1099–104]
A Spatial Analysis of Loop Closing Among Recycling, Remanufacturing, and Waste Treatment Firms in Texas
Authors: Lyons Donald I. 
Published: February 2007

SummaryIndustrial ecology has emerged as a key strategy for improving environmental conditions. A central element of industrial ecology is the concept of closing the loop in material use (cycling) by directing used material and products (wastes) back to production processes. This article examines the issue of geographic scale and loop closing for heterogeneous wastes through an analysis of the location and materials flows of a set of recycling, remanufacturing, recycling manufacturing, and waste treatment (RRWT) firms in Texas. The results suggest that there is no preferable scale at which loop closing should be organized. RRWT firms are ubiquitous and operate successfully throughout the settlement hierarchy. The cycling boundaries of RRWT firms are dependent primarily upon how and where their products are redirected to production processes rather than the firm's location in the settlement hierarchy. In other words, loop closing is dominated by the spatial economic logic of the transactions of the firm involved. These results suggest that we cannot assign loop closing to any particular spatial scale a priori nor can we conceive of closing the loop via RRWT firms in terms of monolithic networks bounded in space or place with internal material flows.
Material Flows in a Social Context: A Vietnamese Case Study Combining the Materials Flow Analysis and Action‐in‐Context Frameworks
Authors: HOBBES Marieke , STALPERS Serge I. P. , KOOIJMAN Jiska , LE Thi Thu Thanh , TRINH Khanh Chi , PHAN Thi Anh Dao 
Published: February 2007

SummaryMaterials flow analysis (MFA) is one of the central achievements of industrial ecology. One direction in which one can move MFA beyond mere accounting is by putting the material flows in their social context. This “socially extended MFA” may be carried out at various levels of aggregation. In this article, specific material flows will be linked to concrete actors and mechanisms that cause these flows—using the action‐in‐context (AiC) framework, which contains, inter alia, both proximate and indirect actors and factors. The case study site is of Tat hamlet in Vietnam, set in a landscape of paddy fields on valley floors surrounded by steep, previously forested slopes. Out of the aggregate MFA of Tat, the study focuses on material flows associated with basic needs and sustainability. The most important actors causing these material flows are farming households, politicians, traders, and agribusiness firms—of which local politicians turned out to be pivotal. The study shows the value of combining MFA with actor‐based social analysis. MFA achieves the balanced quantification of the physical system, thus helping to pinpoint key processes. Actor‐based analysis adds the causal understanding of what drives these key processes, leading to improved scenarios of the future and the effective identification of target groups and instruments for policy making.
Developing Markets for Certified Wood Products: Greening the Supply Chain for Construction Materials
Authors: Irland Lloyd C. 
Published: February 2007

SummaryA growing worldwide movement is seeking to promote the greening of the construction sector. At the design level, proponents of frameworks such as LEED (Leadership in Energy and Environmental Design) seek to motivate designers and building owners to employ environmentally desirable materials. A prominent component of this approach is boosting availability of “green” building materials through programs that will certify to buyers that materials meet environmental standards. For wood products, this has resulted in several forms of “green certification” for forest management. Increasingly large areas of forest are now being certified worldwide. Yet it remains difficult for designers of green buildings, or consumers seeking green furniture, to obtain certified wood products.Many, if not most, of the logs now being harvested on green certified forest land worldwide are not reaching the store shelf with a certified label. Marketing certified wood all the way to the retail shelf has proved to be much harder than initially thought by proponents of certified products. This article explains the sources of these difficulties and outlines an approach to identifying products with high potential for marketing as certified products. Because of complex, multilevel supply chains for many wood products, support is required at all processing and distribution levels for a product to reach the retail customer with its green label.Market participants' purchase size and frequency, basis for product selection, buying influences, and price sensitivity are evaluated to identify product and market approaches likely to increase success rates for certified wood products. The article concludes with recommendations for expanding markets for green building materials.
Material Flows and Economic Growth in Developing China
Authors: XU Ming , ZHANG Tianzhu 
Published: February 2007

SummaryThe concept of sustainable development concerns not only the natural environment but also human societies and economies. The method of economy‐wide materials flow accounting and analysis (EW‐MFA) is internationally recognized as a valuable tool for studying the physical dimensions of economies. EW‐MFA has been carried out in many industrialized countries, but very little work has been done for developing China; this article can be regarded as one of the first attempts to study China's economy in terms of materials flows. In this article we have compiled materials flow accounts for China during the time series 1990 to 2002 and derived indicators associated with international comparison. Results show that the annual material consumption of China's economy continuously increased except for a slump around 1998, whereas the material efficiency exhibited a three‐phase trend reflecting different macropolicies of the Eighth, Ninth, and Tenth Five‐Year Plans implemented by the central government. Based on this experience with EW‐MFA for China, suggestions for methodology development and further research are given for improving EW‐MFA as a more effective tool for environmental management.
Modeling Biowaste Flows for Life‐Cycle Assessment: Calculation of the Potential and Collected Weight of Kitchen and Garden Waste
Authors: Schmidt Sonja , Pahl‐Wostl Claudia 
Published: February 2007

SummaryThis article presents an integrative approach to calculating the weight of potential biowaste and collected biowaste materials, as the basis for a life‐cycle assessment (LCA) of biowaste management. Biowaste contains kitchen and garden (yard) waste of households. This approach could be used for waste management planning and for the implementation of biowaste schemes. Case studies and examples in the literature are analyzed to model the mass of the flow of biowaste. This article defines relevant operands, presents the main assumptions, and describes the calculation principles. Spatial aspects and the uncertainties related to the inclusion of this aspect are explicitly considered in the calculation of the weight of the potential biowaste. We also present the calculation principles for obtaining the weight of (1) biowaste used in home composting, (2) the organic portion of residual waste, (3) biowaste separately collected by a bring system, and (4) biowaste separately collected by curbside collection (known in some areas as kerbside collection). By choosing the biowaste potential in kilograms per capita year (kg/cap yr) as the functional unit, previously ignored options within the biowaste system could be assessed. For example, widening the system boundaries allows LCA studies to assess the contribution of private and public transport of waste to ecological impact categories. It allows examining the effects of supporting home composting through financial incentives and the introduction of a separate collection system. This study focuses on the comparison of different collection types and on the characteristics of the area under investigation. It also incorporates the behavior of the inhabitants of households and includes a sensitivity analysis of relevant operands. This approach is being included in an LCA assessing biowaste management options.
Would Industrial Ecology Exist without Sustainability in the Background?
Authors: Ehrenfeld John R. 
Published: February 2007

SummaryIndustrial ecology rests historically—even in a short lifetime of 15 years or so—on the metaphorical power of natural ecosystems. Its evolution parallels the rise of concerns over unsustainability, that is, the threats to our world's ability to support human life the emergence of sustainability as a normative goal on a global scale. This article examines the relationships between industrial ecology and sustainability and argues that, in its historical relationship to classical ecology models, the field lacks power to address the full range of goals of sustainability, however defined. The classical ecosystem analogy omits aspects of human social and cultural life central to sustainability. But by moving beyond this model to more recent ecosystem models based on complexity theory, the field can expand its purview to address sustainability more broadly and powerfully. Complexity models of living systems can also ground alternative normative models for sustainability as an emergent property rather than the output of a mechanistic economic model for society's workings.