bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of Rituximab-Resistant Lymphoma Clones with Altered Cell Signaling and Cross-Resistance to Chemotherapy
Authors: Jazirehi Ali R. , Vega Mario I. , Bonavida Benjamin 
Published: February 2007

Abstract
Immunotherapy with rituximab (chimeric anti-CD20 monoclonal antibody, Rituxan), alone or in conjunction with chemotherapy, has significantly improved the treatment outcome of lymphoma patients. Via an elusive mechanism, a subpopulation of patients becomes unresponsive and/or relapses. To recapitulate various aspects of acquired resistance, rituximab-resistant (RR) clones were established from lymphoma lines and compared with parental cells. Surface CD20 expression was diminished in the clones. The clones neither responded to rituximab-mediated growth reduction or complement-dependent cytotoxicity nor underwent apoptosis in response to cross-linked rituximab. Rituximab failed to chemosensitize the RR clones, which exhibited constitutive hyperactivation of the nuclear factor-κB and extracellular signal-regulated kinase 1/2 pathways, leading to overexpression of B-cell lymphoma protein 2 (Bcl-2), Bcl-2–related gene (long alternatively spliced variant of Bcl-x gene), and myeloid cell differentiation 1 and higher drug resistance. Unlike parental cells, rituximab neither inhibited the activity of these pathways nor diminished the expression of resistant factors. Pharmacologic inhibitors of the survival pathways or Bcl-2 family members reduced the activity of these pathways, diminished antiapoptotic protein expression, and chemosensitized the RR clones. These novel in vitro results denote that continuous long-term rituximab exposure culminates in RR clones that do not respond to rituximab-mediated effects, have altered cellular signaling dynamics, and exhibit different genetic and phenotypic properties compared with parental cells. The data also reveal that although RR clones exhibit higher resistance to rituximab and cytotoxic drugs, these clones can be chemosensitized following treatment with pharmacologic inhibitors (e.g., dehydroxymethylepoxyquinomicin, bortezomib, PD098059) that target survival/antiapoptotic pathways. The findings also identify intracellular targets for potential molecular therapeutic intervention to increase treatment efficacy. The significance and potential clinical relevance of the findings are discussed. [Cancer Res 2007;67(3):1270–81]
A Single-Chain Fv Diabody against Human Leukocyte Antigen-A Molecules Specifically Induces Myeloma Cell Death in the Bone Marrow Environment
Authors: Sekimoto Etsuko , Ozaki Shuji , Ohshima Takashi , Shibata Hironobu , Hashimoto Toshihiro , Abe Masahiro , Kimura Naoki , Hattori Kunihiro , Kawai Shigeto , Kinoshita Yasuko , Yamada-Okabe Hisafumi , Tsuchiya Masayuki , Matsumoto Toshio 
Published: February 2007

AbstractCross-linked human leukocyte antigen (HLA) class I molecules have been shown to mediate cell death in neoplastic lymphoid cells. However, clinical application of an anti-HLA class I antibody is limited by possible side effects due to widespread expression of HLA class I molecules in normal tissues. To reduce the unwanted Fc-mediated functions of the therapeutic antibody, we have developed a recombinant single-chain Fv diabody (2D7-DB) specific to the α2 domain of HLA-A. Here, we show that 2D7-DB specifically induces multiple myeloma cell death in the bone marrow environment. Both multiple myeloma cell lines and primary multiple myeloma cells expressed HLA-A at higher levels than normal myeloid cells, lymphocytes, or hematopoietic stem cells. 2D7-DB rapidly induced Rho activation and robust actin aggregation that led to caspase-independent death in multiple myeloma cells. This cell death was completely blocked by Rho GTPase inhibitors, suggesting that Rho-induced actin aggregation is crucial for mediating multiple myeloma cell death. Conversely, 2D7-DB neither triggered Rho-mediated actin aggregation nor induced cell death in normal bone marrow cells despite the expression of HLA-A. Treatment with IFNs, melphalan, or bortezomib enhanced multiple myeloma cell death induced by 2D7-DB. Furthermore, administration of 2D7-DB resulted in significant tumor regression in a xenograft model of human multiple myeloma. These results indicate that 2D7-DB acts on multiple myeloma cells differently from other bone marrow cells and thus provide the basis for a novel HLA class I–targeting therapy against multiple myeloma. [Cancer Res 2007;67(3):1184–92]
Evidence that Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Induction by 5-Aza-2′-Deoxycytidine Sensitizes Human Breast Cancer Cells to Adriamycin
Authors: Xu Jing , Zhou Jun-Ying , Tainsky Michael A. , Wu Gen Sheng 
Published: February 2007

AbstractThe DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-CdR) inhibits DNA methyltransferase activity and sensitizes cancer cells to chemotherapy, but the mechanisms of its sensitization are not fully understood. Here, we show that 5-aza-CdR induces tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in the human breast cancer MDA-231 cells. Induction of TRAIL by 5-aza-CdR correlated with inactivation of Akt. Furthermore, we show that overexpression of the active form of Akt by adenovirus infection or inhibition of the Akt downstream target glycogen synthase kinase 3 by its pharmacologic inhibitors abolishes TRAIL induction by 5-aza-CdR. Importantly, we show that the combined treatment of breast cancer cells with 5-aza-CdR and Adriamycin significantly increases apoptotic cell death compared with the treatment with either agent alone. Moreover, the combined treatment activated both death receptor and mitochondrial apoptotic pathways, whereas Adriamycin alone activated only the mitochondrial pathway while 5-aza-CdR failed to activate either. More importantly, down-regulation of TRAIL by small interference RNA silencing decreased 5-aza-CdR–mediated Adriamycin-induced caspase activation and apoptosis, thus conferring Adriamycin resistance. Taken together, our results suggest that induction of TRAIL by 5-aza-CdR is critical for enhancing chemosensitivity of breast cancer cells to Adriamycin. [Cancer Res 2007;67(3):1203–11]
A Small-Molecule Enhancer of Signal Transducer and Activator of Transcription 1 Transcriptional Activity Accentuates the Antiproliferative Effects of IFN-γ in Human Cancer Cells
Authors: Lynch Rebecca A. , Etchin Julia , Battle Traci E. , Frank David A. 
Published: February 2007

Abstract
The transcription factor signal transducer and activator of transcription (STAT) 1 can mediate antiproliferative and proapoptotic effects in cancer cells, and a number of mechanisms have been found whereby STAT1 signaling is attenuated in tumors thereby increasing their malignant behavior. Thus, enhancing gene transcription mediated by STAT1 may be an effective approach to cancer therapy. A high-throughput screen was developed to identify molecules that could enhance STAT1-dependent gene expression. Through this approach, it was found that 2-(1,8-naphthyridin-2-yl)phenol (2-NP) caused a 2-fold increase in STAT1-dependent reporter gene expression compared with that seen with maximally effective concentrations of IFN-γ alone. This effect was specific to STAT1 because 2-NP had no effect on unrelated transcription factors such as nuclear factor (NF) κB or the highly homologous transcription factor STAT3. STAT1-dependent gene activation was enhanced by this compound in a variety of human and murine cell lines and was independent of the stimulus used. Furthermore, 2-NP enhanced the expression of the bona fide endogenous STAT1 target gene interferon regulatory factor 1. 2-NP increased the duration of STAT1 tyrosine phosphorylation in response to IFN-γ, and this may underlie its enhancement of STAT1-dependent transcription. Reflecting the fact that STAT1 can exert tumor-suppressive effects, 2-NP enhanced the ability of IFN-γ to inhibit the proliferation of human breast cancer and fibrosarcoma cells. Tumor cells lacking STAT1 were unaffected by either IFN-γ or 2-NP. These findings indicate that enhancement of STAT1 transcriptional activity may have utility in anticancer therapies, and that cell-based screens for modulators of transcription factor function can be a useful approach for drug discovery. [Cancer Res 2007;67(3):1254–61]
Interleukin-1β–Driven Inflammation Promotes the Development and Invasiveness of Chemical Carcinogen–Induced Tumors
Authors: Krelin Yakov , Voronov Elena , Dotan Shahar , Elkabets Moshe , Reich Eli , Fogel Mina , Huszar Monika , Iwakura Yoichiro , Segal Shraga , Dinarello Charles A. , Apte Ron N. 
Published: February 2007

Abstract
The role of microenvironment interleukin 1 (IL-1) on 3-methylcholanthrene (3-MCA)–induced carcinogenesis was assessed in IL-1–deficient mice, i.e., IL-1β−/−, IL-1α−/−, IL-1α/β−/− (double knockout), and mice deficient in the naturally occurring inhibitor of IL-1, the IL-1 receptor antagonist (IL-1Ra). Tumors developed in all wild-type (WT) mice, whereas in IL-1β–deficient mice, tumors developed slower and only in some of the mice. In IL-1Ra–deficient mice, tumor development was the most rapid. Tumor incidence was similar in WT and IL-1α–deficient mice. Histologic analyses revealed fibrotic structures forming a capsule surrounding droplets of the carcinogen in olive oil, resembling foreign body–like granulomas, which appeared 10 days after injection of 3-MCA and persisted until the development of local tumors. A sparse leukocyte infiltrate was found at the site of carcinogen injection in IL-1β–deficient mice, whereas in IL-1Ra–deficient mice, a dense neutrophilic infiltrate was observed. Treatment of IL-1Ra–deficient mice with recombinant IL-1Ra but not with an inhibitor of tumor necrosis factor abrogated the early leukocytic infiltrate. The late leukocyte infiltrate (day 70), which was dominated by macrophages, was also apparent in WT and IL-1α–deficient mice, but was nearly absent in IL-1β–deficient mice. Fibrosarcoma cell lines, established from 3-MCA–induced tumors from IL-1Ra–deficient mice, were more aggressive and metastatic than lines from WT mice; cell lines from IL-1–deficient mice were the least invasive. These observations show the crucial role of microenvironment-derived IL-1β, rather than IL-1α, in chemical carcinogenesis and in determining the invasive potential of malignant cells. [Cancer Res 2007;67(3):1062–71]
Protein Phosphatase-1α Regulates Centrosome Splitting through Nek2
Authors: Mi Jun , Guo Changyue , Brautigan David L. , Larner James M. 
Published: February 2007

Abstract
ATM is a central mediator of the cellular response to the DNA damage produced by ionizing radiation. We recently showed that protein phosphatase 1 (PP1) is activated by ATM. Because Nek2 is activated by autophosphorylation, and because its dephosphorylation is catalyzed by PP1, we asked if the radiation damage signal to Nek2 was mediated by PP1. Overexpression of Nek2 induces premature centrosome splitting probably by phosphorylating centrosome cohesion proteins C-Nap1 and Rootletin. In this study, we show isoform specificity of PP1 binding and regulation of Nek2. Although both PP1α and PP1γ coimmunoprecipitated with Nek2, only PP1α regulated Nek2 function. Ionizing radiation inhibited Nek2 activity, and this response was dependent on ATM and on PP1 binding to Nek2 and coincident with Thr320 dephosphorylation of PP1. Radiation-induced inhibition of centrosome splitting was abrogated in cells expressing Nek2 mutated in the PP1-binding motif outside the kinase domain. Conversely, cells depleted of PP1α by small interfering RNA showed enhanced centrosome splitting and loss of radiation-induced inhibition of centrosome splitting. The identification of a PP1-specific isoform mediating a checkpoint response opens up the possibility of selectively targeting phosphatases as novel radiation sensitizers. [Cancer Res 2007;67(3):1082–9]
Sensitizing Effect of Galectin-7 in Urothelial Cancer to Cisplatin through the Accumulation of Intracellular Reactive Oxygen Species
Authors: Matsui Yoshiyuki , Ueda Shugo , Watanabe Jun , Kuwabara Ichiro , Ogawa Osamu , Nishiyama Hiroyuki 
Published: February 2007

Abstract
To improve chemotherapeutic efficacy in urothelial cancer, it is important to identify predictive markers for chemosensitivity as well as possible molecules accelerating cell killing mechanisms. In this study, we assessed the possibility of galectin-7 to accelerate cis-diamminedichloroplatinum (CDDP)–induced cell killing in vitro and also to predict chemosensitivity against CDDP in urothelial cancer patients. The expression of galectin-7 was analyzed in five bladder cancer cell lines with different p53 status after treatment with CDDP. The roles of galectin-7 in chemosensitivity against CDDP were analyzed by transfection of the galectin-7 gene into several of these cell lines. Furthermore, the relationship between the expression of galectin-7 and the response to neoadjuvant chemotherapy was analyzed in 17 human bladder cancer specimens. Exposure to CDDP induced galectin-7 in cell lines with wild-type p53 but not in those with mutated p53. When the galectin-7 gene was transfected into cell lines with mutated p53, the sensitivity to CDDP increased compared with control transfectants. In addition, galectin-7–transfected cells exhibited more accumulation of intracellular reactive oxygen species and activation of c-Jun NH2-terminal kinase (JNK) and Bax than control transfectants. SP600125, an inhibitor of JNK, or antioxidant N-acetyl-l-cysteine inhibited the enhancement of chemosensitivity against CDDP by galectin-7 transfection. In clinical samples, the expression levels of galectin-7 were significantly lower in urothelial carcinomas compared with normal urothelium. When chemosensitivity was tested, its expression levels were higher in the chemosensitive group than in the chemoresistant group. Galectin-7 is a candidate for a predictive marker of chemosensitivity against CDDP, and the targeted expression of galectin-7 might overcome the chemoresistance of urothelial cancer. [Cancer Res 2007;67(3):1212–20]
Protein Kinase Cε, which Sensitizes Skin to Sun's UV Radiation–Induced Cutaneous Damage and Development of Squamous Cell Carcinomas, Associates with Stat3
Authors: Aziz Moammir H. , Manoharan Herbert T. , Verma Ajit K. 
Published: February 2007

Abstract
Chronic exposure to UV radiation (UVR) is the major etiologic factor in the development of human skin cancers including squamous cell carcinoma (SCC). We have shown that protein kinase Cε (PKCε), a Ca2+-independent, phospholipid-dependent serine/threonine kinase, is an endogenous photosensitizer. PKCε is among the six isoforms (α, δ, ε, η, μ, and ζ) expressed in both mouse and human skin. PKCε transgenic mice, which overexpress PKCε in the basal epidermal cells and cells of the hair follicle, are highly sensitive to UVR-induced cutaneous damage and development of SCC. We now present that PKCε-overexpressing, but not PKCδ-overexpressing, transgenic mice, when exposed to a single (4 kJ/m2) or repeated (four doses, 2 kJ/m2/dose, thrice weekly) UVR, emitted by Kodacel-filtered FS-40 sun lamps, elicit constitutive phosphorylation of signal transducers and activators of transcription 3 (Stat3) at both Tyr705 and Ser727 residues. UVR-induced phosphorylation of Stat3 accompanied increased expression of Stat3-regulated genes (c-myc, cyclin D1, cdc25A, and COX-2). In reciprocal immunoprecipitation/blotting experiments, phosphorylated Stat3 coimmunoprecipitated with PKCε. As observed in vivo using PKCε knockout mice and in vitro in an immunocomplex kinase assay, PKCε phosphorylated Stat3 at Ser727 residue. These results indicate for the first time that (a) PKCε is a Stat3Ser727 kinase; (b) PKCε-mediated phosphorylation of StatSer727 may be essential for transcriptional activity of Stat3; and (c) UVR-induced phosphorylation of Ser727 may be a key component of the mechanism by which PKCε imparts sensitivity to UVR-induced development of SCC. [Cancer Res 2007;67(3):1385–94]
Erlotinib Directly Inhibits HER2 Kinase Activation and Downstream Signaling Events in Intact Cells Lacking Epidermal Growth Factor Receptor Expression
Authors: Schaefer Gabriele , Shao Lihua , Totpal Klara , Akita Robert W. 
Published: February 2007

AbstractErlotinib (Tarceva), is an orally available, reversible inhibitor of epidermal growth factor receptor (EGFR; HER1) that exhibits inhibitory activity on purified HER2 kinase at much higher concentrations. Despite the minimal activity on purified protein in vitro, in vivo studies show that erlotinib inhibits the growth of HER2-driven systems effectively. Several hypotheses have been put forward to explain this discrepancy. In particular, it has been suggested that erlotinib might indirectly suppress the activity of HER2 by blocking the ability of EGFR to transactivate it when the two receptors are part of a heterodimer complex. However, an alternative possibility that has not been adequately addressed is whether the direct inhibitory action of erlotinib on the HER2 kinase might account for the observed biological responses. To distinguish between a direct effect of erlotinib on HER2 kinase in intact cells or an indirect effect of erlotinib on HER2 activity that is mediated through EGFR, we generated cell lines that express either EGFR-H2 chimeric receptor or HER2 and HER3 receptors in an EGFR-negative background. We show that dose-dependent inhibition of HER2 was achieved at the receptor level, on downstream signaling molecules, and more importantly was also translated into inhibition of cell growth. Our findings imply that the inhibitory effect of erlotinib in HER2-expressing cells may in part be mediated through direct interaction with HER2 rather than indirectly through a process that requires the presence of EGFR. [Cancer Res 2007;67(3):1228–38]
The Tumor Suppressor Activity of the Lysyl Oxidase Propeptide Reverses the Invasive Phenotype of Her-2/neu–Driven Breast Cancer
Authors: Min Chengyin , Kirsch Kathrin H. , Zhao Yingshe , Jeay Sébastien , Palamakumbura Amitha H. , Trackman Philip C. , Sonenshein Gail E. 
Published: February 2007

Abstract
Expression of the lysyl oxidase gene (LOX) was found to inhibit the transforming activity of the ras oncogene in NIH 3T3 fibroblasts and was hence named the ras recision gene (rrg). Lysyl oxidase (LOX) is synthesized and secreted as a 50-kDa inactive proenzyme (Pro-LOX), which is processed by proteolytic cleavage to a functional 32-kDa enzyme and an 18-kDa propeptide (LOX-PP). Recently, the ras recision activity of the LOX gene in NIH 3T3 cells was mapped to its propeptide region. Here, we show for the first time that LOX-PP inhibits transformation of breast cancer cells driven by Her-2/neu, an upstream activator of Ras. LOX-PP expression in Her-2/neu–driven breast cancer cells in culture suppressed Akt, extracellular signal–regulated kinase, and nuclear factor-κB activation. Her-2/neu–induced epithelial to mesenchymal transition was reverted by LOX-PP, as judged by reduced levels of Snail and vimentin; up-regulation of E-cadherin, γ-catenin, and estrogen receptor α; and decreased ability to migrate or to form branching colonies in Matrigel. Furthermore, LOX-PP inhibited Her-2/neu tumor formation in a nude mouse xenograft model. Thus, LOX-PP inhibits signaling cascades induced by Her-2/neu that promote a more invasive phenotype and may provide a novel avenue for treatment of Her-2/neu–driven breast carcinomas. [Cancer Res 2007;67(3):1105–12]
Intermittent Hypoxia Furthers the Rationale for Hypoxia-Inducible Factor-1 Targeting
Authors: Dewhirst Mark W. 
Published: February 2007

Abstract
Hypoxia-inducible factor-1 (HIF-1) stabilization is a pivotal event in the response to hypoxic stress. A study in the December 15, 2006 issue of Cancer Research shows that HIF-1 stabilization occurs more robustly as a result of intermittent hypoxia compared with chronic hypoxia. The findings of this study suggest that intermittent hypoxia might influence the efficacy of radiotherapy by more strongly affecting the growth and survival of vascular endothelial cells. This finding offers additional encouragement to efforts to target HIF-1 for cancer therapy. [Cancer Res 2007;67(3):854–5]
Nitrogen and Phosphorus in the Finnish Energy System, 1900–2003
Authors: Saikku Laura , Antikainen Riina , Kauppi Pekka E. 
Published: February 2007

SummaryIn producing power, humans move the nutrients nitrogen (N) and phosphorus (P) from their long‐term geological and biological stocks and release or emit them in soil, water, and the atmosphere. In Finland, peat combustion is an important driver of N and P fluxes from the environment to human economy. The flows of N and P in the Finnish energy system were quantified with partial substance flow analysis, and the driving forces of emissions of nitrogen oxides (NOx) were analyzed using the ImPACT model.In the year 2000 in Finland, 140,000 tonnes of nitrogen entered the energy system, mainly in peat and hard coal. Combustion released an estimated 66,000 tonnes of N as nitrogen oxides (NOx) and nitrous oxides (N2O) and another 74,000 tonnes as elemental N2. Most of the emissions were borne in traffic. At the same time, 6,000 tonnes of P was estimated to enter the Finnish energy system, mostly in peat and wood. Ash was mainly used in earth construction and disposed in landfills; thus negligible levels of P were recycled back to nature.During the twentieth century, fuel‐borne input of N increased 20‐fold, and of P 8‐fold. In 1900–1950, the increasing use of hard coal slowly boosted N input, whereas wood fuels were the main carrier of P. Since 1970, the fluxes have been on the rise. NOx emissions leveled off in the 1980s, though, and then declined in conjunction with improvements in combustion technologies such as NOx removal (de‐NOx) technologies in energy production and catalytic converters in cars.
Characterizing, Propagating, and Analyzing Uncertainty in Life‐Cycle Assessment: A Survey of Quantitative Approaches
Authors: Lloyd Shannon M. , Ries Robert 
Published: February 2007

SummaryLife‐cycle assessment (LCA) practitioners build models to quantify resource consumption, environmental releases, and potential environmental and human health impacts of product systems. Most often, practitioners define a model structure, assign a single value to each parameter, and build deterministic models to approximate environmental outcomes. This approach fails to capture the variability and uncertainty inherent in LCA. To make good decisions, decision makers need to understand the uncertainty in and divergence between LCA outcomes for different product systems. Several approaches for conducting LCA under uncertainty have been proposed and implemented. For example, Monte Carlo simulation and fuzzy set theory have been applied in a limited number of LCA studies. These approaches are well understood and are generally accepted in quantitative decision analysis. But they do not guarantee reliable outcomes. A survey of approaches used to incorporate quantitative uncertainty analysis into LCA is presented. The suitability of each approach for providing reliable outcomes and enabling better decisions is discussed. Approaches that may lead to overconfident or unreliable results are discussed and guidance for improving uncertainty analysis in LCA is provided.