bluuebunny/crossref_metadata_2025 huggingface dataset:
The Potential Role of Postsynaptic Phospholipase C Activity in Synaptic Facilitation and Behavioral Sensitization inAplysia
Authors: Fulton Daniel , Condro Michael C. , Pearce Kaycey , Glanzman David L.
Published: May 2008

Previous findings indicate that synaptic facilitation, a cellular mechanism underlying sensitization of the siphon withdrawal response (SWR) in Aplysia, depends on a cascade of postsynaptic events, including activation of inositol triphosphate (IP3) receptors and release of Ca2+from postsynaptic intracellular stores. These findings suggest that phospholipase C (PLC), the enzyme that catalyzes IP3formation, may play an important role in postsynaptic signaling during facilitation and learning in Aplysia. Using the PLC inhibitor U73122, we found that PLC activity is required for synaptic facilitation following a 10-min treatment with 5-HT, as measured at 20 min after 5-HT washout. Prior work has indicated that facilitation at this time is supported primarily by postsynaptic processes. To determine whether postsynaptic PLC activity is involved in 5-HT–mediated facilitatory actions, we examined the effect of U73122 on enhancement of the response of motor neurons isolated in cell culture to glutamate, the sensory neuron transmitter. A 10-min application of 5-HT induced persistent (>40 min) enhancement of glutamate-evoked potentials (Glu-EPs) recorded from isolated motor neurons, and this enhancement was blocked by U73122. Finally, we showed that injecting U73122 into intact animals before behavioral training impaired intermediate-term sensitization, indicating that PLC activity contributes to this form of nonassociative learning.
Cortical Transformation of Wide-Field (Multiwhisker) Sensory Responses
Authors: Hirata Akio , Castro-Alamancos Manuel A.
Published: May 2008

In the barrel cortex of rodents, cells respond to a principal whisker (PW) and more weakly to several adjacent whiskers (AWs). Here we show that compared with PW responses, simultaneous wide-field stimulation of the PW and several AWs enhances short-latency responses and suppresses long-latency responses. Multiwhisker enhancement and suppression is first seen at the level of the cortex in layer 4 and not in the ventroposterior medial thalamus. Within the cortex, enhancement is manifested as a reduction in spike latency in layer 4 but also as an increase in spike probability in layer 2/3. Intracellular recordings revealed that multiwhisker enhancement of short-latency responses is caused by synaptic summation that can be explained by synaptic cooperativity (i.e., convergence of synaptic inputs activated by different whiskers). Conversely, multiwhisker suppression of long-latency responses is due to increased recruitment of inhibition in cortical cells. Interestingly, the ability to differentiate multiwhisker and PW responses is lost during rapid sensory adaptation caused by high-frequency whisker stimulation. The results reveal that simultaneous and temporally dispersed wide-field sensory inputs are discriminated at the level of single cells in barrel cortex with high temporal resolution, but the ability to compute this difference is highly dynamic and dependent on the level of adaptation in the thalamocortical network.
Digital Modulation Identification Model Using Wavelet Transform and Statistical Parameters
Authors: Prakasam P. , Madheswaran M.
Published: May 2008

A generalized modulation identification scheme is developed and presented. With the help of this scheme, the automatic modulation classification and recognition of wireless communication signals with a priori unknown parameters are possible effectively. The special features of the procedure are the possibility to adapt it dynamically to nearly all modulation types, and the capability to identify. The developed scheme based on wavelet transform and statistical parameters has been used to identify M‐ary PSK, M‐ary QAM, GMSK, and M‐ary FSK modulations. The simulated results show that the correct modulation identification is possible to a lower bound of 5 dB. The identification percentage has been analyzed based on the confusion matrix. When SNR is above 5 dB, the probability of detection of the proposed system is more than 0.968. The performance of the proposed scheme has been compared with existing methods and found it will identify all digital modulation schemes with low SNR.
On Some New Indicators for the Energo-Ecological Assessment of Thermo-Power Plants Operation
Authors: Cârdu Mircea , Negoiţescu Arina Speranţa , Sandu Dana
Published: May 2008

The authors offer a critical analysis of pollution indicators currently applied for the ecological assessment of the thermo power plant's operation. They forward new “energo-ecological” indicators to highlight both the qualitative aspect of polluting emissions and their quantitative aspect, by relating their concentration in the flue gases purged into the atmosphere to the energy produced during the same interval. The application of these indicators contributes to the attenuation of the global warming phenomenon and to the protection of the world's resources of fossil fuels.
Assessment of Nutrient Limitation in Floodplain Forests with Two Different Techniques
Authors: Neatrour Matthew A. , Jones Robert H. , Golladay Stephen W.
Published: May 2008

We assessed nitrogen and phosphorus limitation in a floodplain forest in southern Georgia in USA using two commonly used methods: nitrogen to phosphorus (N:P) ratios in litterfall and fertilized ingrowth cores. We measured nitrogen (N) and phosphorus (P) concentrations in litterfall to determine N:P mass ratios. We also installed ingrowth cores within each site containing native soil amended with nitrogen (N), phosphorus (P), or nitrogen and phosphorus (N + P) fertilizers or without added fertilizer (C). Litter N:P ratios ranged from 16 to 22, suggesting P limitation. However, fertilized ingrowth cores indicated N limitation because fine-root length density was greater in cores fertilized with N or N + P than in those fertilized with P or without added fertilizer. We feel that these two methods of assessing nutrient limitation should be corroborated with fertilization trials prior to use on a wider basis.
Exponential Attractor for a First‐Order Dissipative Lattice Dynamical System
Authors: Fan Xiaoming
Published: May 2008

We construct an exponential attractor for a first‐order dissipative lattice dynamical system arising from spatial discretization of reaction‐diffusion equations in ℝk. And we obtain fractal dimension of the exponential attractor.
Hexagonal Monopole Strip Antenna with Rectangular Slot for 100–1000 MHz SFCW GPR Applications
Authors: Pramudita A. A. , Kurniawan A. , Suksmono A. Bayu
Published: May 2008

A printed ultra wideband (UWB) monopole antenna is proposed for applications on stepped frequency continuous wave (SFCW) ground penetrating radar (GPR) within a frequency range of 100–1000 MHz. The proposed antenna consists of a hexagonal strip line with resistive loading and a rectangular slot that is added to the ground plane side of the printed antenna implemented on FR4 epoxy materials. The resistive loading at the hexagonal monopole is effective to increase bandwidth in the higher frequency region, while the rectangular slot is used to improve bandwidth characteristic in the lower frequency region. This paper investigates the characteristic improvement in the lower frequency region by applying a parametric study on the rectangular slot that is added at the ground plane side of the UWB monopole antenna. Computer simulation was conducted and measurements were carried out to validate the result.
Human Islet Amyloid Polypeptide Transgenic Mice: In Vivo and Ex Vivo Models for the Role of hIAPP in Type 2 Diabetes Mellitus
Authors: Höppener J. W. M. , Jacobs H. M. , Wierup N. , Sotthewes G. , Sprong M. , de Vos P. , Berger R. , Sundler F. , Ahrén B.
Published: May 2008

Human islet amyloid polypeptide (hIAPP), a pancreatic islet protein of 37 amino acids, is the main component of islet amyloid, seen at autopsy in patients with type 2 diabetes mellitus (DM2). To investigate the roles of hIAPP and islet amyloid in DM2, we generated transgenic mice expressing hIAPP in their islet beta cells. In this study, we found that after a long‐term, high‐fat diet challenge islet amyloid was observed in only 4 of 19 hIAPP transgenic mice. hIAPP transgenic females exhibited severe glucose intolerance, which was associated with a downregulation of GLUT‐2 mRNA expression. In isolated islets from hIAPP males cultured for 3 weeks on high‐glucose medium, the percentage of amyloid containing islets increased from 5.5% to 70%. This ex vivo system will allow a more rapid, convenient, and specific study of factors influencing islet amyloidosis as well as of therapeutic strategies to interfere with this pathological process.
Properties of Reinforced Concrete Steel Rebars Exposed to High Temperatures
Authors: Topçu İlker Bekir , Karakurt Cenk
Published: May 2008

The deterioration of the mechanical properties of yield strength and modulus of elasticity is considered as the primary element affecting the performance of steel structures under fire. In this study, hot-rolled S220 and S420 reinforcement steel rebars were subjected to high temperatures to investigate the fire performance of these materials. It is aimed to determine the remaining mechanical properties of steel rebars after elevated temperatures. Steels were subjected to 20, 100, 200, 300, 500, 800, and950∘C temperatures for 3 hours and tensile tests were carried out. Effect of temperature on mechanical behavior of S220 and S420 were determined. All mechanical properties were reduced due to the temperature increase of the steel rebars. It is seen that mechanical properties of S420 steel was influenced more than S220 steel at elevated temperatures.
Activated Ca2+/Calmodulin-Dependent Protein Kinase IIγ Is a Critical Regulator of Myeloid Leukemia Cell Proliferation
Authors: Si Jutong , Collins Steven J.
Published: May 2008

Ca2+ signaling is an important component of signal transduction pathways regulating B and T lymphocyte proliferation, but the functional role of Ca2+ signaling in regulating myeloid leukemia cell proliferation has been largely unexplored. We observe that the activated (autophosphorylated) Ca2+/calmodulin-dependent protein kinase IIγ (CaMKIIγ) is invariably present in myeloid leukemia cell lines as well as in the majority of primary acute myelogenous leukemia patient samples. In contrast, myeloid leukemia cells induced to terminally differentiate or undergo growth arrest display a marked reduction in this CaMKIIγ autophosphorylation. In cells harboring the bcr-abl oncogene, the activation (autophosphorylation) of CaMKIIγ is regulated by this oncogene. Moreover, inhibition of CaMKIIγ activity with pharmacologic agents, dominant-negative constructs, or short hairpin RNAs inhibits the proliferation of myeloid leukemia cells, and this is associated with the inactivation/down-regulation of multiple critical signal transduction networks involving the mitogen-activated protein kinase, Janus-activated kinase/signal transducers and activators of transcription (Jak/Stat), and glycogen synthase kinase (GSK3β)/β-catenin pathways. In myeloid leukemia cells, CaMKIIγ directly phosphorylates Stat3 and enhances its transcriptional activity. Thus, CaMKIIγ is a critical regulator of multiple signaling networks regulating the proliferation of myeloid leukemia cells. Inhibiting CaMKIIγ may represent a novel approach in the targeted therapy of myeloid leukemia. [Cancer Res 2008;68(10):3733–42]
Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
Authors: Onder Tamer T. , Gupta Piyush B. , Mani Sendurai A. , Yang Jing , Lander Eric S. , Weinberg Robert A.
Published: May 2008

Loss of the epithelial adhesion molecule E-cadherin is thought to enable metastasis by disrupting intercellular contacts—an early step in metastatic dissemination. To further investigate the molecular basis of this notion, we use two methods to inhibit E-cadherin function that distinguish between E-cadherin's cell-cell adhesion and intracellular signaling functions. Whereas the disruption of cell-cell contacts alone does not enable metastasis, the loss of E-cadherin protein does, through induction of an epithelial-to-mesenchymal transition, invasiveness, and anoikis resistance. We find the E-cadherin binding partner β-catenin to be necessary, but not sufficient, for induction of these phenotypes. In addition, gene expression analysis shows that E-cadherin loss results in the induction of multiple transcription factors, at least one of which, Twist, is necessary for E-cadherin loss–induced metastasis. These findings indicate that E-cadherin loss in tumors contributes to metastatic dissemination by inducing wide-ranging transcriptional and functional changes. [Cancer Res 2008;68(10):3645–53]
The Ret Receptor Tyrosine Kinase Pathway Functionally Interacts with the ERα Pathway in Breast Cancer
Authors: Boulay Anne , Breuleux Madlaina , Stephan Christine , Fux Caroline , Brisken Cathrin , Fiche Maryse , Wartmann Markus , Stumm Michael , Lane Heidi A. , Hynes Nancy E.
Published: May 2008

A limited number of receptor tyrosine kinases (e.g., ErbB and fibroblast growth factor receptor families) have been genetically linked to breast cancer development. Here, we investigated the contribution of the Ret receptor tyrosine kinase to breast tumor biology. Ret was expressed in primary breast tumors and cell lines. In estrogen receptor (ER)α-positive MCF7 and T47D lines, the ligand (glial-derived neurotrophic factor) activated signaling pathways and increased anchorage-independent proliferation in a Ret-dependent manner, showing that Ret signaling is functional in breast tumor cells. Ret expression was induced by estrogens and Ret signaling enhanced estrogen-driven proliferation, highlighting the functional interaction of Ret and ER pathways. Furthermore, Ret was detected in primary cancers, and there were higher Ret levels in ERα-positive tumors. In summary, we showed that Ret is a novel proliferative pathway interacting with ER signaling in vitro. Expression of Ret in primary breast tumors suggests that Ret might be a novel therapeutic target in breast cancer. [Cancer Res 2008;68(10):3743–51]
Fhit-Deficient Hematopoietic Stem Cells Survive Hydroquinone Exposure Carrying Precancerous Changes
Authors: Ishii Hideshi , Mimori Koshi , Ishikawa Kazuhiro , Okumura Hiroshi , Pichiorri Flavia , Druck Teresa , Inoue Hiroshi , Vecchione Andrea , Saito Toshiyuki , Mori Masaki , Huebner Kay
Published: May 2008

The fragile FHIT gene is among the first targets of DNA damage in preneoplastic lesions, and recent studies have shown that Fhit protein is involved in surveillance of genome integrity and checkpoint response after genotoxin exposure. We now find that Fhit-deficient hematopoietic cells, exposed to the genotoxin hydroquinone, are resistant to the suppression of stem cell in vitro colony formation observed with wild-type (Wt) hematopoietic cells. In vivo–transplanted, hydroquinone-exposed, Fhit-deficient bone marrow cells also escaped the bone marrow suppression exhibited by Wt-transplanted bone marrow. Comparative immunohistochemical analyses of bone marrow transplants showed relative absence of Bax in Fhit-deficient bone marrow, suggesting insensitivity to apoptosis; assessment of DNA damage showed that occurrence of the oxidized base 8-hydroxyguanosine, a marker of DNA damage, was also reduced in Fhit-deficient bone marrow, as was production of intracellular reactive oxygen species. Treatment with the antioxidant N-acetyl-l-cysteine relieved hydroquinone-induced suppression of colony formation by Wt hematopoietic cells, suggesting that the decreased oxidative damage to Fhit-deficient cells, relative to Wt hematopoietic cells, accounts for the survival advantage of Fhit-deficient bone marrow. Homology-dependent recombination repair predominated in Fhit-deficient cells, although not error-free repair, as indicated by a higher incidence of 6-thioguanine–resistant colonies. Tissues of hydroquinone-exposed Fhit-deficient bone marrow–transplanted mice exhibited preneoplastic alterations, including accumulation of histone H2AX-positive DNA damage. The results indicate that reduced oxidative stress, coupled with efficient but not error-free DNA damage repair, allows unscheduled long-term survival of genotoxin-exposed Fhit-deficient hematopoietic stem cells carrying deleterious mutations. [Cancer Res 2008;68(10):3662–70]
Constitutive Activation of Signal Transducers and Activators of Transcription Predicts Vorinostat Resistance in Cutaneous T-Cell Lymphoma
Authors: Fantin Valeria R. , Loboda Andrey , Paweletz Cloud P. , Hendrickson Ronald C. , Pierce Jacqueline W. , Roth Jennifer A. , Li Lixia , Gooden Frank , Korenchuk Susan , Hou Xiaoli S. , Harrington Elizabeth A. , Randolph Sophia , Reilly John F. , Ware Christopher M. , Kadin Marshall E. , Frankel Stanley R. , Richon Victoria M.
Published: May 2008

Vorinostat is a histone deacetylase inhibitor that induces differentiation, growth arrest, and/or apoptosis of malignant cells both in vitro and in vivo and has shown clinical responses in ∼30% of patients with advanced mycosis fungoides and Sézary syndrome cutaneous T-cell lymphoma (CTCL). The purpose of this study was to identify biomarkers predictive of vorinostat response in CTCL using preclinical model systems and to assess these biomarkers in clinical samples. The signal transducer and activator of transcription (STAT) signaling pathway was evaluated. The data indicate that persistent activation of STAT1, STAT3, and STAT5 correlate with resistance to vorinostat in lymphoma cell lines. Simultaneous treatment with a pan-Janus-activated kinase inhibitor resulted in synergistic antiproliferative effect and down-regulation of the expression of several antiapoptotic genes. Immunohistochemical analysis of STAT1 and phosphorylated tyrosine STAT3 (pSTAT3) in skin biopsies obtained from CTCL patients enrolled in the vorinostat phase IIb trial showed that nuclear accumulation of STAT1 and high levels of nuclear pSTAT3 in malignant T cells correlate with a lack of clinical response. These results suggest that deregulation of STAT activity plays a role in vorinostat resistance in CTCL, and strategies that block this pathway may improve vorinostat response. Furthermore, these findings may be of prognostic value in predicting the response of CTCL patients to vorinostat. [Cancer Res 2008;68(10):3785–94]
Inflammatory Signaling and Aryl Hydrocarbon Receptor Mediate Synergistic Induction of Interleukin 6 in MCF-7 Cells
Authors: Hollingshead Brett D. , Beischlag Timothy V. , DiNatale Brett C. , Ramadoss Preeti , Perdew Gary H.
Published: May 2008

The pleiotropic cytokine interleukin 6 (IL-6) is involved in immune cell homeostasis. Additionally, IL-6 expression and signaling in tumor cells have been shown to elicit both protumor and antitumor properties. There is a plethora of mechanistic knowledge regarding how IL-6 signal transduction translates to biological responses. However, there is little understanding as to what factors control IL-6 expression within a tumor cell environment. The studies presented herein show that, in MCF-7 breast and ECC-1 endocervical cancer cells, the stimulation of aryl hydrocarbon receptor (AHR) activity, in combination with IL-1β or phorbol 12-myristate 13-acetate (PMA) treatment, results in a marked synergistic induction of IL-6 levels over what is seen without AHR activation. Chromatin immunoprecipitation experiments suggest that the regulation of IL-6 mRNA expression occurs at the chromatin level, as AHR presence on the IL-6 promoter was observed in response to treatment with AHR ligand. Synergistic induction of IL-6 expression was sustained for 72 hours, with accumulation of IL-6 protein reaching levels 4.8-fold above IL-1β treatment alone. In addition, transcriptional regulation of the prototypic AHR responsive gene Cyp1a1 was negatively regulated by PMA and IL-1β treatment. Silencing of RELA expression alleviated IL-1β–mediated repression of AHR transcriptional activity, whereas PMA-mediated repression was maintained. Additionally, small interfering RNA studies reveal that AHR and RELA are necessary for synergistic induction of IL-6. The findings presented here reveal the AHR as a potential therapeutic target for selective modulation of IL-6 expression in some tumor cell types. The data also suggest a possible previously unrecognized mechanism of AHR-mediated tumor promotion. [Cancer Res 2008;68(10):3609–17]
Reduced Colitis-Associated Colon Cancer inFat-1(n-3 Fatty Acid Desaturase) Transgenic Mice
Authors: Jia Qian , Lupton Joanne R. , Smith Roger , Weeks Brad R. , Callaway Evelyn , Davidson Laurie A. , Kim Wooki , Fan Yang-Yi , Yang Peiying , Newman Robert A. , Kang Jing X. , McMurray David N. , Chapkin Robert S.
Published: May 2008

Bioactive food components containing n-3 polyunsaturated fatty acids (PUFA) modulate multiple determinants that link inflammation to cancer initiation and progression. Therefore, in this study, fat-1 transgenic mice, which convert endogenous n-6 PUFA to n-3 PUFA in multiple tissues, were injected with azoxymethane followed by three cycles of dextran sodium sulfate (DSS) to induce colitis-associated cancer. Fat-1 mice exhibited a reduced number of colonic adenocarcinomas per mouse (1.05 ± 0.29 versus 2.12 ± 0.51, P = 0.033), elevated apoptosis (P = 0.03), and a decrease in n-6 PUFA–derived eicosanoids, compared with wild-type (wt) mice. To determine whether the chemoprotective effects of n-3 PUFA could be attributed to its pleiotropic anti-inflammatory properties, colonic inflammation and injury scores were evaluated 5 days after DSS exposure followed by either a 3-day or 2-week recovery period. There was no effect of n-3 PUFA at 3 days. However, following a 2-week recovery period, colonic inflammation and ulceration scores returned to pretreatment levels compared with 3-day recovery only in fat-1 mice. For the purpose of examining the specific reactivity of lymphoid elements in the intestine, CD3+ T cells, CD4+ T helper cells, and macrophages from colonic lamina propria were quantified. Comparison of 3-day versus 2-week recovery time points revealed that fat-1 mice exhibited decreased (P < 0.05) CD3+, CD4+ T helper, and macrophage cell numbers per colon as compared with wt mice. These results suggest that the antitumorigenic effect of n-3 PUFA may be mediated, in part, via its anti-inflammatory properties. [Cancer Res 2008;68(10):3985–91]
Targeting AKT Signaling Sensitizes Cancer to Cellular Immunotherapy
Authors: Hähnel Patricia S. , Thaler Sonja , Antunes Edite , Huber Christoph , Theobald Matthias , Schuler Martin
Published: May 2008

The promise of cancer immunotherapy is long-term disease control with high specificity and low toxicity. However, many cancers fail immune interventions, and secretion of immunosuppressive factors, defective antigen presentation, and expression of death ligands or serpins are regarded as main escape mechanisms. Here, we study whether deregulation of growth and survival factor signaling, which is encountered in most human cancers, provides another level of protection against immunologic tumor eradication. We show in two models that activated cell autonomous protein kinase B (PKB)/AKT signaling mediates resistance against tumor suppression by antigen-specific CTLs in vitro and adoptively transferred cellular immune effectors in vivo. PKB/AKT-dependent immunoresistance of established tumors is reversed by genetic suppression of endogenous Mcl-1, an antiapoptotic member of the Bcl-2 family. Mechanistically, deregulated PKB/AKT stabilizes Mcl-1 expression in a mammalian target of rapamycin (mTOR)–dependent pathway. Treatment with the mTOR inhibitor rapamycin effectively sensitizes established cancers to adoptive immunotherapy in vivo. In conclusion, cancer cell–intrinsic PKB/AKT signaling regulates the susceptibility to immune-mediated cytotoxicity. Combined targeting of signal transduction pathways may be critical for improvement of cancer immunotherapies. [Cancer Res 2008;68(10):3899–906]
microRNA-7 Inhibits the Epidermal Growth Factor Receptor and the Akt Pathway and Is Down-regulated in Glioblastoma
Authors: Kefas Benjamin , Godlewski Jakub , Comeau Laurey , Li Yunqing , Abounader Roger , Hawkinson Michael , Lee Jeongwu , Fine Howard , Chiocca E. Antonio , Lawler Sean , Purow Benjamin
Published: May 2008

microRNAs are noncoding RNAs inhibiting expression of numerous target genes, and a few have been shown to act as oncogenes or tumor suppressors. We show that microRNA-7 (miR-7) is a potential tumor suppressor in glioblastoma targeting critical cancer pathways. miR-7 potently suppressed epidermal growth factor receptor expression, and furthermore it independently inhibited the Akt pathway via targeting upstream regulators. miR-7 expression was down-regulated in glioblastoma versus surrounding brain, with a mechanism involving impaired processing. Importantly, transfection with miR-7 decreased viability and invasiveness of primary glioblastoma lines. This study establishes miR-7 as a regulator of major cancer pathways and suggests that it has therapeutic potential for glioblastoma. [Cancer Res 2008;68(10):3566–71]
The Soluble α Chain of Interleukin-15 Receptor: A Proinflammatory Molecule Associated with Tumor Progression in Head and Neck Cancer
Authors: Badoual Cécile , Bouchaud Grégory , Agueznay Nour El Houda , Mortier Erwan , Hans Stéphane , Gey Alain , Fernani Fahima , Peyrard Séverine , -Puig Pierre Laurent , Bruneval Patrick , Sastre Xavier , Plet Ariane , Garrigue-Antar Laure , Quintin-Colonna Françoise , Fridman Wolf H. , Brasnu Daniel , Jacques Yannick , Tartour Eric
Published: May 2008

Interleukin (IL)-15 is a proinflammatory cytokine, as it induces the production of inflammatory cytokines [IL-6, tumor necrosis factor α (TNFα), IL-17, etc.]. A correlation between high intratumoral IL-15 concentrations and poor clinical outcome in lung and head and neck cancer patients has been recently reported. The purpose of this study was to investigate the role of the soluble α chain of IL-15 receptor (sIL-15Rα), a natural regulator of IL-15, in head and neck cancer. Fifty-three newly diagnosed untreated head and neck cancer patients were included in this study. Quantification of sIL-15Rα was performed with a newly developed RIA. Increased serum sIL-15Rα concentrations were found in head and neck cancer patients and were closely correlated with poor clinical outcome both in terms of locoregional control and survival even on multivariate analysis. sIL-15Rα was mainly produced by tumor cells via proteolytic cleavage of IL-15Rα mediated by ADAM-17. A correlation was observed between ADAM-17 expression in tumor cells and serum sIL-15Rα concentrations. Surprisingly, sIL-15Rα did not act in vitro as an IL-15 antagonist but rather as an enhancer of IL-15–induced proinflammatory cytokines (IL-6, TNFα, and IL-17) that may promote tumor progression. This new tumor evasion mechanism based on amplification of the intratumoral inflammatory reaction is probably not restricted to head and neck cancer, as other tumors have been shown to release sIL-15Rα. Overall, these results support for the first time an original protumor role of sIL-15Rα in cancer. [Cancer Res 2008;68(10):3907–14]
Radiation-Induced Gene Translation Profiles Reveal Tumor Type and Cancer-Specific Components
Authors: Kumaraswamy Sandhya , Chinnaiyan Prakash , Shankavaram Uma T. , Lü Xing , Camphausen Kevin , Tofilon Philip J.
Published: May 2008

The microarray analysis of total cellular RNA is a common method used in the evaluation of radiation-induced gene expression. However, profiling the cellular transcriptome does not take into account posttranscriptional processes that affect gene expression. To better define the genes whose expression is influenced by ionizing radiation, we used polysome-bound RNA to generate gene translation profiles for a series of tumor and normal cell lines. Cell lines were exposed to 2 Gy, polysome-bound RNA isolated 6 hours later, and then subjected to microarray analysis. To identify the genes whose translation was affected by radiation, the polysome-bound RNA profiles were compared with their corresponding controls using significance analysis of microarrays (<1% false discovery rate). From the statistically significant genes identified for each cell line, hierarchical clustering was performed by average linkage measurement and Pearson's correlation metric. Ingenuity Pathway Analysis was used for distributing genes into biological networks and for evaluation of functional significance. Radiation-induced gene translation profiles clustered according to tissue of origin; the cell lines corresponding to each tissue type contained a significant number of commonly affected genes. Network analyses suggested that the biological functions associated with the genes whose translation was affected by radiation were tumor type–specific. There was also a set of genes/networks that were unique to tumor or normal cells. These results indicate that radiation-induced gene translation profiles provide a unique data set for the analysis of cellular radioresponse and suggest a framework for identifying and targeting differences in the regulation of tumor and normal cell radiosensitivity. [Cancer Res 2008;68(10):3819–26]
Down-regulation of p57Kip2 Induces Prostate Cancer in the Mouse
Authors: Jin Ren Jie , Lho Yongsoo , Wang Yongqing , Ao Mingfang , Revelo Monica Patricia , Hayward Simon W. , Wills Marcia L. , Logan Susan K. , Zhang Pumin , Matusik Robert J.
Published: May 2008

p57Kip2 has been considered a candidate tumor suppressor gene because of its location in the genome, biochemical activities, and imprinting status. However, little is known about the role of p57Kip2 in tumorigenesis and cancer progression. Here, we show that the expression of p57Kip2 is significantly decreased in human prostate cancer, and the overexpression of p57Kip2 in prostate cancer cells significantly suppressed cell proliferation and reduced invasive ability. In addition, overexpression of p57Kip2 in LNCaP cells inhibited tumor formation in nude mice, resulting in well-differentiated squamous tumors rather than adenocarcinoma. Furthermore, the prostates of p57Kip2 knockout mice developed prostatic intraepithelial neoplasia and adenocarcinoma. Remarkably, this mouse prostate cancer is pathologically identical to human prostate adenocarcinoma. Therefore, these results strongly suggest that p57Kip2 is an important gene in prostate cancer tumorigenesis, and the p57Kip2 pathway may be a potential target for prostate cancer prevention and therapy. [Cancer Res 2008;68(10):3601–8]
OSU-HDAC42, a Histone Deacetylase Inhibitor, Blocks Prostate Tumor Progression in the Transgenic Adenocarcinoma of the Mouse Prostate Model
Authors: Sargeant Aaron M. , Rengel Robert C. , Kulp Samuel K. , Klein Russell D. , Clinton Steven K. , Wang Yu-Chieh , Chen Ching-Shih
Published: May 2008

Histone deacetylase (HDAC) inhibitors suppress tumor cell growth via a broad spectrum of mechanisms, which should prove advantageous in the context of cancer prevention. Here, we examined the effect of dietary administration of OSU-HDAC42, a novel HDAC inhibitor, on prostate tumor progression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Based on a series of pilot studies, an AIN-76A diet was formulated containing 208 ppm OSU-HDAC42, which was estimated to deliver ∼25 mg/kg of drug per day to each mouse and found to cause a suppression of PC-3 xenograft tumor growth equivalent to that achieved by gavage administration of a similar dose. At 6 weeks of age, TRAMP mice received this drug-containing or control diet for 4 or 18 weeks and were evaluated for prostatic intraepithelial neoplasia (PIN) and carcinoma development, respectively. OSU-HDAC42 not only decreased the severity of PIN and completely prevented its progression to poorly differentiated carcinoma (74% incidence in controls versus none in drug-treated mice), but also shifted tumorigenesis to a more differentiated phenotype, suppressing absolute and relative urogenital tract weights by 86% and 85%, respectively, at 24 weeks of age. This tumor suppression was associated with the modulation of intraprostatic biomarkers, including those indicative of HDAC inhibition, increased apoptosis and differentiation, and decreased proliferation. With the exception of completely reversible hematologic alterations and testicular degeneration, no significant changes in body weight or other indicators of general health were observed in drug-treated mice. These results suggest that OSU-HDAC42 has value in prostate cancer prevention. [Cancer Res 2008;68(10):3999–4009]
Differences in Baseline Characteristics and Outcomes at 1- and 2-Year Follow-up of Cancer Survivors Accrued via Self-Referral versus Cancer Registry in the FRESH START Diet and Exercise Trial
Authors: Snyder Denise Clutter , Sloane Richard , Lobach David , Lipkus Isaac M. , Peterson Bercedis , Kraus William , Demark-Wahnefried Wendy
Published: May 2008

Participant accrual to research studies is a challenge; oftentimes, advertisements are used to supplement cases ascertained through clinic caseloads and cancer registries. It is unknown, however, if cases ascertained through these two sources differ. In this study, we compared self-referred (n = 209) and registry-ascertained (n = 334) participants enrolled in FRESH START, a randomized controlled trial promoting a healthy diet and increased exercise among breast and prostate cancer survivors. The two groups were compared on baseline characteristics, adherence, attrition, and outcomes by study arm. Compared with participants enrolled from registries, self-referrals were significantly younger (54.1 ± 10.4 versus 58.7 ± 10.7 years), more likely to have later-stage disease and to have received chemotherapy (40% versus 19%), and more likely to report “fighting spirit” coping styles (50% versus 30%), lower quality-of-life (88.2 ± 15.1 versus 92.0 ± 12.9), fewer comorbid conditions (1.87 ± 1.60 versus 2.24 ± 1.78), and lower consumption of five or more daily servings of fruits and vegetables (35% versus 45%; P values <0.05). Although no differences in behavior change were observed between self-referred and registry-ascertained cases assigned to the tailored intervention arm, this was not the case within the attention control arm. Among those who received the attention control intervention of standardized materials in the public domain, self-referred versus registry-ascertained participants showed significantly greater increases in exercise at 1-year follow-up and significantly greater increases in fruit and vegetable consumption at both 1- and 2-year follow-up (P values <0.05). Several differences exist between self-referred and registry-ascertained participants, including motivation to respond to standardized educational materials, which appears significantly greater in self-referred populations. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1288–94)
Long-term Anti-inflammatory and Antihistamine Medication Use and Adult Glioma Risk
Authors: Scheurer Michael E. , El-Zein Randa , Thompson Patricia A. , Aldape Kenneth D. , Levin Victor A. , Gilbert Mark R. , Weinberg Jeffrey S. , Bondy Melissa L.
Published: May 2008

A personal history of asthma or allergy has been associated with a reduced risk for adult malignant gliomas. Recent reports on the use of nonsteroidal anti-inflammatory drugs (NSAID) and the presence of risk alleles in asthma susceptibility genes showed similar inverse associations. To further explore the relationship between immune mediators and gliomas, we examined the use of NSAID and antihistamines, history of asthma or allergy, and infection in 325 glioma cases and 600 frequency-matched controls from the metropolitan area of Houston, TX (2001-2006). The regular use of NSAID was associated with a 33% reduction in the risk for glioma, suggestive of possible antitumor activity. Surprisingly, regular long-term antihistamine use among those reporting a history of asthma or allergies was significantly associated with a 3.5-fold increase in the risk for glioma. Similar to previous reports, cases in our study were less likely to have reported asthma, allergy, or a history of a number of viral infections (chickenpox or shingles, oral herpes, and mononucleosis) than controls. We therefore speculate that the observed positive association with antihistamine use may reflect an alteration of protective immune factors in susceptible individuals. Our results lend additional support for an important but unknown link between malignant brain tumors and immune mediators. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1277–81)
Evaluating the Effectiveness of Using Standard Mammogram Form to Predict Breast Cancer Risk: Case-Control Study
Authors: Ding Jane , Warren Ruth , Warsi Iqbal , Day Nick , Thompson Deborah , Brady Michael , Tromans Christopher , Highnam Ralph , Easton Douglas
Published: May 2008

Breast density is a well-known breast cancer risk factor. Most current methods of measuring breast density are area based and subjective. Standard mammogram form (SMF) is a computer program using a volumetric approach to estimate the percent density in the breast. The aim of this study is to evaluate the current implementation of SMF as a predictor of breast cancer risk by comparing it with other widely used density measurement methods. The case-control study comprised 634 cancers with 1,880 age-matched controls combined from the Cambridge and Norwich Breast Screening Programs. Data collection involved assessing the films based both on Wolfe's parenchymal patterns and on visual estimation of percent density and then digitizing the films for computer analysis (interactive threshold technique and SMF). Logistic regression was used to produce odds ratios associated with increasing categories of breast density. Density measures from all four methods were strongly associated with breast cancer risk in the overall population. The stepwise rises in risk associated with increasing density as measured by the threshold method were 1.37 [95% confidence interval (95% CI), 1.03-1.82], 1.80 (95% CI, 1.36-2.37), and 2.45 (95% CI, 1.86-3.23). For each increasing quartile of SMF density measures, the risks were 1.11 (95% CI, 0.85-1.46), 1.31 (95% CI, 1.00-1.71), and 1.92 (95% CI, 1.47-2.51). After the model was adjusted for SMF results, the threshold readings maintained the same strong stepwise increase in density-risk relationship. On the contrary, once the model was adjusted for threshold readings, SMF outcome was no longer related to cancer risk. The available implementation of SMF is not a better cancer risk predictor compared with the thresholding method. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1074–81)
Vitamin D Receptor Expression in Normal, Premalignant, and Malignant Human Lung Tissue
Authors: Menezes Ravi J. , Cheney Richard T. , Husain Aliya , Tretiakova Maria , Loewen Gregory , Johnson Candace S. , Jayaprakash Vijay , Moysich Kirsten B. , Salgia Ravi , Reid Mary E.
Published: May 2008

Background: There is a strong interest in identifying chemopreventive agents that might help decrease the burden of lung cancer. The active metabolite of vitamin D, 1,25-dihydroxycholecalciferol (calcitriol), has been shown to have antiproliferative effects in several tumor types, mediated by the vitamin D receptor (VDR). This is the first comprehensive survey of VDR expression in a series of human lung tissues, including normal and premalignant central airway biopsies and lung tumors.

Methods: Immunohistochemical expression of nuclear and cytoplasmic VDR was examined in 180 premalignant or malignant bronchial biopsies from bronchoscopy of 78 high-risk individuals at the Roswell Park Cancer Institute and also in 63 tumor samples from 35 lung cancer patients from the University of Chicago Hospitals. Associations between clinicopathologic data and VDR expression were examined.

Results: VDR expression was present in many samples. In biopsies, VDR was commonly detected throughout the full epithelial layer. Most histologically normal (60%, 53 of 88) and metaplastic (61%, 39 of 64) samples had moderate to high nuclear intensity; dysplastic samples mostly had low nuclear intensity (10 of 18, 55%). In tumor samples, 62% (38 of 61) were lacking cytoplasmic VDR, with nuclear expression present in 79%(49 of 62). Analysis of all samples revealed a positive linear trend between proportion of samples with greater nuclear than cytoplasmic intensity and increasing histologic grade (P < 0.01).

Conclusions: VDR expression spanned the lung carcinogenesis spectrum. Nuclear expression was similar across various histologies, whereas cytoplasmic expression decreased with increasing histologic grade. These results indicate that there is potential for the use of calcitriol as a chemopreventive agent against the development of lung cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1104–10)
Matrix Metalloproteinase 1 (MMP1) Is Associated with Early-Onset Lung Cancer
Authors: Sauter Wiebke , Rosenberger Albert , Beckmann Lars , Kropp Silke , Mittelstrass Kirstin , Timofeeva Maria , Wölke Gabi , Steinwachs Angelika , Scheiner Daniela , Meese Eckart , Sybrecht Gerhard , Kronenberg Florian , Dienemann Hendrik ,   The LUCY-Consortium, Chang-Claude Jenny , Illig Thomas , Wichmann Heinz-Erich , Bickeböller Heike , Risch Angela
Published: May 2008

Matrix metalloproteinases (MMP) play a key role in the breakdown of extracellular matrix and in inflammatory processes. MMP1 is the most highly expressed interstitial collagenase degrading fibrillar collagens. Overexpression of MMP1 has been shown in tumor tissues and has been suggested to be associated with tumor invasion and metastasis. Nine haplotype tagging and additional two intronic single nucleotide polymorphisms (SNP) of MMP1 were genotyped in a case control sample, consisting of 635 lung cancer cases with onset of disease below 51 years of age and 1,300 age- and sex-matched cancer-free controls. Two regions of linkage disequilibrium (LD) of MMP1 could be observed: a region of low LD comprising the 5′ region including the promoter and a region of high LD starting from exon 1 to the end of the gene and including the 3′ flanking region. Several SNPs were identified to be individually significantly associated with risk of early-onset lung cancer. The most significant effect was seen for rs1938901 (P = 0.0089), rs193008 (P = 0.0108), and rs996999 (P = 0.0459). For rs996999, significance vanished after correction for multiple testing. For each of these SNPs, the major allele was associated with an increase in risk with an odds ratio between 1.2 and 1.3 (95% confidence interval, 1.0-1.5). The haplotype analysis supported these findings, especially for subgroups with high smoking intensity. In summary, we identified MMP1 to be associated with an increased risk for lung cancer, which was modified by smoking. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1127–35)
Body Mass Index, Physical Activity, and Bladder Cancer in a Large Prospective Study
Authors: Koebnick Corinna , Michaud Dominique , Moore Steven C. , Park Yikyung , Hollenbeck Albert , Ballard-Barbash Rachel , Schatzkin Arthur , Leitzmann Michael F.
Published: May 2008

Increased body size and lack of physical activity are associated with increased risk of several cancers, but the relations of body mass index (BMI) and physical activity to bladder cancer are poorly understood. We investigated the associations between BMI, physical activity, and bladder cancer in the NIH-AARP Diet and Health Study, a prospective cohort of 471,760 U.S. men and women, followed from 1995 to 2003. During 3,404,642 person-years of follow-up, we documented 1,719 incident cases of bladder cancer. Compared with normal weight, obesity was associated with an up to 28% increased risk for bladder cancer. The multivariate relative risks of bladder cancer for BMI values of 18.5 to 24.9 (reference), 25.0 to 29.9, 30.0 to 34.9, and ≥35 kg/m2 were 1.0, 1.15, 1.22, and 1.28 (95% confidence interval, 1.02-1.61; Ptrend = 0.028). The association between BMI and bladder cancer was consistent among subgroups defined by gender, education, smoking status, and other potential effect modifiers. In contrast, physical activity showed no statistically significant relation with bladder cancer. After multivariate adjustment, including BMI, the relative risks of bladder cancer for increasing frequency of physical activity [0 (reference), <1, 1-2, 3-4, and ≥5 times a week] were 1.0, 0.85, 0.89, 0.91, and 0.87 (95% confidence interval, 0.74-1.02; Ptrend = 0.358), respectively. In conclusion, these findings provide support for a modest adverse effect of adiposity on risk for bladder cancer. In contrast, our results do not suggest a relation between physical activity and bladder cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1214–21)
Effects of Baseline Comorbidities on Cancer Screening Trial Adherence among Older African American Men
Authors: Ford Marvella E. , Havstad Suzanne L. , Fields Maya E. , Manigo Brandy , McClary Beth , Lamerato Lois
Published: May 2008

Background: The purpose of this study was to examine the effects of baseline comorbidities on screening adherence in a sample of older African American men (ages ≥55 years) enrolled in a case management intervention in a cancer screening trial.

Methods: Baseline comorbidity data were obtained from 683 African American men who were randomly assigned to a case management intervention group (n = 344) or to a case management control group (n = 339). The effects of comorbidities on the screening adherence rates of each group were then assessed.

Results: No statistically significant interactions were found between each health history characteristic and the intervention. Therefore, analyses were not stratified by intervention status. In general, participants with comorbidities were no less likely to adhere to trial screening than participants without comorbidities. Exceptions were current smokers and participants with chronic bronchitis. Current smokers were less likely than others to adhere to the prostate-specific antigen test (P = 0.02) and the digital rectal examination for prostate cancer screening (P = 0.01), to the chest X-ray for lung cancer screening (P < 0.01), and to the flexible sigmoidoscopy for colorectal cancer screening (P = 0.04). Participants with chronic bronchitis had lower rates of adherence to the chest X-ray (P = 0.06). Having a relative with cancer positively influenced adherence to the digital rectal examination (P = 0.05).

Conclusions: Overall, older African American men with comorbidities appear to be very good candidates for participation in longitudinal cancer screening trials. However, smoking had a statistically significant and deleterious effect on adherence to all types of screening. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1234–9)
Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer
Authors: Engelman Jeffrey A. , Jänne Pasi A.
Published: May 2008

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib are effective therapies for non–small cell lung cancer patients whose tumors harbor somatic mutations in EGFR. All patients, however, ultimately develop resistance to these agents. Thus, there is a great need to understand how patients become resistant to develop effective therapies for these cancers. Studies over the last few years have identified two different EGFR tyrosine kinase inhibitor resistance mechanisms, a secondary mutation in EGFR, EGFR 790M, and amplification of the MET oncogene. These findings have led to clinical trials using newly designed targeted therapies that can overcome these resistance mechanisms and have shown promise in laboratory studies. Ongoing research efforts will likely continue to identify additional resistance mechanisms, and these findings will hopefully translate into effective therapies for non–small cell lung cancer patients.