bluuebunny/crossref_metadata_2025 huggingface dataset:
The Generalized PSO: A New Door to PSOEvolution
Authors: Fernández Martínez J. L. , García Gonzalo E.
Published: May 2008

A generalized form of the particle swarm optimization (PSO) algorithm is
presented. Generalized PSO (GPSO) is derived from a continuous version of PSO adopting a
time step different than the unit. Generalized continuous particle swarm optimizations are compared in terms of
attenuation and oscillation. The deterministic and stochastic stability regions and their respective
asymptotic velocities of convergence are analyzed as a function of the time step and the
GPSO parameters. The sampling distribution of the GPSO algorithm helps to study the effect
of stochasticity on the stability of trajectories. The stability regions for the second‐, third‐, and
fourth‐order moments depend on inertia, local, and global accelerations and the time step and are
inside of the deterministic stability region for the same time step. We prove that stability regions
are the same under stagnation and with a moving center of attraction. Properties of the
second‐order moments variance and covariance serve to propose some promising parameter sets. High
variance and temporal uncorrelation improve the exploration task while solving ill‐posed inverse
problems. Finally, a comparison is made between PSO and GPSO by means of numerical experiments
using well‐known benchmark functions with two types of ill‐posedness commonly found in inverse
problems: the Rosenbrock and the “elongated” DeJong functions (global minimum located in a
very flat area), and the Griewank function (global minimum surrounded by multiple minima).
Numerical simulations support the results provided by theoretical analysis. Based on these results,
two variants of Generalized PSO algorithm are proposed, improving the convergence and the
exploration task while solving real applications of inverse problems.
Photoactive Thin Silver Films by Atmospheric Pressure CVD
Authors: Yates Heather M. , Brook Lucy A. , Sheel David W.
Published: May 2008

We report the visible and UV activity of thin silver films. The films are grown using a CVD process employing aqueous‐based silver precursors, flame‐assisted chemical vapour deposition. This approach overcomes many of the previously encountered limitations to silver deposition by employing an atmospheric pressure process, low‐cost and low‐toxicity precursors. The resultant films are assessed for activity using stearic acid destruction as a model compound. We also report on the addition of titania to these silver films to increase the potential functionality. This activity is also demonstrated, where the films appear largely transparent to the eye, further widening the potential application of this work. It is speculated that the nanoparticulate nature, of the CVD silver, is crucial in determining photoactivity.
Mathematical Modeling of Wet Magnesia Flue Gas Desulphurization Process
Authors: Mondal M. K.
Published: May 2008

Desulphurization of flue gases from various
chemical industries in a techno‐econo‐enviro manner is a demanding
technology. The concentrations of sulphur dioxide in and around
these plants overshoot the danger point. In recent years, the
process analysis of chemical absorption in a slurry has become
important in rational design and development of wet scrubbing
processes for the removal of SO2 from flue gases. The elementary
steps encountered in wet scrubbing by slurries are diffusion and
reaction of gaseous species and solid dissolution in liquid film.
In the present work, the process of the absorption of sulphur
dioxide into wet magnesia slurry was theoretically analyzed
according to the two‐reaction plane model incorporating the solid
dissolution promoted by the reactions with absorbed sulphur
dioxide in the liquid film. A model based on Fick′s second law
has been developed to calculate enhancement factor for absorption
of Sulphur dioxide into Mg(OH) 2 slurry. The concentration of
accumulated species in the bulk of the liquid phase (sulphite ions
for this case) which substantially control the absorption rates
was included in the model for the prediction of theoretical
enhancement factor. The values of theoretical enhancement factors
obtained from model were compared with experimental enhancement
factors available in literature. The model values of enhancement
factors agreed well with the values of experimental enhancement
factor available in literature.
Phosphorylation Regulates Transcriptional Activity of PAX3/FKHR and Reveals Novel Therapeutic Possibilities
Authors: Amstutz Ralf , Wachtel Marco , Troxler Heinz , Kleinert Peter , Ebauer Margret , Haneke Torsten , Oehler-Jänne Christoph , Fabbro Doriano , Niggli Felix K. , Schäfer Beat W.
Published: May 2008

Inhibition of constitutive active signaling pathways, which are a characteristic phenomenon for many tumors, can be an effective therapeutic strategy. In contrast, oncogenic transcription factors, often activated by mutational events, are in general less amenable to small-molecule inhibition despite their obvious importance as therapeutic targets. One example of this is alveolar rhabdomyosarcoma (aRMS), in which specific translocations lead to the formation of the chimeric transcription factor PAX3/FKHR. Here, we found unexpectedly that the transcriptional activity of PAX3/FKHR can be inhibited by the kinase inhibitor PKC412. This occurs via specific phosphorylation sites in the PAX3 domain, phosphorylation of which is required for efficient DNA-binding and subsequent transcriptional activity. Consequently, we show that PKC412 exerts a potent antitumorigenic potential for aRMS treatment both in vitro and in vivo. Our study suggests that posttranscriptional modifications of oncogenic transcription factors can be explored as a promising avenue for targeted cancer therapy. [Cancer Res 2008;68(10):3767–76]
Antagonistic Roles of CD4+ and CD8+ T-Cells in 7,12-Dimethylbenz(a)anthracene Cutaneous Carcinogenesis
Authors: Yusuf Nabiha , Nasti Tahseen H. , Katiyar Santosh K. , Jacobs Michael K. , Seibert Megan D. , Ginsburg Alexis C. , Timares Laura , Xu Hui , Elmets Craig A.
Published: May 2008

The role that cell-mediated immune responses play during cutaneous carcinogenesis has received little attention. In this study, we evaluated the contribution of CD4+ and CD8+ T cells in C3H/HeN mice that were subjected to a two-stage 7,12-dimethylbenz(a)anthracene (DMBA) initiation, 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion skin carcinogenesis protocol. In CD8 knockout (CD8−/−) mice, allergic contact hypersensitivity to DMBA was reduced compared with wild-type (WT) C3H/HeN mice. On the other hand, CD4 knockout (CD4−/−) mice developed an exaggerated contact hypersensitivity response. CD4+ T cells from DMBA contact–sensitized mice preferentially produced interleukin 4 (IL-4), IL-10, and IL-17; CD8+ T cells, on the other hand, secreted IFN-γ. When CD4−/−, CD8−/−, and WT mice were subjected to a standard two-stage DMBA/TPA cutaneous carcinogenesis protocol, the percentage of mice with tumors was much greater (P < 0.001) in CD8−/− mice than in WT mice. In contrast, the percentage of tumors was significantly less (P < 0.001) in CD4−/− mice than in WT mice. Similar results were obtained when the data were evaluated as the number of tumors per mouse. These findings indicate that (a) CD8+ T cells are the predominant effector cells in allergic contact hypersensitivity to DMBA and that CD4+ T cells have an inhibitory role and (b) the development of CD8+ T cells plays a protective role in skin tumor development whereas CD4+ T cells have the opposite effect. Manipulation of T-cell subpopulations that are induced by carcinogenic chemicals, like DMBA, could be a means of preventing skin cancers caused by these agents. [Cancer Res 2008;68(10):3924–30]
Inactivation of gadd45a Sensitizes Epithelial Cancer Cells to Ionizing Radiation In vivo Resulting in Prolonged Survival
Authors: Lu Xiangdong , Yang Chunyu , Hill Reginald , Yin Chaoyin , Hollander M. Christine , Fornace Albert J. , Van Dyke Terry
Published: May 2008

Ionizing radiation (IR) therapy is one of the most commonly used treatments for cancer patients. The responses of tumor cells to IR are often tissue specific and depend on pathway aberrations present in the tumor. Identifying molecules and mechanisms that sensitize tumor cells to IR provides new potential therapeutic strategies for cancer treatment. In this study, we used two genetically engineered mouse carcinoma models, brain choroid plexus carcinoma (CPC) and prostate, to test the effect of inactivating gadd45a, a DNA damage response p53 target gene, on tumor responses to IR. We show that gadd45a deficiency significantly increases tumor cell death after radiation. Effect on survival was assessed in the CPC model and was extended in IR-treated mice with gadd45a deficiency compared with those expressing wild-type gadd45a. These studies show a significant effect of gadd45a inactivation in sensitizing tumor cells to IR, implicating gadd45a as a potential drug target in radiotherapy management. [Cancer Res 2008;68(10):3579–83]
Attenuation of Melanoma Invasion by a Secreted Variant of Activated Leukocyte Cell Adhesion Molecule
Authors: van Kilsdonk Jeroen W.J. , Wilting Roel H. , Bergers Mieke , van Muijen Goos N.P. , Schalkwijk Joost , van Kempen Léon C.L.T. , Swart Guido W.M.
Published: May 2008

Activated leukocyte cell adhesion molecule (ALCAM/CD166/MEMD), a marker of various cancers and mesenchymal stem cells, is involved in melanoma metastasis. We have exploited a secreted NH2-terminal fragment, sALCAM, to test the hypothesis that ALCAM coordinates tissue growth and cell migration. Overexpression of sALCAM in metastatic melanoma cells disturbed clustering of endogenous ALCAM and inhibited activation of matrix metalloproteinase-2 (MMP-2). Exposure of HT1080 fibrosarcoma cells to sALCAM similarly inhibited MMP-2, suggesting a broader effect on ALCAM-positive tumor cells. In contrast to the previously reported, promotive effects of an NH2-terminally truncated, transmembrane variant (ΔN-ALCAM), sALCAM impaired the migratory capacity of transfected cells in vitro, reduced basement membrane penetration in reconstituted human skin equivalents, and diminished metastatic capacity in nude mice. Remarkably, L1 neuronal cell adhesion molecule (L1CAM/CD171), another progression marker of several cancers including melanoma, was suppressed upon sALCAM overexpression but was up-regulated by ΔN-ALCAM. The partially overlapping and opposite effects induced by alternative strategies targeting ALCAM functions collectively attribute an integrative role to ALCAM in orchestrating cell adhesion, growth, invasion, and proteolysis in the tumor tissue microenvironment and disclose a therapeutic potential for sALCAM. [Cancer Res 2008;68(10):3671–9]
Functions of Anti-MAGE T-Cells Induced in Melanoma Patients under Different Vaccination Modalities
Authors: Connerotte Thierry , Van Pel Aline , Godelaine Danièle , Tartour Eric , Schuler-Thurner Beatrice , Lucas Sophie , Thielemans Kris , Schuler Gerold , Coulie Pierre G.
Published: May 2008

Tumor regressions have been observed in a small proportion of melanoma patients vaccinated with a MAGE-A3 peptide presented by HLA-A1, administered as peptide, ALVAC canarypox virus containing a MAGE-A3 minigene, or peptide-pulsed dendritic cells (DC). There was a correlation between tumor regression and the detection of anti–MAGE-3.A1 CTL responses. These responses were monoclonal and often of a very low magnitude after vaccination with peptide or ALVAC, and usually polyclonal and of a higher magnitude after DC vaccination. These results suggested that, at least in some patients, surprisingly few anti–MAGE-3.A1 T-cells could initiate a tumor regression process. To understand the role of these T cells, we carried out a functional analysis of anti–MAGE-3.A1 CTL clones derived from vaccinated patients who displayed tumor regression. The functional avidities of these CTL clones, evaluated in lysis assays, were surprisingly low, suggesting that high avidity was not part of the putative capability of these CTL to trigger tumor rejection. Most anti–MAGE-3.A1 CTL clones obtained after DC vaccination, but not after peptide or ALVAC vaccination, produced interleukin 10. Transcript profiling confirmed these results and indicated that approximately 20 genes, including CD40L, prostaglandin D2 synthase, granzyme K, and granzyme H, were highly differentially expressed between the anti–MAGE-3.A1 CTL clones derived from patients vaccinated with either peptide-ALVAC or peptide-pulsed DC. These results indicate that the modality of vaccination with a tumor-specific antigen influences the differentiation pathway of the antivaccine CD8 T-cells, which may have an effect on their capacity to trigger a tumor rejection response. [Cancer Res 2008;68(10):3931–40]
Cancer Immunotherapy UsingIn vitroGenetically Modified Targeted Dendritic Cells
Authors: Wei Huafeng , Wang Hao , Lu Bing , Li Bohua , Hou Sheng , Qian Weizhu , Fan Kexing , Dai Jianxin , Zhao Jian , Guo Yajun
Published: May 2008

Modest clinical outcomes of dendritic cell (DC) vaccine trials call for novel strategies. In this study, we have created a chimeric CD40 molecule that incorporates a single chain Fv (scFv) molecule specific for human ErbB2 antigen and fusing to the membrane spanning and cytosolic domains of murine CD40. After adenoviral transfer to bone marrow–derived DC, this chimeric receptor (CR) induced nuclear factor-κB (NF-κB)–dependent DC activation and effector function when cultured with immobilized ErbB2 protein or ErbB2-positive tumor cells in vitro. In vivo migration assays showed that ∼40% injected CR-modified DC (scFv-CD40-DC) effectively migrated to ErbB2-positive tumors, where they were activated after ErbB2 antigen stimulation, and sequentially homed into the draining lymph nodes. In murine ErbB2-positive D2F2/E2 breast tumor (BALB/c) and EL4/E2 thymoma (C57BL/6) models, i.v. injection of 1 × 106 scFv-CD40-DC significantly inhibited tumor growth and cured established tumors. Importantly, the cured mice treated by injection of scFv-CD40-DC were effective in preventing both ErbB2-positive and parental ErbB2-negative tumor rechallenge. Analysis of the underlying mechanism revealed that i.v. infusion of scFv-CD40-DC elicited tumor-specific CTL responses, and the transfer of CTLs from scFv-CD40-DC–treated mice protected naive mice against a subsequent tumor challenge. These results support the concept that genetic modification of DC with tumor-associated antigen-specific CD40 chimeric receptor might be a useful strategy for treatment of human cancers. [Cancer Res 2008;68(10):3854–62]
Characterization of TMPRSS2-ETS Gene Aberrations in Androgen-Independent Metastatic Prostate Cancer
Authors: Mehra Rohit , Tomlins Scott A. , Yu Jianjun , Cao Xuhong , Wang Lei , Menon Anjana , Rubin Mark A. , Pienta Kenneth J. , Shah Rajal B. , Chinnaiyan Arul M.
Published: May 2008

Recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS transcription factor family members ERG, ETV1, and ETV4 have been identified as a critical event in prostate cancer development. In this study, we characterized the prevalence and diversity of these rearrangements in hormone-refractory metastatic prostate cancer. We used a fluorescence in situ hybridization (FISH) split probe strategy to comprehensively evaluate TMPRSS2-ETS aberrations across 97 nonosseous metastatic sites of prostate cancer from 30 rapid autopsies of men who died of androgen-independent disease. Tissue microarrays were constructed representing multiple metastatic sites from each patient, and split signal FISH probes for TMPRSS2, ERG, ETV1, and ETV4 were used to assess for TMPRSS2-ETS rearrangements. In patients exhibiting these aberrations, multiple sites from an individual case harbored the same gene fusion molecular subtype suggesting clonal expansion of disease. The most common prostate cancer gene fusion, TMPRSS2-ERG, can be generated by the mechanism of interstitial deletion (Edel) about 39% to 60% of the time in clinically localized disease. Interestingly, we observed that all of the androgen-independent metastatic prostate cancer sites harboring TMPRSS2-ERG were associated with Edel. These findings suggest that TMPRSS2-ERG with Edel is an aggressive and, in this study, uniformly lethal molecular subtype of prostate cancer associated with androgen-independent disease. [Cancer Res 2008;68(10):3584–90]
213Bi (α-Emitter)–Antibody Targeting of Breast Cancer Metastases in theneu-N Transgenic Mouse Model
Authors: Song Hong , Shahverdi Karineh , Huso David L. , Esaias Caroline , Fox James , Liedy Allison , Zhang Zhe , Reilly R. Todd , Apostolidis Christos , Morgenstern Alfred , Sgouros George
Published: May 2008

Treatment failure in breast cancer is largely the failure to control metastatic dissemination. In this study, we investigated the efficacy of an antibody against the rat variant of HER-2/neu, labeled with the α-particle emitter 213Bi to treat widespread metastases in a rat/neu transgenic mouse model of metastatic mammary carcinoma. The model manifests wide-spread dissemination of tumor cells leading to osteolytic bone lesions and liver metastases, common sites of clinical metastases. The maximum tolerated dose was 120 μCi of 213Bi-7.16.4. The kinetics of marrow suppression and subsequent recovery were determined. Three days after left cardiac ventricular injection of 105 rat HER-2/neu--expressing syngeneic tumor cells, neu-N mice were treated with (a) 120 μCi 213Bi-7.16.4, (b) 90 μCi 213Bi-7.16.4, (c) 120 μCi 213Bi-Rituximab (unreactive control), and (d) unlabeled 7.16.4. Treatment with 120 μCi 213Bi-7.16.4 increased median survival time to 41 days compared with 28 days for the untreated controls (P < 0.0001); corresponding median survival times for groups b, c, and d were 36 (P < 0.001), 31 (P < 0.01), and 33 (P = 0.05) days, respectively. Median survival relative to controls was not significantly improved in mice injected with 10-fold less cells or with multiple courses of treatment. We concluded that α-emitter 213Bi-labeled monoclonal antibody targeting the HER-2/neu antigen was effective in treating early-stage HER-2/neu--expressing micrometastases. Analysis of the results suggests that further gains in efficacy may require higher specific activity constructs or target antigens that are more highly expressed on tumor cells. [Cancer Res 2008;68(10):3873–80]
Myc-Mediated Transcriptional Repression by Recruitment of Histone Deacetylase
Authors: Kurland John F. , Tansey William P.
Published: May 2008

Myc is a transcription factor that features prominently in cancer. The oncogenicity of Myc stems from its ability to regulate expression of genes required for cell growth and proliferation. Although the mechanisms through which Myc activates transcription have been extensively studied, less is known about how Myc represses transcription. Recently, we reported that a conserved element within Myc–MbIII– is important for transcriptional repression. Here, we investigate the mechanism through which MbIII contributes to repression. We show that Myc represses transcription of target genes Id2 and Gadd153 by a process that involves histone deacetylation. We show that MbIII is important for repression of these genes and present evidence that this element contributes to repression by recruiting the histone deacetylase HDAC3 to the Id2 and Gadd153 promoters. These results describe a mechanistic role for MbIII in transcription, and reveal that recruitment of HDAC3 is a process by which Myc represses gene activity. [Cancer Res 2008;68(10):3624–9]
The Cannabinoid Receptors Are Required for Ultraviolet-Induced Inflammation and Skin Cancer Development
Authors: Zheng Duo , Bode Ann M. , Zhao Qing , Cho Yong-Yeon , Zhu Feng , Ma Wei-Ya , Dong Zigang
Published: May 2008

Solar UV irradiation is an important carcinogen that leads to the development of skin cancer, which is the most common human cancer. However, the receptors that mediate UV-induced skin carcinogenesis have not yet been unequivocally identified. Here we showed that UV irradiation directly activates cannabinoid receptors 1 and 2 (CB1/2). Notably, our data indicated that the absence of the CB1/2 receptors in mice results in a dramatic resistance to UVB-induced inflammation and a marked decrease in UVB-induced skin carcinogenesis. A marked attenuation of UVB-induced activation of mitogen-activated protein kinases and nuclear factor- κB was associated with CB1/2 deficiency. These data provide direct evidence indicating that the CB1/2 receptors play a key role in UV-induced inflammation and skin cancer development. [Cancer Res 2008;68(10):3992–7]
Targeted Knockout of BRG1 Potentiates Lung Cancer Development
Authors: Glaros Selina , Cirrincione Georgina M. , Palanca Ariel , Metzger Daniel , Reisman David
Published: May 2008

Brahma-related gene 1 (BRG1) is a catalytic subunit of the switch in mating type/sucrose nonfermentation complex and plays an important role in cancer development. Mouse homozygous knockout experiments testing the role of BRG1 in tumorigenesis have been hampered because BRG1 inactivation is embryonic lethal. To bypass this constraint, we developed a lung-specific conditional knockout of BRG1 and examined the effect of BRG1 inactivation in an ethyl carbamate lung carcinogenesis mouse model. We found that the heterozygous loss of BRG1 resulted in increases in both the number and size of tumors when compared with controls. In contrast, when both BRG1 alleles were inactivated, neither the number nor the size of tumors increased compared with controls. In mouse lung tissue where BRG1 was homozygously inactivated, immunostaining for apoptotic markers showed significant increase in Apo-BrdUrd and cleaved caspase-3. These data indicate that a loss of cell viability underlies why biallelic inactivation of BRG1 does not increase tumorigenesis. We also examined mice when exposed to the carcinogen ethyl carbamate and then subjected to BRG1 inactivation. In these cells, loss of BRG1 after carcinogen exposure potentiated tumor development. A subset of tumors retained BRG1 expression, whereas others showed either partial or complete loss of BRG1 expression. Tumors completely devoid of BRG1 expression were significantly larger and expressed higher levels of two markers of proliferation, proliferating cell nuclear antigen and Ki67. Although biallelic inactivation of BRG1 could not initiate tumor development in untransformed cells, our results indicate that transformation and tumor progression are greatly affected by loss of BRG1. [Cancer Res 2008;68(10):3689–96]
A Small Molecule Disruptor of Rb/Raf-1 Interaction Inhibits Cell Proliferation, Angiogenesis, and Growth of Human Tumor Xenografts in Nude Mice
Authors: Kinkade Rebecca , Dasgupta Piyali , Carie Adam , Pernazza Daniele , Carless Melanie , Pillai Smitha , Lawrence Nicholas , Sebti Said M. , Chellappan Srikumar
Published: May 2008

Although it is well established that cyclin-dependent kinases phosphorylate and inactivate Rb, the Raf-1 kinase physically interacts with Rb and initiates the phosphorylation cascade early in the cell cycle. We have identified an orally active small molecule, Rb/Raf-1 disruptor 251 (RRD-251), that potently and selectively disrupts the Rb/Raf-1 but not Rb/E2F, Rb/prohibitin, Rb/cyclin E, and Rb/HDAC binding. The selective inhibition of Rb/Raf-1 binding suppressed the ability of Rb to recruit Raf-1 to proliferative promoters and inhibited E2F1-dependent transcriptional activity. RRD-251 inhibited anchorage-dependent and anchorage-independent growth of human cancer cells and knockdown of Rb with short hairpin RNA or forced expression of E2F1 rescued cells from RRD-251–mediated growth arrest. P.o. treatment of mice resulted in significant tumor growth suppression only in tumors with functional Rb, and this was accompanied by inhibition of angiogenesis, inhibition of proliferation, decreased phosphorylated Rb levels, and inhibition of Rb/Raf-1 but not Rb/E2F1 binding in vivo. Thus, selective targeting of Rb/Raf-1 interaction seems to be a promising approach for developing novel chemotherapeutic agents. [Cancer Res 2008;68(10):3810–8]
Reversible Dysfunction of Wild-Type p53 following Homeodomain-Interacting Protein Kinase-2 Knockdown
Authors: Puca Rosa , Nardinocchi Lavinia , Gal Hilah , Rechavi Gideon , Amariglio Ninette , Domany Eytan , Notterman Daniel A. , Scarsella Marco , Leonetti Carlo , Sacchi Ada , Blandino Giovanni , Givol David , D'Orazi Gabriella
Published: May 2008

About half of cancers sustain mutations in the TP53 gene, whereas the other half maintain a wild-type p53 (wtp53) but may compromise the p53 response because of other alterations. Homeodomain-interacting protein kinase-2 (HIPK2) is a positive regulator of p53 oncosuppressor function. Here, we show, by microarray analysis, that wtp53 lost the target gene activation following stable knockdown of HIPK2 (HIPK2i) in colon cancer cell line. Our data show that the stable knockdown of HIPK2 led to wtp53 misfolding, as detected by p53 immunoprecipitation with conformation-specific antibodies, and that p53 protein misfolding impaired p53 DNA binding and transcription of target genes. We present evidence that zinc supplementation to HIPK2i cells increased p53 reactivity to conformation-sensitive PAb1620 (wild-type conformation) antibody and restored p53 sequence-specific DNA binding in vivo and transcription of target genes in response to Adriamycin treatment. Finally, combination of zinc and Adriamycin suppressed tumor growth in vivo and activated misfolded p53 that induced its target genes in nude mice tumor xenografts derived from HIPK2i cells. Bioinformatics analysis of microarray data from colon cancer patients showed significant association of poor survival with low HIPK2 expression only in tumors expressing wtp53. These results show a critical role of HIPK2 in maintaining the transactivation activity of wtp53 and further suggest that low expression of HIPK2 may impair the p53 function in tumors harboring wtp53. [Cancer Res 2008;68(10):3707–13]
Repair of 2′-C-Cyano-2′-Deoxy-1-β-d-arabino-Pentofuranosylcytosine–Induced DNA Single-Strand Breaks by Transcription-Coupled Nucleotide Excision Repair
Authors: Wang Yaqing , Liu Xiaojun , Matsuda Akira , Plunkett William
Published: May 2008

The cytosine nucleoside analogue 2′-C-cyano-2′-deoxy-1-β-d-arabino-pentofuranosylcytosine (CNDAC) causes DNA single-strand breaks after its incorporation into DNA. This investigation sought to determine if DNA excision repair pathways were activated to repair this damage. Neither the base excision repair nor the mismatch repair pathway seemed to be involved. Cells deficient in the CSB protein, which initiates transcription-coupled nucleotide excision repair (NER) pathway (TC-NER), exhibited increased clonogenic sensitivity to CNDAC, whereas cells deficient in XPC, which initiates global genome NER, were slightly resistant relative to wild-type cells. The cells lacking either helicase XPB, which unwinds 5′ of the lesion, or endonuclease XPF, which incises 5′ to a lesion, exhibited increased clonogenic sensitivity to CNDAC, as did cells lacking the XPF partner protein ERCC1. This sensitization was independent of p53 function. Repletion of XPF restored sensitivity comparable with the wild type. In contrast, cells lacking either XPD, the 3′-helicase, or the 3′-endonuclease XPG were equally as sensitive as wild-type cells. In comparison, cells deficient in XPF were not sensitized to other cytosine nucleoside analogues, troxacitabine and cytarabine. Thus, the single-strand nick caused by CNDAC is recognized and, in part, repaired by the TC-NER pathway. NER proteins that function in the 5′ direction relative to the UV-induced lesion also participate in the repair of the CNDAC-induced nick, in contrast to proteins that process on the 3′ side of the lesion. [Cancer Res 2008;68(10):3881–9]
Memory Th1 Cells Augment Tumor-Specific CTL following Transcutaneous Peptide Immunization
Authors: Hosoi Akihiro , Takeda Yayoi , Furuichi Yoshihiro , Kurachi Makoto , Kimura Kiminori , Maekawa Ryuji , Takatsu Kiyoshi , Kakimi Kazuhiro
Published: May 2008

Targeting dendritic cells in vivo by transcutaneous peptide immunization (TCI) represents an efficient immunization strategy to induce tumor-specific CTL because it reflects the physiologic conditions occurring during pathogen infection. Here we show that including a Th1 peptide in TCI can activate preexisting memory Th1 (mTh1) responses and thereby enhance the CTL response. For this purpose, peptide-25, a major Th1 epitope of Ag85B from Mycobacterium tuberculosis, was selected. We adoptively transferred peptide-25–specific mTh1 cells and hgp100-specific naive CTL (pmel-1 TCR transgenic) into C57BL/6 mice. Subsequently, mice were transcutaneously immunized with CTL peptide (hgp100) and Th1 peptide (peptide-25). Five days after TCI, the frequency and function of pmel-1 cells was monitored by intracellular IFN-γ staining, ELISPOT, and in vivo cytotoxicity assays. TCI efficiently expanded hgp100-specific, IFN-γ–producing, strongly cytotoxic CD8+ T cells. Concurrent activation of mTh1 cells by peptide-25 induced a 1.5-fold increase in the number of hgp100-specific CTL with enhanced effector functions. Furthermore, TCI elicited not only prophylactic but also therapeutic antitumor responses that were augmented by peptide-25. These results show that TCI facilitates peptide-specific activation of CD4+ T cells, responsible for the augmenting effect of peptide-25 on the hgp100-specific CTL response. Because a significant proportion of the Japanese population has been vaccinated with Bacillus Calmette-Guerin, they are likely to possess Ag85B- or peptide-25–specific mTh1 cells. Therefore, concomitant activation of Ag85B- or peptide-25–specific mTh1 cells together with tumor-specific CTL by TCI might augment antitumor immune responses in a sizeable fraction of patients. [Cancer Res 2008;68(10):3941–9]
An Anti–Transforming Growth Factor β Antibody Suppresses Metastasis via Cooperative Effects on Multiple Cell Compartments
Authors: Nam Jeong-Seok , Terabe Masaki , Mamura Mizuko , Kang Mi-Jin , Chae Helen , Stuelten Christina , Kohn Ethan , Tang Binwu , Sabzevari Helen , Anver Miriam R. , Lawrence Scott , Danielpour David , Lonning Scott , Berzofsky Jay A. , Wakefield Lalage M.
Published: May 2008

Overexpression of transforming growth factor β (TGF-β) is frequently associated with metastasis and poor prognosis, and TGF-β antagonism has been shown to prevent metastasis in preclinical models with surprisingly little toxicity. Here, we have used the transplantable 4T1 model of metastatic breast cancer to address underlying mechanisms. We showed that efficacy of the anti–TGF-β antibody 1D11 in suppressing metastasis was dependent on a synergistic combination of effects on both the tumor parenchyma and microenvironment. The main outcome was a highly significant enhancement of the CD8+ T-cell–mediated antitumor immune response, but effects on the innate immune response and on angiogenesis also contributed to efficacy. Treatment with 1D11 increased infiltration of natural killer cells and T cells at the metastatic site, and enhanced expression of coactivators (NKG2D) and cytotoxic effectors (perforin and granzyme B) on CD8+ T cells. On the tumor cells, increased expression of an NKG2D ligand (Rae1γ) and of a death receptor (TNFRSF1A) contributed to enhanced immune cell-mediated recognition and lysis. The data suggest that elevated TGF-β expression in the tumor microenvironment modulates a complex web of intercellular interactions that aggregately promote metastasis and progression. TGF-β antibodies reverse this effect, and the absence of a major effect of TGF-β antagonism on any one cell compartment may be critical for a good therapeutic window and the avoidance of autoimmune complications. [Cancer Res 2008;68(10):3835–43]
Abnormal Cytokinesis after X-Irradiation in Tumor Cells that Override the G2 DNA Damage Checkpoint
Authors: Huang Haomin , Fletcher Lynda , Beeharry Neil , Daniel Rene , Kao Gary , Yen Tim J. , Muschel Ruth J.
Published: May 2008

X-irradiation–induced DNA damage perturbs the G1, S, and G2 phases of the cell cycle. The behavior of cells after they have experienced a DNA damage checkpoint delay is poorly characterized. We therefore examined the fates of irradiated tumor cells that have overcome a prolonged G2 checkpoint delay. Most irradiated cells progressed through mitosis without significant delay, but failed to complete cytokinesis as they remained tethered to each other at the midbody. We observed that the movement of centrioles at the time of cytokinesis was impaired in the irradiated, bridged cells. We attribute the perturbation of centriole dynamics to the presence of chromatin bridges that spanned the daughter cells. The bridged cells exhibited different fates that included death, fusion that formed multinucleated cells, or another round of mitosis with no noticeable cell cycle delays. The presence of γH2AX foci in the bridge as well as in the separated nuclei indicated that cells were proliferating despite the presence of DNA damage. It seems that DNA damage checkpoints were not reactivated in cells that overrode a prolonged G2 delay. Cells deficient in ATM, H2AX, XRCC3, or ligase 4 exhibited a higher frequency of radiation-induced bridges than controls, suggesting that the DNA bridges resulted from inadequate DNA repair. These data show a previously unappreciated cytologic hallmark of DNA damage in dividing cells. Chromatin bridges that interfere with cytokinesis are likely to contribute to the replication failure and clonogenic death of cells exposed to irradiation. [Cancer Res 2008;68(10):3724–32]
DNA Methylation in Benign Breast Epithelium in Relation to Age and Breast Cancer Risk
Authors: Euhus David M. , Bu Dawei , Milchgrub Sara , Xie Xian-Jin , Bian Aihua , Leitch A. Marilyn , Lewis Cheryl M.
Published: May 2008

Background: Many established breast cancer risk factors are related to the timing and duration of exposure to reproductive hormones, which are known to drive breast epithelial cell proliferation. The epigenetic molecular clock hypothesis suggests that CpG island methylation records the cell division history of benign epithelium. In proliferative epithelium, such as breast, this may provide an individualized cell-based measure of cancer risk.

Methods: Methylation of cyclin D2, APC, HIN1, RASSF1A, and RAR-β2 was measured by quantitative multiplex methylation-specific PCR in 290 benign and malignant breast epithelial cell samples obtained by palpation-directed fine-needle aspiration biopsy from 164 women. Univariate, multivariate, and unsupervised cluster analysis was used to establish the relationship between TSG methylation and a personal history of breast cancer, predicted breast cancer risk, and specific breast cancer risk factors.

Results: RASSF1A methylation was highly correlated with breast cancer risk [odds ratio (OR), 5.28; 95% confidence interval (95% CI), 1.95-14.32; P = 0.001], atypical cytology (OR, 4.11; 95% CI, 1.30-12.98; P = 0.016), and benign breast disease requiring biopsy (OR, 6.12; 95% CI, 1.41-26.51; P = 0.016). RASSF1A methylation increased linearly between ages 32 and 55. Increasing parity was associated with decreased APC methylation.

Conclusions: TSG methylation increases in benign breast epithelium with increasing age. Because it is independently related to a personal history of benign or malignant breast disease and to predicted breast cancer risk, it may have value for breast cancer risk stratification and as a surrogate endpoint marker in prevention trials. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1051–9)
Polymorphisms in Steroid Hormone Biosynthesis Genes and Risk of Breast Cancer and Fibrocystic Breast Conditions in Chinese Women
Authors: Sakoda Lori C. , Blackston Christie , Doherty Jennifer A. , Ray Roberta M. , Lin Ming Gang , Stalsberg Helge , Gao Dao Li , Feng Ziding , Thomas David B. , Chen Chu
Published: May 2008

Common variants in genes encoding for key enzymes involved in steroidogenesis may alter sex steroid hormone levels, thereby influencing susceptibility to breast carcinoma and related conditions. In a case-control study of Chinese women, we examined genotypes of the CYP11A1 pentanucleotide [(TAAAA)n] repeat (D15S520), CYP17A1 rs743572, and HSD17B1 rs605059 polymorphisms in relation to the risk of breast cancer and fibrocystic breast conditions, comparing 615 women with breast cancer and 467 women with fibrocystic breast conditions separately with 879 women without clinical breast disease. We also evaluated whether these relationships differed by the presence of proliferation in the extratumoral epithelium or fibrocystic lesions, menopausal status, or body mass index. Only CYP11A1 genotype was related to breast cancer risk, with women homozygous for the 4-repeat allele, relative to those homozygous for the 6-repeat allele, at reduced risk (age-adjusted odds ratio, 0.58; 95% confidence interval, 0.37-0.91). There was some suggestion of a stronger inverse association for breast cancer with evidence of proliferation in the extratumoral epithelium than for breast cancer without extratumoral proliferation. Breast cancer risk associated with CYP11A1 genotype did not differ by menopausal status or body mass index level. No associations between CYP11A1, CYP17A1, and HSD17B1 genotypes and risk of fibrocystic breast conditions were observed. Our findings support the possibility that common allelic variation at the CYP11A1 D15S520 locus alters breast cancer risk in Chinese women. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1066–73)
Measurement of Tobacco Smoke Exposure: Comparison of Toenail Nicotine Biomarkers and Self-Reports
Authors: Al-Delaimy Wael K. , Willett Walter C.
Published: May 2008

Background: Accurate measurement tools of exposure for use in large epidemiologic studies are lacking. Biomarkers of tobacco exposure provide additional advantages to self-reports and there is a need to further develop and validate them. The objective is to compare toenail nicotine levels, a novel biomarker of tobacco exposure, with self-reports of tobacco exposure from a large cohort study.

Methods: In this cross-sectional analysis, toenail samples were collected from 2,485 women participating in the Nurses' Health Study in 1982. Detailed self-reports of smoking habits and reported exposure to secondhand smoke (SHS) were collected from these women near the time of toenail collection. The toenail samples were analyzed by a high-performance liquid chromatography method for measuring nicotine.

Results: The 5 to 95 percentile range of toenail nicotine was from 0.06 to 4.06 ng/mg toenail and the median level was 0.21 ng/mg. There was a significant difference in toenail nicotine levels according to reported smoking status (the median level for nonsmokers with no SHS was 0.10 ng/mg, the median level for nonsmokers with SHS was 0.14 ng/mg, and the median level for active smokers was 1.77 ng/mg). However there was considerable overlap in nicotine levels according to reported smoking status. Toenail nicotine level was strongly associated with reported smoking level (Spearman r = 0.63), but there was no complete concordance, suggesting that the two methods are measuring different aspects of the same exposure.

Conclusion: Our findings show that toenail nicotine levels capture the overall burden of tobacco smoke exposure and provide additional information on exposure not captured by reported history. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1255–61)
Biochemical Markers for Monitoring Response to Therapy: Evidence for Higher Bone Specificity by a Novel Marker Compared with Routine Markers
Authors: Leeming Diana Julie , Hegele Axel , Byrjalsen Inger , Hofmann Rainer , Qvist Per , Karsdal Morten Asser , Schrader Andres Jan , Wagner Reinhold , Olbert Peter
Published: May 2008

The aim of the present study was to compare a novel marker for high bone turnover with two routine markers for screening in prostate cancer patients. The markers were evaluated in two studies: (a) a cross-sectional study of 170 prostate cancer patients with local disease stratified by ±lymph node metastases (N0, N1) compared with controls and (b) a longitudinal study of 40 hormone refractory prostate cancer patients stratified by skeletal involvement and followed during docetaxel (+/−BM) and zoledronate (+BM) treatment. Presence or absence of bone metastases (BM) was assessed by imaging techniques (magnetic resonance imaging or X-ray) and technetium-99m scintigraphy. The serum or urinary levels of alpha C-telopeptide of collagen type I (ααCTX), prostate-specific antigen (PSA), and total alkaline phosphatase (tALP) were assessed. PSA was elevated in both N0 and N1 patients compared with controls, whereas ααCTX was elevated only in N1 patients. tALP exhibited no difference in any of the groups. In the treatment study, PSA decreased with treatment in both the −BM and +BM groups compared with baseline values, showing similar effect of docetaxel or docetaxel/zoledronate treatment on this marker. On the contrary, ααCTX and tALP did not decrease with docetaxel treatment in the −BM group compared with baseline, whereas it decreased significantly with docetaxel/zoledronate treatment in the +BM group, already after 1 month of treatment for ααCTX. Results suggest that ααCTX is superior to PSA and tALP for identifying patients having a high risk of metastatic disease and for monitoring skeletal progression in +BM prostate cancer patients during treatment. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1269–76)
Functional Polymorphisms in Folate Metabolism Genes Influence the Risk of Meningioma and Glioma
Authors: Bethke Lara , Webb Emily , Murray Anne , Schoemaker Minouk , Feychting Maria , Lönn Stefan , Ahlbom Anders , Malmer Beatrice , Henriksson Roger , Auvinen Anssi , Kiuru Anne , Salminen Tiina , Johansen Christoffer , Christensen Helle Collatz , Muir Kenneth , McKinney Patricia , Hepworth Sarah , Dimitropoulou Polyxeni , Lophatananon Artitaya , Swerdlow Anthony , Houlston Richard
Published: May 2008

Folate metabolism plays an important role in carcinogenesis. To test the hypothesis that polymorphic variation in the folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) influences the risk of primary brain tumors, we genotyped 1,005 glioma cases, 631 meningioma cases, and 1,101 controls for the MTHFR C677A and A1298C, MTRR A66G, and MTR A2756G variants. MTHFR C677T-A1298C diplotypes were associated with risk of meningioma (P = 0.002) and glioma (P = 0.02); risks were increased with genotypes associated with reduced MTHFR activity. The highest risk of meningioma was associated with heterozygosity for both MTHFR variants [odds ratio (OR), 2.11; 95% confidence interval (95% CI), 1.42-3.12]. The corresponding OR for glioma was 1.23 (95% CI, 0.91-1.66). A significant association between risk of meningioma and homozygosity for MTRR 66G was also observed (OR, 1.41; 95% CI, 1.02-1.94). Our findings provide support for the role of folate metabolism in the development of primary brain tumors. In particular, genotypes associated with increased 5,10-methylenetetrahydrofolate levels are associated with elevated risk. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1195–202)
Cytokinesis-Blocked Micronucleus Cytome Assay Biomarkers Identify Lung Cancer Cases Amongst Smokers
Authors: El-Zein Randa A. , Fenech Michael , Lopez Mirtha S. , Spitz Margaret R. , Etzel Carol J.
Published: May 2008

The multi-endpoint cytokinesis-blocked micronucleus assay is used for assessing chromosome aberrations. We have recently reported that this assay is extremely sensitive to genetic damage caused by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and that the binucleated cells with micronuclei, nucleoplasmic bridges, and nuclear buds in lymphocytes (chromosome damage endpoints measured by the assay) are strong predictors of lung cancer risk. In the current study, we refined our analysis to include toxicity endpoints (micronuclei in mononucleated cells, apoptosis, necrosis, and nuclear division index) to investigate the benefit of including these variables on improving the predictive value of the assay. Baseline and NNK-induced micronuclei in mononucleated cells were significantly higher in patients (n = 139) than controls (n = 130; P < 0.001). Baseline apoptosis was higher among cases; however, the controls showed a significant higher fold increase in NNK-induced apoptosis compared with baseline (P < 0.001). Principal components analysis was used to derive a summary measure for all endpoints and calculate the positive predictive value (PPV) and negative predictive value (NPV) for disease status. First principal component for NNK-induced chromosome damage endpoints (binucleated cells with micronuclei, nucleoplasmic bridges, and nuclear buds) had an area under the curve = 97.9 (95% confidence interval, 95.9-99.0), PPV = 94.8, and NPV = 92.6. The discriminatory power improved when micronuclei in mononucleated cells were included: area under the curve = 99.1 (95% confidence interval, 97.9-100.0), PPV = 98.7 and NPV = 95.6. The simplicity, rapidity, and sensitivity of the assay together with potential for automation make it a valuable tool for screening and prioritizing potential cases for intensive screening. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1111–9)
Nonsteroidal Anti-inflammatory Drugs and Change in Mammographic Density: A Cohort Study Using Pharmacy Records on Over 29,000 Postmenopausal Women
Authors: Terry Mary Beth , Buist Diana S.M. , Trentham-Dietz Amy , James-Todd Tamarra M. , Liao Yuyan
Published: May 2008

Background: Use of nonsteroidal anti-inflammatory drugs (NSAID) has been associated with a decrease in breast cancer risk, but it is unknown if they also reduce mammographic density, a strong intermediate marker of breast cancer risk.

Methods: We investigated NSAID use and mammographic density in 29,284 postmenopausal women who had two screening mammograms at Group Health in Seattle. We used pharmacy records to classify women as NSAID nonusers, continuers, initiators, or discontinuers based on use between the two mammograms and nine separate prescription and nonprescription NSAID classes. Using unordered polytomous logistic regression methods, we modeled the odds ratio (OR) of staying not dense, decreasing density, or increasing density relative to remaining dense based on Breast Imaging Reporting Data System classification of density.

Results: There was no association with density change from initiation or continuation of NSAIDs. However, both initiators and continuers of any NSAIDs were more likely to stay not dense than stay dense [OR, 1.12; 95% confidence interval (95% CI), 1.04-1.20; OR, 1.25; 95% CI, 1.05-1.49, respectively]. This association with staying not dense for initiators and continuers of any NSAID use was observed primarily among women ages <65 years at first mammogram (OR, 1.24; 95% CI, 1.12-1.36; OR, 1.48; 95% CI, 1.14-1.93, respectively).

Conclusions: Initiation of NSAID use did not reduce mammographic density over the short term. Continuers of NSAID use were more likely to stay not dense compared with nonusers, suggesting that it is plausible that longer-term use of NSAIDs may be needed to reduce density. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1088–95)