bluuebunny/crossref_metadata_2025 huggingface dataset:
The Expression of CD30 in Anaplastic Large Cell Lymphoma Is Regulated by Nucleophosmin-Anaplastic Lymphoma Kinase–Mediated JunB Level in a Cell Type–Specific Manner
Authors: Hsu Faye Yuan-Yi , Johnston Patrick B. , Burke Kathleen A. , Zhao Yi
Published: September 2006

Chromosomal translocation t(2;5) and the resulting fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) are detected in 50% to 70% of anaplastic large cell lymphoma (ALCL), which is a T/null cell non–Hodgkin's lymphoma showing anaplastic morphology with cell surface expression of CD30. Because aberrant CD30 expression was also observed in the T-cell lymphoma derived from lineage-specific NPM-ALK transgenic mice, we tested the hypothesis that there might be a functional relationship between the two neoplastic-related proteins: NPM-ALK and CD30. In this study, we used the RNA interference method to modulate NPM-ALK protein expression in ALCL-derived, t(2;5)-positive Karpas 299 cells. We observed decreased CD30 expression when NPM-ALK was repressed. Further analysis suggested that JunB functioned as the mediator of NPM-ALK-derived CD30 transcriptional regulation. The NPM-ALK-repressed cells, which had low CD30 expression, were characterized with lower cell proliferation compared with cells in the control group, suggesting that altered CD30 expression may correlate to NPM-ALK-mediated tumor cell growth inhibition. Combination of NPM-ALK repression and CD30 ligand leads to significantly increased tumor cell growth inhibition compared with one method alone, suggesting its potential application for ALCL-specific cancer treatment. (Cancer Res 2006; 66(18): 9002-8)
KRN951, a Highly Potent Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, Has Antitumor Activities and Affects Functional Vascular Properties
Authors: Nakamura Kazuhide , Taguchi Eri , Miura Toru , Yamamoto Atsushi , Takahashi Kazumi , Bichat Francis , Guilbaud Nicolas , Hasegawa Kazumasa , Kubo Kazuo , Fujiwara Yasunari , Suzuki Rika , Kubo Kinya , Shibuya Masabumi , Isae Toshiyuki
Published: September 2006

Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis by stimulating the proangiogenic signaling of endothelial cells via activation of VEGF receptor (VEGFR) tyrosine kinases. Therefore, VEGFRs are an attractive therapeutic target for cancer treatment. In the present study, we show that a quinoline-urea derivative, KRN951, is a novel tyrosine kinase inhibitor for VEGFRs with antitumor angiogenesis and antigrowth activities. KRN951 potently inhibited VEGF-induced VEGFR-2 phosphorylation in endothelial cells at in vitro subnanomolar IC50 values (IC50 = 0.16 nmol/L). It also inhibited ligand-induced phosphorylation of platelet-derived growth factor receptor-β (PDGFR-β) and c-Kit (IC50 = 1.72 and 1.63 nmol/L, respectively). KRN951 blocked VEGF-dependent, but not VEGF-independent, activation of mitogen-activated protein kinases and proliferation of endothelial cells. In addition, it inhibited VEGF-mediated migration of human umbilical vein endothelial cells. Following p.o. administration to athymic rats, KRN951 decreased the microvessel density within tumor xenografts and attenuated VEGFR-2 phosphorylation levels in tumor endothelium. It also displayed antitumor activity against a wide variety of human tumor xenografts, including lung, breast, colon, ovarian, pancreas, and prostate cancer. Furthermore, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) analysis revealed that a significant reduction in tumor vascular hyperpermeability was closely associated with the antitumor activity of KRN951. These findings suggest that KRN951 is a highly potent, p.o. active antiangiogenesis and antitumor agent and that DCE-MRI would be useful in detecting early responses to KRN951 in a clinical setting. KRN951 is currently in phase I clinical development for the treatment of patients with advanced cancer. (Cancer Res 2006; 66(18): 9134-42)
Hypoxic Stress Induces Dimethylated Histone H3 Lysine 9 through Histone Methyltransferase G9a in Mammalian Cells
Authors: Chen Haobin , Yan Yan , Davidson Todd L. , Shinkai Yoichi , Costa Max
Published: September 2006

Dimethylated histone H3 lysine 9 (H3K9me2) is a critical epigenetic mark for gene repression and silencing and plays an essential role in embryogenesis and carcinogenesis. Here, we investigated the effects of hypoxic stress on H3K9me2 at both global and gene-specific level. We found that hypoxia increased global H3K9me2 in several mammalian cell lines. This hypoxia-induced H3K9me2 was temporally correlated with an increase in histone methyltransferase G9a protein and enzyme activity. The increase in H3K9me2 was significantly mitigated in G9a−/− mouse embryonic stem cells following hypoxia challenge, indicating that G9a was involved in the hypoxia-induced H3K9me2. In addition to the activation of G9a, our results also indicated that hypoxia increased H3K9me2 by inhibiting H3K9 demethylation processes. Hypoxic mimetics, such as deferoxamine and dimethyloxalylglycine, were also found to increase H3K9me2 as well as G9a protein and activity. Finally, hypoxia increased H3K9me2 in the promoter regions of the Mlh1 and Dhfr genes, and these increases temporally correlated with the repression of these genes. Collectively, these results indicate that G9a plays an important role in the hypoxia-induced H3K9me2, which would inhibit the expression of several genes that would likely lead to solid tumor progression. (Cancer Res 2006; 66(18): 9009-16)
Inhibition of the Janus Kinase Family Increases Extracellular Signal-Regulated Kinase 1/2 Phosphorylation and Causes Endoreduplication
Authors: Reiterer Gudrun , Yen Andrew
Published: September 2006

The role of Janus-activated kinase (JAK) signaling in cell cycle transit and maintenance of genomic stability was determined in HL-60 myeloblastic leukemia cells. Inhibition of JAKs, all JAKs (JAK1, JAK2, JAK3, and tyrosine kinase 2), JAK2, or JAK3, caused a significant reduction in cell growth with a major G2-M arrest evident 24 hours after treatment. Targeting all JAKs also caused endoreduplication 48 and 72 hours after treatment. We discovered mitotic cells in both G2 (4N DNA) and G4 (8N DNA) subpopulations of cells treated with an inhibitor of all JAKs as detected by phosphorylated histone H3 expression. Treatment with inhibitors of just JAK2 or JAK3 drastically reduced such mitotic cells. We observed a complete blockage of IFN-γ and interleukin-6-induced signal transducer and activator of transcription (STAT)-1 and STAT-3 response when all JAKs were inhibited. At the same time, we found baseline phosphorylated extracellular signal-regulated kinase (ERK) 1/2 to be elevated by JAK inhibition, particularly when all JAKs were inhibited. The G2-M arrest and endoreduplication induced by JAK inhibitors were reduced in cells pretreated with PD98059 to inhibit ERK. PD98059 also increased back the expression of the MAD2 cell cycle checkpoint protein that was down-regulated during “all JAKs inhibitor”–mediated endoreduplication. These data suggest that JAK signaling is needed for G2-M transit with inhibition of ERK. (Cancer Res 2006; 66(18): 9083-9) (Cancer Res 2006; 66(18): 9083-9)
Daxx Represses Expression of a Subset of Antiapoptotic Genes Regulated by Nuclear Factor-κB
Authors: Croxton Rhonda , Puto Lorena A. , de Belle Ian , Thomas Michael , Torii Seiji , Hanaii Farid , Cuddy Michael , Reed John C.
Published: September 2006

Daxx is a nuclear protein that localizes to PML oncogenic domains, sensitizes cells to apoptosis, and functions as a transcriptional repressor. We found that Daxx represses the expression of several antiapoptotic genes regulated by nuclear factor-κB, including cIAP2, in human tumor cell lines. Daxx interacts with RelB and inhibits RelB-mediated transcriptional activation of the human cIAP2 gene promoter. Daxx also forms complexes with RelB while bound to its target sites in the cIAP2 promoter, as shown by electrophoretic mobility shift assays and chromatin immunoprecipitation experiments. Using cells from daxx−/− mouse embryos, we observed that levels of the corresponding murine c-IAP mRNA and protein are increased in cells lacking Daxx. Conversely, c-IAP mRNA and protein levels were reduced in relB−/− cells. Taken together, these observations provide a mechanism that links two previously ascribed functions of Daxx: transcriptional repression and sensitization to apoptosis. (Cancer Res 2006; 66(18): 9026-35)
Nelfinavir Down-regulates Hypoxia-Inducible Factor 1α and VEGF Expression and Increases Tumor Oxygenation: Implications for Radiotherapy
Authors: Pore Nabendu , Gupta Anjali K. , Cerniglia George J. , Jiang Zibin , Bernhard Eric J. , Evans Sydney M. , Koch Cameron J. , Hahn Stephen M. , Maity Amit
Published: September 2006

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway can increase vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α (HIF-1α) expression. We examined the effect of nelfinavir, an HIV protease inhibitor that inhibits Akt signaling, on VEGF and HIF-1α expression and on angiogenesis, tumor oxygenation, and radiosensitization. Nelfinavir decreases VEGF expression under normoxia via the transcription factor Sp1, which regulates the proximal core VEGF promoter. Nelfinavir decreased Sp1 phosphorylation and decreased Sp1 binding to a probe corresponding to the proximal VEGF promoter in a gel shift assay. Nelfinavir also decreased the hypoxic induction of HIF-1α, which also regulates the VEGF promoter, most likely by decreasing its translation. The effect of nelfinavir on VEGF expression had the functional consequence of decreasing angiogenesis in an in vivo Matrigel plug assay. To determine the effect this might have on tumor radiosensitization, we did tumor regrowth assays with xenografts in nude mice. The combination of nelfinavir and radiation increased time to regrowth compared with radiation alone whereas nelfinavir alone had little effect on tumor regrowth. This radiosensitizing effect was greater than suggested by in vitro clonogenic survival assays. One possible explanation for the discordance is that nelfinavir has an effect on tumor oxygenation. Therefore, we examined this with the hypoxia marker EF5 and found that nelfinavir leads to increased oxygenation within tumor xenografts. Our results suggest that nelfinavir decreases HIF-1α/VEGF expression and tumor hypoxia, which could play a role in its in vivo radiosensitizing effect. These data support the use of nelfinavir in combination with radiation in future clinical trials. (Cancer Res 2006; 66(18): 9252-9)
A Dimeric Peptide That Binds Selectively to Prostate-Specific Membrane Antigen and Inhibits its Enzymatic Activity
Authors: Aggarwal Saurabh , Singh Pratap , Topaloglu Ozlem , Isaacs John T. , Denmeade Samuel R.
Published: September 2006

Prostate-specific membrane antigen (PSMA) is highly expressed by both normal and malignant prostate epithelial cells and by the neovasculature of many tumor types; however, it is not expressed by normal endothelial cells or other normal tissues. PSMA, therefore, represents an attractive candidate for selectively targeted therapies for prostate and/or other solid tumors. As an alternative approach to antibody-based anti-PSMA therapies, small peptides that bind selectively to PSMA-producing cells can be used to deliver cytotoxic drugs, protein toxins, and viruses selectively to malignant sites while minimizing systemic toxicity to normal tissues. Small peptides are relatively inexpensive to produce, not immunogenic, and easily coupled to cytotoxic agents. In the present study, a random phage library consisting of linear 12 amino acid peptides was used to identify peptides that bound selectively to PSMA. From a series of monomeric peptides, one with the sequence WQPDTAHHWATL was used to show binding of soluble peptide to PSMA. A dimeric version of this peptide showed markedly enhanced binding to soluble PSMA and an IC50 of 2.2 μmol/L for inhibition of PSMA enzymatic activity. Fluorescently labeled dimeric peptide bound selectively to PSMA-producing prostate cancer cells in vitro with no significant binding to non–PSMA-producing cells. Molecular modeling of the dimeric peptide revealed that histidine residues in close vicinity can efficiently coordinate a divalent ion and hold the peptide in a favorable configuration for binding and subsequent inhibition. These dimeric peptides, therefore, represent putative PSMA-selective targeting agents that are currently being evaluated for selective binding in vivo. (Cancer Res 2006; 66(18): 9171-7)
Quantifying the Activity of Adenoviral E1A CR2 Deletion Mutants Using Renilla Luciferase Bioluminescence and 3′-Deoxy-3′-[18F]Fluorothymidine Positron Emission Tomography Imaging
Authors: Leyton Julius , Lockley Michelle , Aerts Joeri L. , Baird Sarah K. , Aboagye Eric O. , Lemoine Nicholas R. , McNeish Iain A.
Published: September 2006

The adenoviral E1A CR2 mutant dl922-947 has potent activity in ovarian cancer. We have used Renilla luciferase bioluminescence imaging to monitor viral E1A expression and replication and [18F]fluorothymidine positron emission tomography ([18F]FLT-PET) to quantify the activity of dl922-947 in vivo. We created dlCR2 Ren, with the same E1A CR2 deletion as dl922-947 and the luciferase gene from Renilla reniformis downstream of E1. Light emitted from s.c. and i.p. IGROV1 ovarian carcinoma xenografts was measured following treatment with dlCR2 Ren. Mice bearing s.c. IGROV1 xenografts were injected with 2.96 to 3.7 MBq of [18F]FLT 48 and 168 hours following i.t. injection of dl922-947 or control virus Ad LM-X. The presence of Renilla luciferase in dlCR2 Ren did not reduce in vitro nor in vivo potency compared with dl922-947. Light emission correlated closely with E1A expression in vitro and peaked 48 hours after dlCR2 Ren injection in both s.c. and i.p. IGROV1 xenografts. It diminished by 168 hours in s.c. tumors but persisted for at least 2 weeks in i.p. models. Normalized tumor [18F]FLT uptake at 60 minutes (NUV60), fractional retention, and area under radioactivity curve all decreased marginally 48 hours after dl922-947 treatment and significantly at 168 hours compared with controls. There was a close linear correlation between NUV60 and both tumor proliferation (Ki67 labeling index) and thymidine kinase 1 expression. Renilla luciferase bioluminescence and [18F]FLT-PET imaging are capable of quantifying the activity and effectiveness of E1A CR2–deleted adenoviral mutants in ovarian cancer. (Cancer Res 2006; 66(18): 9178-85)
PDZ-Binding Kinase/T-LAK Cell-Originated Protein Kinase, a Putative Cancer/Testis Antigen with an Oncogenic Activity in Breast Cancer
Authors: Park Jae-Hyun , Lin Meng-Lay , Nishidate Toshihiko , Nakamura Yusuke , Katagiri Toyomasa
Published: September 2006

Breast cancer is one of the most common cancers among women. To discover molecular targets that are applicable for development of novel breast cancer therapy, we previously did genome-wide expression profile analysis of 81 breast cancers and found dozens of genes that were highly and commonly up-regulated in breast cancer cells. Among them, we here focused on one gene that encodes PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK), including a kinase domain. Northern blot analyses using mRNAs of normal human organs, breast cancer tissues, and cancer cell lines indicated this molecule to be a novel cancer/testis antigen. Reduction of PBK/TOPK expression by small interfering RNA resulted in significant suppression of cell growth probably due to dysfunction in the cytokinetic process. Immunocytochemical analysis with anti-PBK/TOPK antibody implicated a critical role of PBK/TOPK in an early step of mitosis. PBK/TOPK could phosphorylate histone H3 at Ser10 in vitro and in vivo, and mediated its growth-promoting effect through histone H3 modification. Because PBK/TOPK is the cancer/testis antigen and its kinase function is likely to be related to its oncogenic activity, we suggest PBK/TOPK to be a promising molecular target for breast cancer therapy. (Cancer Res 2006; 66(18): 9186-95)
All-trans-Retinoic Acid Improves Differentiation of Myeloid Cells and Immune Response in Cancer Patients
Authors: Mirza Noweeda , Fishman Mayer , Fricke Ingo , Dunn Mary , Neuger Anthony M. , Frost Timothy J. , Lush Richard M. , Antonia Scott , Gabrilovich Dmitry I.
Published: September 2006

Abnormal dendritic cell differentiation and accumulation of immature myeloid suppressor cells (ImC) is one of the major mechanisms of tumor escape. We tested the possibility of pharmacologic regulation of myeloid cell differentiation using all-trans-retinoic acid (ATRA). Eighteen patients with metastatic renal cell carcinoma were treated with ATRA followed by s.c. interleukin 2 (IL-2). Eight healthy individuals comprised a control group. As expected, the cancer patients had substantially elevated levels of ImC. We observed that ATRA dramatically reduced the number of ImC. This effect was observed only in patients with high plasma concentration of ATRA (>150 ng/mL), but not in patients with lower ATRA concentrations (<135 ng/mL). Effects of ATRA on the proportions of different dendritic cell populations were minor. However, ATRA significantly improved myeloid/lymphoid dendritic cell ratio and the ability of patients' mononuclear cells to stimulate allogeneic T cells. This effect was associated with significant improvement of tetanus-toxoid–specific T-cell response. During the IL-2 treatment, the ATRA effect was completely eliminated. To assess the role of IL-2, specimens from 15 patients with metastatic renal cell carcinoma who had been treated with i.v. IL-2 alone were analyzed. In this group also, IL-2 significantly reduced the number and function of dendritic cells as well as T-cell function. These data indicate that ATRA at effective concentrations eliminated ImC, improved myeloid/lymphoid dendritic cell ratio, dendritic cell function, and antigen-specific T-cell response. ATRA treatment did not result in significant toxicity and it could be tested in therapeutic combination with cancer vaccines. (Cancer Res 2006; 66(18): 9299-307)
Role of Apoptotic Nuclease Caspase-Activated DNase in Etoposide-Induced Treatment-Related Acute Myelogenous Leukemia
Authors: Hars Eszter S. , Lyu Yi Lisa , Lin Chao-Po , Liu Leroy F.
Published: September 2006

Etoposide-induced treatment-related acute myelogenous leukemia (t-AML) is characterized by rearrangements of the mixed lineage leukemia (MLL) gene with one of its >50 partner genes, most probably as a consequence of etoposide-induced DNA double-strand breaks (DSBs). Recent studies have shown that etoposide-induced DSBs occur predominantly within the breakpoint cluster region (bcr) of the MLL gene. However, bcr-specific DSBs induced by etoposide are not topoisomerase II–linked but the result of apoptotic nuclease–mediated DNA cleavage. Here, we test the involvement of caspase-activated DNase (CAD) and other apoptotic components in etoposide-induced gene rearrangements using two methods. First, we measured the effect of etoposide on the integration frequency of a transfected plasmid. Etoposide strongly stimulated plasmid integration in CAD cDNA–complemented mouse embryonic fibroblasts (MEFs) but not in CAD knockout (KO) MEFs. Consistently, down-regulation of ICAD (inhibitor of CAD, also required for proper folding of CAD) in an HT29-derived cell line, which leads to decreased CAD activity, significantly reduced etoposide-induced plasmid integration. Second, we used long-template inverse PCR to focus on gene rearrangements at the MLL locus. Etoposide stimulated MLL fusion product formation in CAD cDNA–complemented MEFs but not in CAD KO MEFs. Together, these results suggest that CAD and other apoptotic components may play an important role in etoposide-induced t-AML. (Cancer Res 2006; 66(18): 8975-9)
Magnetic Resonance Visualization of Tumor Angiogenesis by Targeting Neural Cell Adhesion Molecules with the Highly Sensitive Gadolinium-Loaded Apoferritin Probe
Authors: Geninatti Crich Simonetta , Bussolati Benedetta , Tei Lorenzo , Grange Cristina , Esposito Giovanna , Lanzardo Stefania , Camussi Giovanni , Aime Silvio
Published: September 2006

Tumor vessel imaging could be useful in identifying angiogenic blood vessels as well as being a potential predictive marker of antiangiogenic treatment response. We recently reported the expression of the neural cell adhesion molecule (NCAM) in the immature and tumor endothelial cell (TEC) lining vessels of human carcinomas. Exploiting an in vivo model of human tumor angiogenesis obtained by implantation of TEC in Matrigel in severe combined immunodeficiency mice, we aimed to image angiogenesis by detecting the expression of NCAM with magnetic resonance imaging. The imaging procedure consisted of (a) targeting NCAMs with a biotinylated derivative of C3d peptide that is known to have high affinity for these epitopes and (b) delivery of a streptavidin/gadolinium (Gd)-loaded apoferritin 1:1 adduct at the biotinylated target sites. The remarkable relaxation enhancement ability of the Gd-loaded apoferritin system allowed the visualization of TEC both in vitro and in vivo when organized in microvessels connected to the mouse vasculature. Gd-loaded apoferritin displayed good in vivo stability and tolerability. The procedure reported herein may be easily extended to the magnetic resonance visualization of other epitopes suitably targeted by proper biotinylated vectors. (Cancer Res 2006; 66(18): 9196-201)
Epigenetic Silencing of Occludin Promotes Tumorigenic and Metastatic Properties of Cancer Cells via Modulations of Unique Sets of Apoptosis-Associated Genes
Authors: Osanai Makoto , Murata Masaki , Nishikiori Nami , Chiba Hideki , Kojima Takashi , Sawada Norimasa
Published: September 2006

Occludin is the first identified integral protein for the tight junction (TJ), and its long COOH-terminal domain is considered to have functions in receiving and transmitting cell survival signals. Loss of TJ-associated molecules, such as occludin, has been correlated with tumor progression in carcinogenesis; however, the precise molecular mechanisms explaining its loss of expression and whether occludin expression has any effects on cancer phenotypes remain to be clarified. Here, we show that forced expression of occludin in cancer cells exhibits enhanced sensitivity to differently acting apoptogenic factors, and thus inhibits the tumorigenicity of transformed cells, via modulation of unique sets of apoptosis-associated genes. In addition, studies using deletion mutants of occludin constructs show that 44 amino acids at the COOH-terminal end play a critical role in modifying the cellular phenotypes. Interestingly, occludin decreases cellular invasiveness and motility, thereby abrogating metastatic potencies of cancer cells. We also found that occludin expression is silenced by CpG island hypermethylation on its promoter region. Synergy with a demethylator and histone deacetylase inhibitor or retinoids that stimulate retinoic acid receptor α induces endogenous occludin, which is sufficient for apoptotic sensitization. Our results show the functional diversity of occludin and suggest that methylator phenotype of occludin provides enhanced tumorigenic, invasive, and metastatic properties of cancer cells, identifying occludin as a likely candidate for a tumor-suppressor gene in certain types of cancer. (Cancer Res 2006; 66(18): 9125-33)
HBXIP, Cellular Target of Hepatitis B Virus Oncoprotein, Is a Regulator of Centrosome Dynamics and Cytokinesis
Authors: Fujii Ryoji , Zhu Changjun , Wen Yunfei , Marusawa Hiroyuki , Bailly-Maitre Beatrice , Matsuzawa Shu-ichi , Zhang Hong , Kim Youngsoo , Bennett C. Frank , Jiang Wei , Reed John C.
Published: September 2006

Hepatitis B virus accounts for more than 1 million cancer deaths annually, but the mechanism by which this virus promotes hepatocellular carcinoma remains unclear. The hepatitis B virus genome encodes an oncoprotein, HBx, which binds various cellular proteins including HBXIP. We show here that HBXIP is a regulator of centrosome duplication, required for bipolar spindle formation in HeLa human carcinoma cells and primary mouse embryonic fibroblast cells. We found that most cells deficient in HBXIP arrest in prometaphase with monopolar spindles whereas HBXIP overexpression causes tripolar or multipolar spindles due to excessive centrosome replication. Additionally, a defect in cytokinesis was seen in HBXIP-deficient HeLa cells, with most cells failing to complete division and succumbing eventually to apoptosis. Expression of viral HBx in HeLa cells mimicked the effects of HBXIP overexpression, causing excessive centrosome replication, resulting in tripolar and multipolar spindles and defective cytokinesis. Immunolocalization and fluorescent protein tagging experiments showed that HBXIP associates with microtubules of dividing cells and colocalizes with HBx on centrosomes. Thus, viral HBx and its cellular target HBXIP regulate centrosome dynamics and cytokinesis affecting genetic stability. In vivo experiments using antisense oligonucleotides targeting HBXIP in a mouse model of liver regeneration showed a requirement for HBXIP for growth and survival of replicating hepatocytes. Thus, HBXIP is a critical regulator of hepatocyte cell growth in vivo, making it a strong candidate for explaining the tumorigenic actions of viral HBx. (Cancer Res 2006; 66(18): 9099-107)
MCT-1 Protein Interacts with the Cap Complex and Modulates Messenger RNA Translational Profiles
Authors: Reinert Line S. , Shi Bo , Nandi Suvobroto , Mazan-Mamczarz Krystyna , Vitolo Michele , Bachman Kurtis E. , He Huili , Gartenhaus Ronald B.
Published: September 2006

MCT-1 is an oncogene that was initially identified in a human T cell lymphoma and has been shown to induce cell proliferation as well as activate survival-related pathways. MCT-1 contains the PUA domain, a recently described RNA-binding domain that is found in several tRNA and rRNA modification enzymes. Here, we established that MCT-1 protein interacts with the cap complex through its PUA domain and recruits the density-regulated protein (DENR/DRP), containing the SUI1 translation initiation domain. Through the use of microarray analysis on polysome-associated mRNAs, we showed that up-regulation of MCT-1 was able to modulate the translation profiles of BCL2L2, TFDP1, MRE11A, cyclin D1, and E2F1 mRNAs, despite equivalent levels of mRNAs in the cytoplasm. Our data establish a role for MCT-1 in translational regulation, and support a linkage between translational control and oncogenesis. (Cancer Res 2006; 66(18): 8994-9001)
Pictorial Naming Specificity across Ages and Cultures: A Latent Class Analysis of Picture Norms for Younger and Older Americans and Chinese
Authors: Yoon Carolyn , Feinberg Fred , Gutchess Angela H.
Published: September 2006

Background: Cognitive aging research, as well as cross-cultural research, often relies on pictorial stimuli to address how perceptions of common objects vary by population group. Objective: We investigate naming specificity – the degree of detail elicited for object labels – across age (younger-older) and culture (American-Chinese). Methods: Using latent class analysis techniques, we segregated picture-item responses into multiple specificity levels. The analysis was conducted for 260 pictures, across four groups of younger (aged 17–25 years) and older (aged 59–76 years) adults in the US and mainland China. Results: Overall, three naming specificity classes were supported. Age differences were modest compared to those across culture. In particular, Chinese groups showed far greater variation, naming more items both with high and with low specificity than age-matched American counterparts. Our results differed from prior studies using familiarity and latency measures. Moreover, approximately 28% of commonly-used picture items differed across all four groups. Conclusion: These results highlight the need to select appropriate pictorial stimuli for studies involving populations diverse in age and cultural background.
Calreticulin as a new histone binding protein in mitotic chromosomes
Authors: Kobayashi S. , Uchiyama S. , Sone T. , Noda M. , Lin L. , Mizuno H. , Matsunaga S. , Fukui K.
Published: September 2006

Calreticulin (CRT) is a multifunctional Ca2+-binding protein that mainly functions in the endoplasmic reticulum as a molecular chaperone for newly synthesized proteins. Recently we reported the protein composition of human metaphase chromosomes (Uchiyama et al., 2004), which included CRT. Here we describe new characteristics of CRT in vitro as well as its localization on the surface of metaphase chromosomes in vivo. CRT was detected in the chromosomal fraction by Western blotting and its binding partners were identified as core and linker histones by ligand overlay assay. Surface plasmon resonance sensor analyses revealed that CRT is bound to chromatin fibers. Moreover, we found that CRT has both supercoiling activity, which assists core histone assembly into chromatin fibers, and binding ability to histone H2A/H2B dimers and histone H3/H4 tetramers. Unlike the chromosome scaffold proteins, indirect immunofluorescent staining revealed that CRT is located on the surface of metaphase chromosomes. These results suggest that CRT plays a role which involves chromatin dynamics on the surface of mitotic chromosomes.
A family case of fertile human 45,X,psu dic(15;Y) males
Authors: Wimmer R. , Schempp W. , Gopinath P.M. , Nagarajappa C.S. , Chandra N. , Palaniappan I. , Hansmann I.
Published: September 2006

We report on a familial case including four male probands from three generations with a 45,X,psu dic(15;Y)(p11.2;q12) karyotype. 45,X is usually associated with a female phenotype and only rarely with maleness, due to translocation of small Y chromosomal fragments to autosomes. These male patients are commonly infertile because of missing azoospermia factor regions from the Y long arm. In our familial case we found a pseudodicentric translocation chromosome, that contains almost the entire chromosomes 15 and Y. The translocation took place in an unknown male ancestor of our probands and has no apparent effect on fertility and phenotype of the carrier. FISH analysis demonstrated the deletion of the pseudoautosomal region 2 (PAR2) from the Y chromosome and the loss of the nucleolus organizing region (NOR) from chromosome 15. The formation of the psu dic(15;Y) chromosome is a reciprocal event to the formation of the satellited Y chromosome (Yqs). Statistically, the formation of 45,X,psu dic(15;Y) (p11.2;q12) is as likely as the formation of Yqs. Nevertheless, it has not been described yet. This can be explained by the dicentricity of this translocation chromosome that usually leads to mitotic instability and meiotic imbalances. A second event, a stable inactivation of one of the two centromeres is obligatory to enable the transmission of the translocation chromosome and thus a stably reduced chromosome number from father to every son in this family.
Further Investigation of the Tolerance and Mechanical Adjustability of the *Acri.Tec AR-1 PC/IOL in Rabbit Eyes: An Intraocular Lens with Reversibly Adjustable Optical Power
Authors: Jahn Claus E. , Fromberg Ingeborg , Fesser Nicole , Allgoewer Ingrid , Jahn Christoph H. , Wakili Nina S. , Hofmann-Rummelt Carmen R. , Holbach Leonard M. , Kamppeter Bernd A.
Published: September 2006

Purpose: To examine the tolerance and mechanical function of an adjustable intraocular lens (IOL) in rabbit eyes. Methods: Implantation of the *Acri.Tec AR-1 PC/IOL into 14 rabbit eyes. Manipulation of the lens 8 weeks after implantation in order to change the refractive power. Follow-up for up to 5 months. Histopathologic examination of the eyes. Results: Implantation and mechanical adjustment of the PC/IOL were possible. Eyes healed normally. No difference between eyes containing the *Acri.Tec AR-1 PC/IOL and eyes containing the control PC/IOL could be detected with respect to signs of inflammatory reaction, corneal transparency, intraocular pressure and histopathologic appearance. Histopathologic examination of the eyes showed that the *Acri.Tec AR-1 PC/IOL did not cause any damage in rabbit eyes. Conclusion: The *Acri.Tec AR-1 PC/IOL is well tolerated in rabbit eyes for extended periods of time, suggesting that this PC/IOL should be well tolerated in the long run. Surgical adjustment of the adjusting element can be performed with little effort several weeks after implantation.
Do Lesions Involving the Cortical Cholinergic Pathways Help or Hinder Efficacy of Donepezil in Patients with Alzheimer’s Disease?
Authors: Fukui Toshiya , Hieda Soutaro , Bocti Christian
Published: September 2006

Aims: To investigate the influences of vascular lesions detected by MRI, lesions involving the cortical cholinergic pathways and hippocampal thickness on therapeutic responsiveness to donepezil in patients with Alzheimer’s disease (AD). Methods: The study cohort contained 67 patients with probable AD. We used the revised Hasegawa Dementia Rating (HDS-R) and the Clock Drawing Test (CDT) to evaluate drug efficacy for 24 months. The Cholinergic Pathways Hyperintensities Scale (CHIPS), a newly developed visual scale, was used to semiquantify lesions on the cholinergic pathways. Results: Over the 24-month period, the results of the CDT showed more apparent and constant association with white matter hyperintensities (WMH) and lesions on the cholinergic pathways than the HDS-R. WMH may enhance, while lesions on the cholinergic pathways may attenuate sensitivity to donepezil treatment when judged by the CDT. No apparent association between the thicknesses of hippocampi with baseline cognition or therapeutic responsiveness to donepezil was found. Conclusion: Donepezil may be more efficacious when further executive dysfunction caused by WMH is added to AD dementia and less so when cholinergic reserves are further impinged upon by lesions involving the cortical cholinergic pathways.
N
ε
-(Carboxymethyl)lysine Depositions in Intramyocardial Blood Vessels in Human and Rat Acute Myocardial Infarction
Authors: Baidoshvili A. , Krijnen P.A.J. , Kupreishvili K. , Ciurana C. , Bleeker W. , Nijmeijer R. , Visser C.A. , Visser F.C. , Meijer C.J.L.M. , Stooker W. , Eijsman L. , van Hinsbergh V.W.M. , Hack C.E. , Niessen H.W.M. , Schalkwijk C.G.
Published: September 2006

Objective—

Advanced glycation end products (AGEs), such as N
ε
-(carboxymethyl)lysine (CML), are implicated in vascular disease. We previously reported increased CML accumulation in small intramyocardial blood vessels in diabetes patients. Diabetes patients have an increased risk for acute myocardial infarction (AMI). Here, we examined a putative relationship between CML and AMI.

Methods and Results—

Heart tissue was stained for CML, myeloperoxidase, and E-selectin in AMI patients (n=26), myocarditis patients (n=17), and control patients (n=15). In AMI patients, CML depositions were 3-fold increased compared with controls in the small intramyocardial blood vessels and predominantly colocalized with activated endothelium (E-selectin–positive) both in infarction and noninfarction areas. A trend of increased CML positivity of the intima of epicardial coronary arteries did not reach significance in AMI patients. In the rat heart AMI model, CML depositions were undetectable after 24 hours of reperfusion, but became clearly visible after 5 days of reperfusion. In line with an inflammatory contribution, human myocarditis was also accompanied by accumulation of CML on the endothelium of intramyocardial blood vessels.

Conclusions—

CML, present predominantly on activated endothelium in small intramyocardial blood vessels in patients with AMI, might reflect an increased risk for AMI rather than being a result of AMI.
Phospholipase A
2
–Modified Low-Density Lipoprotein Activates the Phosphatidylinositol 3-Kinase-Akt Pathway and Increases Cell Survival in Monocytic Cells
Authors: Namgaladze Dmitry , Brüne Bernhard
Published: September 2006

Objective—

Monocyte survival is an important determinant in the development of atherosclerotic lesions. We investigated the influence of phospholipase A
2
-modified LDL (PLA-LDL), a pro-atherogenic factor, on activation of the pro-survival kinase Akt and cell death in monocytic cells.

Methods and Results—

PLA-LDL induced robust phosphorylation and activation of Akt in THP1 cells. It also attenuated oxidative stress-induced cell death, an effect abolished by phosphatidylinositol 3-kinase (PI3K) inhibition. In addition, PLA-LDL increased survival of human monocytes. We noticed that lipid products derived from LDL phospholipolysis are mediators of PLA-LDL–induced Akt activation. Arachidonic acid, which is released on phospholipase treatment of LDL, induced Akt phosphorylation and increased cell survival, whereas lysophosphatidylcholine, another compound generated by LDL phospholipolysis, induced only transient Akt phosphorylation and was cytotoxic.

Conclusions—

Our data indicate that PLA-LDL induces activation of the PI3K-Akt pathway and promotes monocytic cell survival, which may contribute to the pro-atherogenic effects of phospholipase A
2
-modified LDL.
HRM Inside UK E-commerce Firms
Authors: Dietz Graham , van der Wiele Ton , van Iwaarden Jos , Brosseau Julie
Published: September 2006

The e-commerce approach to people management (i.e. HRM) is popularly believed to be radically new and an innovative rewriting of the ‘old’ rules of employment. Yet little is known about which HR practices are used by such companies, and what might explain these companies’ policy selections in the realm of HR. Exploratory survey data based on a sample of 30 small-medium UK e-commerce firms reports use of employee involvement in decision-making, internal communication, financial participation and reward schemes, performance evaluation, training and provision for employment security. Insights from interviews with five senior managers from the sample augment the survey data with qualitative evidence on e-commerce firms’ approach to HR. The findings suggest that this approach falls somewhere between radical ‘new’ innovations and enduring continuities with ‘old’ people management techniques, and that this has parallels with the experience of small-medium enterprises generally.
Dying and Grieving Seen Through a Unitary Lens
Authors: Malinski Violet M.
Published: September 2006

In this column, Todaro-Franceschi presents a unitary view of energy, grounded within Rogers’ (1992) science of unitary human beings, that supports a new view of dying and grieving, one based on the assumption that energy transforms, but is never lost. She briefly discusses her research on synchronicities related to dead loved ones as a basis for a new healing modality for the bereaved. Pilkington summarizes five studies on the lived experience of grieving within Parse’s human becoming theory that were conducted either by her or William Cody. The unified description that emerged can assist nurses in being truly present with those who are grieving a loss.
Humanistic Nursing, Interpersonal Relations Theory, and the Empathy-Altruism Hypothesis
Authors: McCamant Karen L.
Published: September 2006

The purpose of this paper is to illuminate the relevance and applicability of theory for nursing research and practice. Following a brief explanation of the four levels of theoretical abstraction recognized by nursing, Paterson and Zderad’s humanistic nursing theory and Peplau’s theory of interpersonal relations are described. In addition, one social psychology theory, the empathy-altruism hypothesis, is also explained. The value and implications of the three theories for nursing research and practice are discussed, and several research questions are proposed.
A Phenomenological Study: The Lived Experience of Persons Having a Different Sense of Hearing
Authors: Aquino-Russell Catherine E.
Published: September 2006

Living with a different sense of hearing, including loss of hearing, is a worldwide phenomenon, known to be a silencing condition that can change persons’ patterns of relating and divest effective ways of giving and receiving messages of sound. This research describes the meaning of this experience for 7 participants. The researcher followed Giorgi’s descriptive phenomenological method for analysis-synthesis to arrive at a general structural description of the experience. Parse’s theory of human becoming framed the researcher’s theoretical perspective. Findings build on Parse’s theory and may enhance nurses’ understanding, in turn altering the way nurses approach persons having a different sense of hearing.
Nursing in Turkey
Authors: Baumann Steven L.
Published: September 2006

The current discussion on the nursing shortage needs to focus as much on nursing job satisfaction and retention as on nursing recruitment and education. Selected aspects of the motivational psychology of Abraham Maslow, Mihaly Csikszentmihalyi, and Frederick Hertzberg are here discussed in light of the challenges-opportunities of nursing in Turkey and elsewhere. Also discussed is an innovative program to support the application of nursing theory and professional development in Toronto, Canada.
Living Ethics: Contributing to Knowledge Building Through Qualitative Inquiry
Authors: Kostas-Polston Elizabeth A. , Hayden Susan J.
Published: September 2006

In this column, the authors discuss ethical and scientific standards in research and publication in light of their worldviews; human science; human becoming; and Parse’s conceptual, ethical, methodological, and interpretive dimensions of the research process.
Jo Ann Ashley 30 Years Later: Legacy for Practice
Authors: Kagan Paula N.
Published: September 2006

Jo Ann Ashley, nurse scholar, educator, and feminist activist died at age 41 in 1980. Ashley illuminated the historical foundations of modern medicine, nursing, and hospital care in her pivotal book published in 1976, Hospitals, Paternalism, and the Role of the Nurse. Ashley’s innovative research uncovered a web of pervasive gender and class bias in the delivery of healthcare in the United States. This column commemorates the 30-year anniversary of that publication with a remembrance of her life and ideas. It examines Ashley’s relevance for nursing theory and current practice through an analysis of her many scholarly works and through interviews with those who knew her.
Nursing Satisfaction and Job Enrichment in Turkey
Authors: Öztürk Havva , Bahcecik Nefise , Baumann Steven L.
Published: September 2006

Survey research was conducted with the aim of better understanding nurses’ perceptions of organizational factors which relate to their job satisfaction and motivation in Turkey. Nurses (N = 290) who were employed at a training and research hospital, part of the Turkish Republic Ministry of Health, were included. The questionnaire used was developed for this study based on Hackman and Oldman’s job enrichment theory. The results showed that only one third of the nurse leaders and one in five of the staff nurses reported being satisfied with their job. The participants saw the five core job dimensions of Hackman and Oldman’s work design model: skill variety, task identity, task significance, autonomy, and feedback as important for nurses. Nursing was described by the participants as hard and challenging, but they also found it meaningful and said that it gave them the opportunity to use their skills and abilities.
Measures of scale based on the wavelet scalogram with applications to seismic attenuation
Authors: Li Hongbing , Zhao Wenzhi , Cao Hong , Yao Fengchang , Shao Longyi
Published: September 2006

The attenuation of seismic signal is usually characterized in the frequency domain using Fourier power spectra and is often usefully characterized by average measures, such as the center frequency or spectral mean. Fourier analysis, however, suffers from time-frequency resolution problems. Wavelet analysis has better time-frequency localization and offers superior spectral decomposition. In this paper, we show that seismic attenuation can be characterized by the scalogram (also called energy density) in the wavelet domain. A single scale encompasses a frequency band. The scalogram relates absorption to peak-scale variations. The peak scale is the scale of maximum amplitude in the scalogram. Seismic attenuation can be estimated directly from the scalogram according to the scale shift of the data and can also be described indirectly by the centroid of scale (the mean of a scalogram).

In absorbing media, seismic attenuation increases with frequency, i.e., decreases with scale. In the wavelet domain, small-scale energies of the seismic signal are attenuated more rapidly than are large-scale energies as waves propagate. As a result, both the peak scale and the centroid of the signal’s scalogram increase during propagation. Under the assumption of a frequency-independent [Formula: see text] model, these increases of the peak scale and the centroid of scale are inversely proportional to the quality factor, i.e., a lower quality factor results in an upshift of the peak scale in the scalogram and an increase of the centroid of scale. The peak-scale-shift method can be applied to seismic data with sufficiently broad signal bandwidth. The centroid of scale can be used as an attribute to qualitatively characterize seismic attenuation. Examples of gas detection in both synthetic and field data show the value of this technique.
Wavefield and AVO modeling using elastic thin-slab method
Authors: Wu Xian-Yun , Wu Ru-Shan
Published: September 2006

We propose a dual-domain, one-way, elastic thin-slab method for fast and accurate amplitude variation with offset (AVO) modeling. In this method, the wavefield propagates in the wavenumber domain and interacts with heterogeneity in the space domain. The approach requires much less memory and is two to three orders of magnitude faster than a full-wave method using finite difference or finite element.

The thin-bed AVO and AVOs with lateral parameter variations have been conducted using the thin-slab method and compared with reflectivity and finite-difference methods, respectively. It is shown that the thin-slab method can be used to accurately model reflections for most sedimentary rocks that have intermediate parameter perturbations ([Formula: see text] for P-wave velocity and [Formula: see text] for S-wave velocity). The combined effects of overburden structure and the scattering associated with heterogeneities on AVO have been investigated using the thin-slab method. Properties of the target zone and overburden structure control the AVO trends at overall offsets. Scattering associated with heterogeneities increases local variance in the reflected amplitudes and becomes significant for the sedimentary models with weak reflections. Interpretation of AVO observations based on homogeneous elastic models would therefore bias the estimated properties of the target. Furthermore, these effects can produce different apparent AVO trends in different offset ranges.
Delineating a shallow fault zone and dipping bedrock strata using multichannal analysis of surface waves with a land streamer
Authors: Ivanov Julian , Miller Richard D. , Lacombe Pierre , Johnson Carole D. , Lane John W.
Published: September 2006

The multichannel analysis of surface waves (MASW) seismic method was used to delineate a fault zone and gently dipping sedimentary bedrock at a site overlain by several meters of regolith. Seismic data were collected rapidly and inexpensively using a towed 30-channel land streamer and a rubberband-accelerated weight-drop seismic source. Data processed using the MASW method imaged the subsurface to a depth of about [Formula: see text] and allowed detection of the overburden, gross bedding features, and fault zone. The fault zone was characterized by a lower shear-wave velocity [Formula: see text] than the competent bedrock, consistent with a large-scale fault, secondary fractures, and in-situ weathering. The MASW 2D [Formula: see text] section was further interpreted to identify dipping beds consistent with local geologic mapping. Mapping of shallow-fault zones and dipping sedimentary rock substantially extends the applications of the MASW method.