bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retinal Afferent Ingrowth to Neocortical Transplants in the Adult Rat Superior Colliculus is due to the Regeneration of Damaged Axons
Authors: Ross D. T. , Das G. D. 
Published: March 2007

Retinal afferent ingrowth to embryonic
neural transplants in the adult rat superior
colliculus may represent either sprouting of
intact axons or the regeneration of transected
axons. If ingrowth represents regeneration of
damaged retinofugai axons, then lesions that
axotomize more retinofugal axons at the
transplantation site should induce greater
retinal afferent ingrowth. Alternately, if
ingrowth represents terminal or collateral
sprouting of intact retinofugal axons at or near
the transplant/host optic layer interface, then
the magnitude of retinal afferent ingrowth
should be directly related to the total area of this
interface. To test between these two hypotheses
surgical knife wounds were made either parallel
(in the sagittal plane) or perpendicular (in the
transverse plane) to the course of axons in the
stratum opticum, embryonic neocortical tissue
was transplanted at the coordinates of these
tectal slits, and retinal afferent ingrowth
visualized 1‐90 days after surgery using
anterogradely transported HRP.A zone of traumatic reaction (ztr) in the optic
layers was seen in every case, characterized by
hypertrophied axons and swollen terminal clubs
at 1 day. Between 30 and 90 days the damaged
retinofugal axons in the zone formed dense
fascicles and neuroma‐like tangles. Retinal
afferent ingrowth occurred only across
transplant interface regions with the ztr. The
magnitude of ingrowth was directly related to
the area of the ztr interface and not the total
optic layer interface area. Retinal afferent
ingrowth appears to reflect the intrinsic
regenerative capacity of adult mammalian
retinal ganglion cells and not sprouting of
undamaged axons.
Dominant-Negative Activator Protein 1 (TAM67) Targets Cyclooxygenase-2 and Osteopontin under Conditions in which It Specifically Inhibits Tumorigenesis
Authors: Matthews Connie P. , Birkholz Alysia M. , Baker Alyson R. , Perella Christine M. , Beck George R. , Young Matthew R. , Colburn Nancy H. 
Published: March 2007

Abstract
Activation of activator protein 1 (AP-1) and nuclear factor κB (NFκB)–dependent transcription is required for tumor promotion in cell culture models and transgenic mice. Dominant-negative c-Jun (TAM67) blocks AP-1 activation by dimerizing with Jun or Fos family proteins and blocks NFκB activation by interacting with NFκB p65. Two-stage [7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis experiments in a model relevant to human cancer risk, transgenic mice expressing human papillomavirus 16 E7 oncogene (K14-HPV16-E7), show E7-enhanced tumor promotion. A cross to K14-TAM67–expressing mice results in dramatic inhibition of tumor promoter–induced AP-1 luciferase reporter activation and papillomagenesis. Epithelial specific TAM67 expression inhibits tumorigenesis without affecting TPA- or E7-induced hyperproliferation of the skin. Thus, the mouse model enriches for TAM67 targets relevant to tumorigenesis rather than to general cell proliferation or hyperplasia, implicating a subset of AP-1– and/or NFκB-dependent genes. The aim of the present study was to identify target genes responsible for TAM67 inhibition of DMBA-TPA–induced tumorigenesis. Microarray expression analysis of epidermal tissues revealed small sets of genes in which expression is both up-regulated by tumor promoter and down-regulated by TAM67. Among these, cyclooxygenase-2 (Cox-2/Ptgs2) and osteopontin (Opn/Spp1) are known to be functionally significant in driving carcinogenesis. Results identify both Cox-2 and Opn as transcriptional targets of TAM67 with CRE, but not NFκB sites important in the Cox-2 promoter and an AP-1 site important in the Opn promoter. [Cancer Res 2007;67(6):2430–8]
Anaplastic, Plasmablastic, and Plasmacytic Plasmacytomas of Mice: Relationships to Human Plasma Cell Neoplasms and Late-Stage Differentiation of Normal B Cells
Authors: Qi Chen-Feng , Zhou Jeff X. , Lee Chang Hoon , Naghashfar Zohreh , Xiang Shao , Kovalchuk Alexander L. , Fredrickson Torgny N. , Hartley Janet W. , Roopenian Derry C. , Davidson Wendy F. , Janz Siegfried , Morse Herbert C. 
Published: March 2007

AbstractWe have compared histologic features and gene expression profiles of newly identified plasmacytomas from NFS.V+ congenic mice with plasmacytomas of IL6 transgenic, Fasl mutant, and SJL-β2M−/− mice. NFS.V+ tumors comprised an overlapping morphologic spectrum of high-grade/anaplastic, intermediate-grade/plasmablastic, and low-grade/plasmacytic cases with similarities to subsets of human multiple myeloma and plasmacytoma. Microarray and immunohistochemical analyses of genes expressed by the most prevalent tumors, plasmablastic plasmacytomas, showed them to be most closely related to immunoblastic lymphomas, less so to plasmacytomas of Fasl mutant and SJL mice, and least to plasmacytic plasmacytomas of IL6 transgenic mice. Plasmablastic tumors seemed to develop in an inflammatory environment associated with gene signatures of T cells, natural killer cells, and macrophages not seen with plasmacytic plasmacytomas. Plasmablastic plasmacytomas from NFS.V+ and SJL-β2M−/− mice did not have structural alterations in Myc or T(12;15) translocations and did not express Myc at high levels, regular features of transgenic and pristane-induced plasmacytomas. These findings imply that, as for human multiple myeloma, Myc-independent routes of transformation contribute to the pathogenesis of these tumors. These findings suggest that plasma cell neoplasms of mice and humans exhibit similar degrees of complexity. Mouse plasmacytomas, previously considered to be homogeneous, may thus be as diverse as their human counterparts with respect to oncogenic mechanisms of plasma cell transformation. Selecting specific types of mouse plasmacytomas that relate most closely to subtypes of human multiple myeloma may provide new opportunities for preclinical testing of drugs for treatment of the human disease. [Cancer Res 2007;67(6):2439–47]
Combining Adoptive Cellular and Immunocytokine Therapies to Improve Treatment of B-Lineage Malignancy
Authors: Singh Harjeet , Serrano Lisa Marie , Pfeiffer Timothy , Olivares Simon , McNamara George , Smith David D. , Al-Kadhimi Zaid , Forman Stephen J. , Gillies Stephen D. , Jensen Michael C. , Colcher David , Raubitschek Andrew , Cooper Laurence J.N. 
Published: March 2007

Abstract
Currently, the lineage-specific cell-surface molecules CD19 and CD20 present on many B-cell malignancies are targets for both antibody- and cell-based therapies. Coupling these two treatment modalities is predicted to improve the antitumor effect, particularly for tumors resistant to single-agent biotherapies. This can be shown using an immunocytokine, composed of a CD20-specific monoclonal antibody fused to biologically active interleukin 2 (IL-2), combined with ex vivo expanded human umbilical cord blood–derived CD8+ T cells, that have been genetically modified to be CD19 specific, for adoptive transfer after allogeneic hematopoietic stem-cell transplantation. We show that a benefit of targeted delivery of recombinant IL-2 by the immunocytokine to the CD19+CD20+ tumor microenvironment is improved in vivo persistence of the CD19-specific T cells, and this results in an augmented cell-mediated antitumor effect. Phase I trials are under way using anti-CD20-IL-2 immunocytokine and CD19-specific T cells as monotherapies, and our results warrant clinical trials using combination of these two immunotherapies. [Cancer Res 2007;67(6):2872–80]
Mullerian-Inhibiting Substance Induces Gro-β Expression in Breast Cancer Cells through a Nuclear Factor-κB–Dependent and Smad1-Dependent Mechanism
Authors: Gupta Vandana , Yeo Giminna , Kawakubo Hirofumi , Rangnekar Vivek , Ramaswamy Preethi , Hayashida Tetsu , MacLaughlin David T. , Donahoe Patricia K. , Maheswaran Shyamala 
Published: March 2007

AbstractMullerian-inhibiting substance (MIS), a transforming growth factor-β family member, activates the nuclear factor-κB (NF-κB) pathway and induces the expression of B-cell translocation gene 2 (BTG2), IFN regulatory factor-1 (IRF-1), and the chemokine Gro-β. Inhibiting NF-κB activation with a phosphorylation-deficient IκBα mutant abrogated MIS-mediated induction of all three genes. Expression of dominant-negative Smad1, in which serines at the COOH-terminal SSVS motif are converted to alanines, suppressed MIS-induced Smad1 phosphorylation and impaired MIS-stimulated Gro-β promoter-driven reporter expression and Gro-β mRNA. Suppressing Smad1 expression using small interfering RNA also mitigated MIS-induced Gro-β mRNA, suggesting that regulation of Gro-β expression by MIS was dependent on activation of NF-κB as well as Smad1. However, induction of IRF-1 and BTG2 mRNAs by MIS was independent of Smad1 activation. Characterization of κB-binding sequences within Gro-β, BTG2, and IRF-1 promoters showed that MIS stimulated binding of p50 and p65 subunits to all three sites, whereas phosphorylated Smad1 (phospho-Smad1) protein was detectable only in the NF-κB complex bound to the κB site of the Gro-β promoter. Consistent with these observations, chromatin immunoprecipitation assays showed recruitment of both phospho-Smad1 and p65 to the Gro-β promoter in vivo, whereas p65, but not phospho-Smad1, was recruited to the BTG2 promoter. These results show a novel interaction between MIS-stimulated Smad1 and NF-κB signaling in which enhancement of NF-κB DNA binding and gene expression by phospho-Smad1 is dependent on the sequence of the κB consensus site within the promoter. [Cancer Res 2007;67(6):2747–56]
Mutant p53 Enhances Nuclear Factor κB Activation by Tumor Necrosis Factor α in Cancer Cells
Authors: Weisz Lilach , Damalas Alexander , Liontos Michalis , Karakaidos Panagiotis , Fontemaggi Giulia , Maor-Aloni Revital , Kalis Marina , Levrero Massimo , Strano Sabrina , Gorgoulis Vassilis G. , Rotter Varda , Blandino Giovanni , Oren Moshe 
Published: March 2007

Abstract
Mutations in the p53 tumor suppressor are very frequent in human cancer. Often, such mutations lead to the constitutive overproduction of mutant p53 proteins, which may exert a cancer-promoting gain of function. We now report that cancer-associated mutant p53 can augment the induction of nuclear factor κB (NFκB) transcriptional activity in response to the cytokine tumor necrosis factor α (TNFα). Conversely, down-regulation of endogenous mutant p53 sensitizes cancer cells to the apoptotic effects of TNFα. Analysis of human head and neck tumors and lung tumors reveals a close correlation between the presence of abundant mutant p53 proteins and the constitutive activation of NFκB. Together, these findings suggest that p53 mutations may promote cancer progression by augmenting NFκB activation in the context of chronic inflammation. [Cancer Res 2007;67(6):2396–401]
Characterization of MicroRNA Expression Levels and Their Biological Correlates in Human Cancer Cell Lines
Authors: Gaur Arti , Jewell David A. , Liang Yu , Ridzon Dana , Moore Jason H. , Chen Caifu , Ambros Victor R. , Israel Mark A. 
Published: March 2007

Abstract
MicroRNAs are small noncoding RNAs that function by regulating target gene expression posttranscriptionally. They play a critical role in developmental and physiologic processes and are implicated in the pathogenesis of several human diseases including cancer. We examined the expression profiles of 241 human microRNAs in normal tissues and the NCI-60 panel of human tumor-derived cell lines. To quantify microRNA expression, we employed a highly sensitive technique that uses stem-loop primers for reverse transcription followed by real-time PCR. Most microRNAs were expressed at lower levels in tumor-derived cell lines compared with the corresponding normal tissue. Agglomerative hierarchical clustering analysis of microRNA expression revealed four groups among the NCI-60 cell lines consisting of hematologic, colon, central nervous system, and melanoma tumor–derived cell lines clustered in a manner that reflected their tissue of origin. We identified specific subsets of microRNAs that provide candidate molecular signatures characteristic of the tumor-derived cell lines belonging to these four clusters. We also identified specific microRNA expression patterns that correlated with the proliferation indices of the NCI-60 cell lines, and we developed evidence for the identification of specific microRNAs as candidate oncogenes and tumor suppressor genes in different tumor types. Our results provide evidence that microRNA expression patterns may mark specific biological characteristics of tumors and/or mediate biological activities important for the pathobiology of malignant tumors. These findings call attention to the potential of microRNAs to provide etiologic insights as well as to serve as both diagnostic markers and therapeutic targets for many different tumor types. [Cancer Res 2007;67(6):2456–68]
Low-Level TOP2A Amplification in Prostate Cancer Is Associated with HER2 Duplication, Androgen Resistance, and Decreased Survival
Authors: Murphy Amanda J. , Hughes Caroline A. , Barrett Ciara , Magee Hilary , Loftus Barbara , O'Leary John J. , Sheils Orla 
Published: March 2007

Abstract
HER2 and TOP2A genes, located on 17q, can be coamplified in cancer. Overexpression of both genes has been reported in high-grade, androgen-resistant prostate cancer. Both genes have not been compared in a single prostate cancer study and the frequency of TOP2A amplifications in prostate cancer is unknown. Using tissue microarrays, we did immunohistochemistry and fluorescence in situ hybridization for HER2 and TOP2A in 100 prostate cancers (41 localized and 59 advanced) and 42 cases of benign prostatic hyperplasia (BPH). Amplification was defined as a target/centromere signal ratio of ≥1.5. HER2 immunohistochemistry was scored from 0 to 3+. Percentage nuclei staining for topoisomerase IIα (topoIIα) was recorded; overexpression was defined as ≥5% cells staining. Eighteen (31%) advanced prostate cancers showed topoIIα overexpression; 12 (26%) showed TOP2A low-level amplification; 9 (16%) expressed HER2; and 6 (13%) showed HER2 low-level amplification. No high-level amplification of either gene (target/centromere signal ratio of ≥3.0) was detected. TOP2A coexpression and coamplification were seen in 75% and 66% of HER2-positive cases, respectively. Localized prostate cancer or BPH showed no gene amplification or topoIIα overexpression. Gene amplification or overexpression correlated with high stage and Gleason score. The presence of TOP2A amplification in advanced cancer was associated with androgen resistance and decreased survival by multivariate analysis. This is the first study to document low-level TOP2A amplification in prostate cancer and an association with reduced survival. TOP2A amplification may occur with or without HER2 duplication and is often associated with topoIIα expression. Therapies directed against topoIIα (and HER2) in such patients may improve survival. [Cancer Res 2007;67(6):2893–8]
Destabilized Adhesion in the Gastric Proliferative Zone and c-Src Kinase Activation Mark the Development of Early Diffuse Gastric Cancer
Authors: Humar Bostjan , Fukuzawa Ryuji , Blair Vanessa , Dunbier Anita , More Helen , Charlton Amanda , Yang Han Kwang , Kim Woo Ho , Reeve Anthony E. , Martin Iain , Guilford Parry 
Published: March 2007

AbstractThe initial development of diffuse gastric cancer (DGC) is poorly understood. The study of E-cadherin (CDH1) germ line mutation carriers predisposed to DGC provides a rare opportunity to elucidate the genetic and biological events surrounding disease initiation. Samples from various stages of hereditary and sporadic DGC were investigated to determine general mechanisms underlying early DGC development. Paraffin-embedded tissues from 13 CDH1 mutation carriers and from 10 sporadic early DGC cases were analyzed. Immunofluorescence and immunohistochemistry using differentiation, proliferation, and adhesion markers showed that DGC initiation seems to occur at the proliferative zone (the upper neck) of the gastric epithelium and correlates with absent or reduced expression of junctional proteins (β-actin, p120, Lin-7). Slow proliferation of neoplastic cells at the upper gastric neck leads to the formation of intramucosal signet-ring cell carcinoma (SRCC) displaying differentiated features. As shown by immunolabeling, invasion from SRCC lesions beyond the gastric mucosa is associated with poor differentiation, increased proliferation, activation of the c-Src system, and an epithelial-mesenchymal transition. Our results provide a molecular description of the early development of DGC and explain the relationship between the two main DGC types, poorly differentiated carcinoma and SRCC: both share their origin, but SRCC develops following cancer cell differentiation and seems relatively indolent in its intramucosal stage. [Cancer Res 2007;67(6):2480–9]
15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits Transcriptional Activity of Estrogen Receptor-α via Covalent Modification of DNA-Binding Domain
Authors: Kim Han-Jong , Kim Joon-Young , Meng Zhaojing , Wang Li Hua , Liu Fa , Conrads Thomas P. , Burke Terrence R. , Veenstra Timothy D. , Farrar William L. 
Published: March 2007

Abstract
The cyclopentenone 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) inhibits proliferation of cancer cells, including breast cancers, by peroxisome proliferator-activated receptor-γ (PPARγ)–dependent and PPARγ-independent mechanisms. However, little is known about its effect on the transcriptional activity of estrogen receptor-α (ERα) that plays vital roles in the growth of breast cancers. Here, we show that 15d-PGJ2 inhibits both 17β-estradiol (E2)–dependent and E2-independent ERα transcriptional activity by PPARγ-independent mechanism. In addition, 15d-PGJ2 directly modifies ERα protein via its reactive cyclopentenone moiety, evidenced by incorporation of biotinylated 15d-PGJ2 into ERα, both in vitro and in vivo. Nanoflow reverse-phase liquid chromatography tandem mass spectrometry analysis identifies two cysteines (Cys227 and Cys240) within the COOH-terminal zinc finger of ERα DNA-binding domain (DBD) as targets for covalent modification by 15d-PGJ2. Gel mobility shift and chromatin immunoprecipitation assays show that 15d-PGJ2 inhibits DNA binding of ERα and subsequent repression of ERα target gene expression, such as pS2 and c-Myc. Therefore, our results suggest that 15d-PGJ2 can block ERα function by covalent modification of cysteine residues within the vulnerable COOH-terminal zinc finger of ERα DBD, resulting in fundamental inhibition of both hormone-dependent and hormone-independent ERα transcriptional activity. [Cancer Res 2007;67(6):2595–602]
Therapy of Established Tumors in a Novel Murine Model Transgenic for Human Carcinoembryonic Antigen and HLA-A2 with a Combination of Anti-idiotype Vaccine and CTL Peptides of Carcinoembryonic Antigen
Authors: Saha Asim , Chatterjee Sunil K. , Foon Kenneth A. , Celis Esteban , Bhattacharya-Chatterjee Malaya 
Published: March 2007

AbstractInduction of potent and sustained antitumor immunity depends on the efficient activation of CD8+ and CD4+ T cells. Immunization using dendritic cells loaded with tumor antigens constitute a powerful platform for stimulating cellular immunity. Our previous studies suggested that vaccination with an anti-idiotype antibody 3H1, which mimics a specific epitope of carcinoembryonic antigen (CEA), has the potential to break immune tolerance to CEA and induce anti-CEA antibody as well as CEA-specific CD4+ T-helper responses in colon cancer patients as well as in mice transgenic for human CEA. Here, we have combined the anti-idiotype 3H1 with the CTL peptides of CEA to augment both T-helper and CTL responses in a clinically relevant mouse model, which is transgenic for both CEA and HLA-A2. We have evaluated the potential of two different HLA-A2–restricted epitopes of CEA pulsed into dendritic cells in a therapeutic setting. The overall immune responses and survival were enhanced in groups of mice immunized with agonist peptide for CEA691 (YMIGMLVGV)–pulsed dendritic cells or CAP1-6D (YLSGADLNL, agonist peptide for CAP-1)–pulsed dendritic cells. Mice immunized with peptide-pulsed dendritic cells along with 3H1-pulsed dendritic cells resulted in significant increase in survival compared with mice immunized with peptide-pulsed dendritic cells alone (P &lt; 0.02). IFN-γ ELISPOT and 51Cr-release assays showed that HLA-A2–restricted, CEA-specific CTL responses were augmented by combined dendritic cell vaccinations. The combined vaccination strategy resulted in increased antigen-specific proliferation of splenocytes and secretion of Th1 cytokines by CD4+ T cells that correlated with increased survival. These results suggest the potential use of this vaccination strategy for future clinical applications. [Cancer Res 2007;67(6):2881–92]
A Target Cell–Specific Activatable Fluorescence Probe for In vivo Molecular Imaging of Cancer Based on a Self-Quenched Avidin-Rhodamine Conjugate
Authors: Hama Yukihiro , Urano Yasuteru , Koyama Yoshinori , Kamiya Mako , Bernardo Marcelino , Paik Ronald S. , Shin In Soo , Paik Chang H. , Choyke Peter L. , Kobayashi Hisataka 
Published: March 2007

Abstract
A target cell–specific activation strategy for improved molecular imaging of peritoneal implants has been proposed, in which fluorophores are activated only in living targeted cells. A current example of an activatable fluorophore is one that is normally self-quenched by attachment to a peptide backbone but which can be activated by specific proteases that degrade the peptide resulting in “dequenching.” In this study, an alternate fluorescence activation strategy is proposed whereby self-quenching avidin-rhodamine X, which has affinity for lectin on cancer cells, is activated after endocytosis and degradation within the lysosome. Using this approach in a mouse model of peritoneal ovarian metastases, we document target-specific molecular imaging of submillimeter cancer nodules with minimal contamination by background signal. Cellular internalization of receptor-ligand pairs with subsequent activation of fluorescence via dequenching provides a generalizable and highly sensitive method of detecting cancer microfoci in vivo and has practical implications for assisting surgical and endoscopic procedures. [Cancer Res 2007;67(6):2791–9]