bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early integration of high copy HPV16 detectable in women with normal and low grade cervical cytology and histology
Authors: Kulmala S-M A , Syrjänen S M , Gyllensten U B , Shabalova I P , Petrovichev N , Tosi P , Syrjänen K J , Johansson B C 
Published: February 2006

Background:Integration of human papillomavirus (HPV) DNA has been considered a late event in cervical carcinogenesis. However, integrated forms of HPV were recently detected in cancer precursor lesions using a new real time polymerase chain reaction (PCR) to detect the deletions at the 3362–3443 region of HPV16 E2Objective:To study the frequency of HPV16 DNA integration in cervical lesions and compare the sensitivity of an additional upstream region of the E2 ORF (2962–3138) in detecting HPV integration.Methods:Using the TaqMan based PCR, HPV16 positive DNA samples were analysed in 164 cervical scrapings from women participating in a multicentre screening trial. Biopsy confirmation was available in 62 cases.Results:Primers targeting the 3362–3443 region detected the majority of E2 deletions. In only 23% of the samples was the E2 upstream region equal or better target than the 3362–3443 region. Mixed (episomal/integrated) pattern was the most prevalent physical state of HPV16, also present in PAP smears with normal morphology. Pure integrated form was most prevalent in HSIL and cancer lesions, but also detectable in low grade abnormalities (NSIL, ASC-US, LSIL). Women with only integrated HPV16 were almost 10 years older than those with episomal HPV16. Viral load of integrated HPV16 was related to cytological abnormality (p = 0.003) but not to histology.Conclusions:Integrated HPV16 is present in low grade cervical lesions, mostly mixed with the episomal form. Women with the pure integrated form of HPV16 are older than those with the other forms.
ON THE QUARTIC HIGHER-DERIVATIVE GRAVITATIONAL TERMS IN THE HETEROTIC SUPERSTRING THEORY
Authors: POLLOCK M. D. 
Published: February 2006

The quartic higher-derivative gravitational terms [Formula: see text] in the heterotic-superstring effective Lagrangian [Formula: see text], defined from the Riemann ten-tensor [Formula: see text], are expanded, after reduction to the conformally-flat physical D-space gij, in terms of the Ricci tensor Rij and scalar R. The resulting quadratic term [Formula: see text] is tachyon-free and agrees exactly with the prediction from global supersymmetry in the nonlinear realization of Volkov and Akulov of the flat-space, quadratic fermionic Lagrangian [Formula: see text] for a massless Dirac or Weyl spinor, only when D = 4, assuming the Einstein equation [Formula: see text] for the energy–momentum tensor. This proves that the heterotic superstring has to be reduced from ten to four dimensions if supersymmetry is to be correctly incorporated into the theory, and it rules out the bosonic string and type-II superstring, for which [Formula: see text] has the different a priori forms ±(R2-4RijRij) derived from [Formula: see text], which also contain tachyons (that seem to remain after the inclusion of a further contribution to [Formula: see text] from [Formula: see text]). The curvature of space–time introduces a mass into the Dirac equation, [Formula: see text], while quadratic, higher-derivative terms [Formula: see text] make an additional contribution to the Einstein equations, these two effects causing a difference between [Formula: see text] and [Formula: see text] on the one hand, and the predictions from [Formula: see text] and [Formula: see text] on the other. The quartic terms [Formula: see text] still possess some residual symmetry, however, enabling us to estimate the radius-squared of the internal six-dimensional space [Formula: see text] in units of the Regge slope-parameter α′ as B r ≈ 1.75, indicating that compactification occurs essentially at the Planck era, due to quantum mechanical processes, when the action evaluated within the causal horizon is S h ~ 1. This symmetry is also discussed with regard to the zero-action hypothesis. The dimensionality D = 4 of space–time is rederived from the Wheeler–DeWitt equation (Schrödinger equation) of quantum cosmology in the mini-superspace approximation, by demanding invariance and positive-semi-definiteness of the potential [Formula: see text] under Wick rotation of the time coordinate, which also determines the three-space to be flat, so that K = 0, and again involves the nonlinearity of gravitation.
Direct Demonstration of Instabilities in Oxygen Concentrations within the Extravascular Compartment of an Experimental Tumor
Authors: Lanzen Jennifer , Braun Rod D. , Klitzman Bruce , Brizel David , Secomb Timothy W. , Dewhirst Mark W. 
Published: February 2006

Abstract
To test the hypothesis that temporal variations in microvessel red cell flux cause unstable oxygen levels in tumor interstitium, extravascular oxygenation of R3230Ac mammary tumors grown in skin-fold window chambers was measured using recessed tip polarographic microelectrodes. Red cell fluxes in microvessels surrounding pO2 measurement locations were measured using fluorescently labeled red cells. Temporal pO2 instability was observed in all experiments. Median pO2 was inversely related to radial distance from microvessels. Transient fluctuations above and below 10 mm Hg were consistently seen, except in one experiment near the oxygen diffusion distance limit (140 μm) where pO2 fluctuations were &lt;2 mm Hg and median pO2 was &lt;5 mm Hg. Vascular stasis was not seen in these experiments. These results show that fluctuations in red cell flux, as opposed to vascular stasis, can cause temporal variations in pO2 that extend from perivascular regions to the maximum oxygen diffusion distance. (Cancer Res 2006; 66(4): 2219-23)
Identification of Small Molecules that Sensitize Resistant Tumor Cells to Tumor Necrosis Factor-Family Death Receptors
Authors: Schimmer Aaron D. , Thomas Michael P. , Hurren Rose , Gronda Marcela , Pellecchia Maurizio , Pond Gregory R. , Konopleva Marina , Gurfinkel Debbie , Mawji Imtiaz A. , Brown Ewan , Reed John C. 
Published: February 2006

AbstractTwo major pathways for apoptosis have been identified, involving either mitochondria (intrinsic) or tumor necrosis factor (TNF)-family death receptors (extrinsic) as initiators of caspase protease activation and cell death. Because tumor resistance to TNF-family death receptor ligands is a common problem, helping malignant cells evade host immune defenses, we sought to identify compounds that selectively sensitize resistant tumor cells to death receptor ligands. We screened a 50,000-compound library for agents that enhanced anti-FAS antibody–mediated killing of FAS-resistant PPC-1 prostate cancer cell, then did additional analysis of the resulting hits to arrive at eight compounds that selectively sensitized PPC-1 cells to anti-FAS antibody (extrinsic pathway agonist) without altering sensitivity to staurosporine and etoposide (VP-16; intrinsic pathway agonists). These eight compounds did not increase Fas surface levels and also sensitized PPC-1 cells to apoptosis induced by TNF-family member TNF-related apoptosis-inducing ligand, consistent with a post-receptor mechanism. Of these, two reduced expression of c-FLIP, an intracellular antagonist of the extrinsic pathway. Characterization of the effects of the eight compounds on a panel of 10 solid tumor cell lines revealed two structurally distinct compounds that frequently sensitize to extrinsic pathway agonists. Structure-activity relation studies of one of these compounds revealed a pharmacophore from which it should be possible to generate analogues with improved potency. Altogether, these findings show the feasibility of identifying compounds that selectively enhance apoptosis via the extrinsic pathway, thus providing research tools for uncovering resistance mechanisms and a starting point for novel therapeutics aimed at restoring sensitivity of tumor cells to immune effector mechanisms. (Cancer Res 2006; 66(4): 2367-75)
Targeting of the Receptor Protein Tyrosine Phosphatase β with a Monoclonal Antibody Delays Tumor Growth in a Glioblastoma Model
Authors: Foehr Erik D. , Lorente Gustavo , Kuo Jane , Ram Rosie , Nikolich Karoly , Urfer Roman 
Published: February 2006

Abstract
The receptor protein tyrosine phosphatase β (RPTPβ) is a functional biomarker for several solid tumor types. RPTPβ expression is largely restricted to the central nervous system and overexpressed primarily in astrocytic tumors. RPTPβ is known to facilitate tumor cell adhesion and migration through interactions with extracellular matrix components and the growth factor pleiotrophin. Here, we show that RPTPβ is expressed in a variety of solid tumor types with low expression in normal tissue. To assess RPTPβ as a potential target for treatment of glioblastoma and other cancers, antibodies directed to RPTPβ have been developed and profiled in vitro and in vivo. The recombinant extracellular domain of human short RPTPβ was used to immunize mice and generate monoclonal antibodies that selectively recognize RPTPβ and bind to the antigen with low nanomolar affinities. Moreover, these antibodies recognized the target on living tumor cells as measured by flow cytometry. These antibodies killed glioma cells in vitro when coupled to the cytotoxin saporin either directly or via a secondary antibody. Finally, in vivo studies showed that an anti-RPTPβ immunotoxin (7E4B11-SAP) could significantly delay human U87 glioma tumors in a mouse xenograft model. Unconjugated 7E4B11 provides a modest but statistically significant tumor growth delay when delivered systemically in mice bearing U87 glioma tumors. (Cancer Res 2006; 66(4): 2271-8)
Stalled Replication Induces p53 Accumulation through Distinct Mechanisms from DNA Damage Checkpoint Pathways
Authors: Ho Chui Chui , Siu Wai Yi , Lau Anita , Chan Wan Mui , Arooz Talha , Poon Randy Y.C. 
Published: February 2006

Abstract
Stalled replication forks induce p53, which is required to maintain the replication checkpoint. In contrast to the well-established mechanisms of DNA damage-activated p53, the downstream effectors and upstream regulators of p53 during replication blockade remain to be deciphered. Hydroxyurea triggered accumulation of p53 through an increase in protein stability. The requirement of p53 accumulation for the replication checkpoint was not due to p21CIP1/WAF1 as its down-regulation with short-hairpin RNA did not affect the checkpoint. Similar to DNA damage, stalled replication triggered the activation of the MRN–ataxia telangiectasia mutated (ATM)/ATM and Rad3-related–CHK1/CHK2 axis. Down-regulation of CHK1 or CHK2, however, reduced p53 basal expression but not the hydroxyurea-dependent induction. Moreover, p53 was still stabilized in ataxia telangiectasia cells or in cells treated with caffeine, suggesting that ATM was not a critical determinant. These data also suggest that the functions of ATM, CHK1, and CHK2 in the replication checkpoint were not through the p53-p21CIP1/WAF1 pathway. In contrast, induction of p53 by hydroxyurea was defective in cells lacking NBS1 and BLM. In this connection, the impaired replication checkpoint in several other genetic disorders has little correlation with the ability to stabilize p53. These data highlighted the different mechanisms involved in the stabilization of p53 after DNA damage and stalled replication forks. (Cancer Res 2006; 66(4): 2233-41)
Pten Deficiency Activates Distinct Downstream Signaling Pathways in a Tissue-Specific Manner
Authors: Yoo Lina I. , Liu David W. , Vu Sandrine Le , Bronson Roderick T. , Wu Hong , Yuan Junying 
Published: February 2006

Abstract
PTEN deficiency predisposes to a subset of human cancers, but the mechanism that underlies such selectivity is unknown. We have generated a mouse line that conditionally deletes Pten in urogenital epithelium. These mice develop carcinomas at high frequency in the prostate but at relatively low frequency in the bladder, despite early and complete penetrance of hyperplasia in both organs. Cell proliferation is initially high in the bladder of newborn Pten-deficient mice but within days is inhibited by p21 induction. In contrast, proliferation remains elevated in Pten-deficient prostate, where p21 is never induced, suggesting that p21 induction is a bladder-specific compensatory mechanism to inhibit proliferation caused by Pten deletion. Furthermore, the AKT/mammalian target of rapamycin growth pathway, which is highly activated in Pten-deficient prostate, is not activated in bladder epithelium. Our results reveal alternative downstream signaling pathways activated by Pten deficiency that lead to tissue-specific susceptibilities to tumorigenesis. (Cancer Res 2006; 66(4): 1929-39)
Stimulation of Cyclooxygenase-2 Expression by Bone-Derived Transforming Growth Factor-β Enhances Bone Metastases in Breast Cancer
Authors: Hiraga Toru , Myoui Akira , Choi Mary E. , Yoshikawa Hideki , Yoneda Toshiyuki 
Published: February 2006

Abstract
Cyclooxygenase-2 (COX-2), the rate-limiting enzyme of prostaglandin synthesis, has been implicated in invasiveness and distant metastases of cancer. Bone is one of the most common target sites of cancer metastasis. However, the role of COX-2 in bone metastasis is unclear. We examined the surgical specimens of bone metastases from patients with various types of cancers by using immunohistochemistry and observed evident COX-2 expression in these bone metastases. In a nude mouse model of bone metastasis, the MDA-MB-231 human breast cancer cells showed no COX-2 expression at orthotopic sites, whereas these cells, when metastasized to bone, intensely expressed COX-2, suggesting that the bone microenvironment induced COX-2 expression. Consistent with this notion, inhibition of bone resorption by the bisphosphonate ibandronate reduced COX-2 expression in MDA-MB-231 cells in bone. Transforming growth factor-β (TGFβ), one of the most abundant growth factors stored in bone, increased COX-2 expression and prostaglandin E2 production in MDA-MB-231 cells in culture. MDA-MB-231 cells overexpressing dominant-negative TGFβ type II receptors showed decreased bone metastases and reduced osteoclastic bone resorption with impaired COX-2 expression. The COX-2 inhibitors, NS-398 and nimesulide, significantly suppressed bone metastases with decreased osteoclast number and increased apoptosis in MDA-MB-231 cells. These results suggest that bone-derived TGFβ up-regulates COX-2 expression in breast cancer cells, thereby increasing prostaglandin E2 production, which in turn, stimulates osteoclastic bone destruction, leading to the progression of bone metastases. Our results also suggest that COX-2 is a potential therapeutic target for bone metastases in breast cancer. (Cancer Res 2006; 66(4): 2067-73)
Soluble IGF2 Receptor Rescues Apc
Min/+ Intestinal Adenoma Progression Induced by Igf2 Loss of Imprinting
Authors: Harper James , Burns Jason L. , Foulstone Emily J. , Pignatelli Massimo , Zaina Silvio , Hassan A. Bassim 
Published: February 2006

Abstract
The potent growth-promoting activity of insulin-like growth factor-II (IGF-II) is highly regulated during development but frequently up-regulated in tumors. Increased expression of the normally monoallelic (paternally expressed) mouse (Igf2) and human (IGF2) genes modify progression of intestinal adenoma in the ApcMin/+ mouse and correlate with a high relative risk of human colorectal cancer susceptibility, respectively. We examined the functional consequence of Igf2 allelic dosage (null, monoallelic, and biallelic) on intestinal adenoma development in the ApcMin/+ by breeding with mice with either disruption of Igf2 paternal allele or H19 maternal allele and used these models to evaluate an IGF-II–specific therapeutic intervention. Increased allelic Igf2 expression led to elongation of intestinal crypts, increased adenoma growth independent of systemic growth, and increased adenoma nuclear β-catenin staining. By introducing a transgene expressing a soluble form of the full-length IGF-II/mannose 6-phosphate receptor (sIGF2R) in the intestine, which acts as a specific inhibitor of IGF-II ligand bioavailability (ligand trap), we show rescue of the Igf2-dependent intestinal and adenoma phenotype. This evidence shows the functional potency of allelic dosage of an epigenetically regulated gene in cancer and supports the application of an IGF-II ligand–specific therapeutic intervention in colorectal cancer. (Cancer Res 2006; 66(4): 1940-8)
Effects of the Vascular Disrupting Agent ZD6126 on Interstitial Fluid Pressure and Cell Survival in Tumors
Authors: Skliarenko Julia V. , Lunt Sarah Jane , Gordon Maggie L. , Vitkin Alex , Milosevic Michael , Hill Richard P. 
Published: February 2006

AbstractInterstitial fluid pressure (IFP) is elevated in tumors due to abnormal vasculature, lack of lymphatic drainage, and alterations in the tumor interstitium. ZD6126 is a tubulin-binding agent that selectively disrupts tumor vasculature resulting in tumor necrosis. This study examined the effect of ZD6126 on tumor IFP and the response of tumors with different IFP levels to ZD6126. Pretreatment IFP was measured using the wick-in-needle method in tumors (murine KHT-C and human CaSki) growing i.m. in the hind legs of mice. Mice were treated i.p. with a single dose of ZD6126 (100 or 200 mg/kg) and posttreatment IFP measurements were made. Blood flow imaging was conducted using Doppler optical coherence tomography, whereas oxygen partial pressure was measured using a fiber optic probe. Clonogenic assays were done to determine tumor cell survival. In KHT-C tumors, IFP dropped significantly at 1 hour posttreatment, returned to pretreatment values at 3 hours, and then declined to ∼25% of the pretreatment values by 72 hours. In CaSki tumors, the IFP decreased progressively, beginning at 1 hour, to ∼30% of pretreatment values by 72 hours. Clonogenic cell survival data indicated that ZD6126 was less effective in tumors with high IFP values (&gt;25 mm Hg). Vascular disrupting agents, such as ZD6126, can affect IFP levels and initial IFP levels may predict tumor response to these agents. The higher cell survival in high IFP tumors may reflect greater microregional blood flow limitations in these tumors and reduced access of the drug to the target endothelial cells. (Cancer Res 2006; 66(4): 2074-80)
SKI-606 Decreases Growth and Motility of Colorectal Cancer Cells by Preventing pp60(c-Src)–Dependent Tyrosine Phosphorylation of β-Catenin and Its Nuclear Signaling
Authors: Coluccia Addolorata Maria Luce , Benati Daniela , Dekhil Hafedh , De Filippo Annamaria , Lan Cathy , Gambacorti-Passerini Carlo 
Published: February 2006

AbstractInhibition of deregulated protein tyrosine kinases represents an attractive strategy for controlling cancer growth. However, target specificity is an essential aim of this strategy. In this report, pp60(c-Src) kinase and β-catenin were found physically associated and constitutively activated on tyrosine residues in human colorectal cancer cells. The use of specific small-interfering RNAs (siRNA) validated pp60(c-Src) as the major kinase responsible for β-catenin tyrosine phosphorylation in colorectal cancer. Src-dependent activation of β-catenin was prevented by SKI-606, a novel Src family kinase inhibitor, which also abrogated β-catenin nuclear function by impairing its binding to the TCF4 transcription factor and its trans-activating ability in colorectal cancer cells. These effects were seemingly specific, as cyclin D1, a crucial β-catenin/TCF4 target gene, was also down-regulated by SKI-606 in a dose-dependent manner accounting, at least in part, for the reduced growth (IC50, 1.5-2.4 μmol/L) and clonogenic potential of colorectal cancer cells. Protein levels of β-catenin remained substantially unchanged by SKI-606, which promoted instead a cytosolic/membranous retention of β-catenin as judged by immunoblotting analysis of cytosolic/nuclear extracts and cell immunofluorescence staining. The SKI-606-mediated relocalization of β-catenin increased its binding affinity to E-cadherin and adhesion of colorectal cancer cells, with ensuing reduced motility in a wound healing assay. Interestingly, the siRNA-driven knockdown of β-catenin removed the effect of SKI-606 on cell-to-cell adhesion, which was associated with prolonged stability of E-cadherin protein in a pulse-chase experiment. Thus, our results show that SKI-606 operates a switch between the transcriptional and adhesive function of β-catenin by inhibiting its pp60(c-Src)–dependent tyrosine phosphorylation; this could constitute a new therapeutic target in colorectal cancer. (Cancer Res 2006; 66(4): 2279-86)
Embryonic Stem Cell–Derived Dendritic Cells Expressing Glypican-3, a Recently Identified Oncofetal Antigen, Induce Protective Immunity against Highly Metastatic Mouse Melanoma, B16-F10
Authors: Motomura Yutaka , Senju Satoru , Nakatsura Tetsuya , Matsuyoshi Hidetake , Hirata Shinya , Monji Mikio , Komori Hiroyuki , Fukuma Daiki , Baba Hideo , Nishimura Yasuharu 
Published: February 2006

AbstractWe have recently established a method to generate dendritic cells from mouse embryonic stem cells. By introducing exogenous genes into embryonic stem cells and subsequently inducing differentiation to dendritic cells (ES-DC), we can now readily generate transfectant ES-DC expressing the transgenes. A previous study revealed that the transfer of genetically modified ES-DC expressing a model antigen, ovalbumin, protected the recipient mice from a challenge with an ovalbumin-expressing tumor. In the present study, we examined the capacity of ES-DC expressing mouse homologue of human glypican-3, a recently identified oncofetal antigen expressed in human melanoma and hepatocellular carcinoma, to elicit protective immunity against glypican-3-expressing mouse tumors. CTLs specific to multiple glypican-3 epitopes were primed by the in vivo transfer of glypican-3-transfectant ES-DC (ES-DC-GPC3). The transfer of ES-DC-GPC3 protected the recipient mice from subsequent challenge with B16-F10 melanoma, naturally expressing glypican-3, and with glypican-3-transfectant MCA205 sarcoma. The treatment with ES-DC-GPC3 was also highly effective against i.v. injected B16-F10. No harmful side effects, such as autoimmunity, were observed for these treatments. The depletion experiments and immunohistochemical analyses suggest that both CD8+ and CD4+ T cells contributed to the observed antitumor effect. In conclusion, the usefulness of glypican-3 as a target antigen for antimelanoma immunotherapy was thus shown in the mouse model using the ES-DC system. Human dendritic cells expressing glypican-3 would be a promising means for therapy of melanoma and hepatocellular carcinoma. (Cancer Res 2006; 66(4): 2414-22)