bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preferential Expression of Very Late Antigen-4 on Type 1 CTL Cells Plays a Critical Role in Trafficking into Central Nervous System Tumors
Authors: Sasaki Kotaro , Zhu Xinmei , Vasquez Cecilia , Nishimura Fumihiko , Dusak Jill E. , Huang Jian , Fujita Mitsugu , Wesa Amy , Potter Douglas M. , Walker Paul R. , Storkus Walter J. , Okada Hideho 
Published: July 2007

AbstractWe have previously shown preferential tumor-homing and therapeutic efficacy of adoptively transferred type 1 CTL (Tc1) when compared with type 2 CTL (Tc2) in mice bearing intracranial ovalbumin-transfected melanoma (M05). Further characterizing the expression of a panel of homing receptors on Tc1 and Tc2 cells, we found that very late antigen (VLA)-4 (a heterodimer of CD49d and CD29), but none of other receptors evaluated, was expressed at significantly higher levels on Tc1 cells than on Tc2 cells. Although CD49d (α4 integrin) can form heterodimers with both β1 (CD29) and β7 integrins, α4β7 complexes were not expressed by either Tc1 or Tc2 cells, suggesting that CD49d is solely expressed in VLA-4 complexes. VLA-4 expression on Tc2 cells was down-regulated in an interleukin (IL)-4 dose-dependent manner but not by other type 2 cytokines, such as IL-10 and IL-13, suggesting that IL-4 uniquely down-regulates VLA-4 expression on these cells. In accordance with the differential expression of VLA-4 on Tc1 versus Tc2 cells, Tc1 cells alone were competent to adhere to plate-bound VCAM-1-Ig fusion protein. Finally, the efficient trafficking of Tc1 cells into intracranial M05 lesions in vivo was efficiently blocked by administration of monoclonal antibodies against CD49d or VCAM-1 or small interfering RNA–mediated silencing of CD49d on Tc1 cells. Collectively, these data support the critical role of VLA-4 in the effective intracranial tumor homing of adoptive-transferred, antigen-specific Tc1 cells and suggest that more effective vaccine and/or ex vivo T-cell activation regimens may be developed by promoting the generation of VLA-4+ antitumor Tc1 cells. [Cancer Res 2007;67(13):6451–8]
Podocalyxin Increases the Aggressive Phenotype of Breast and Prostate Cancer Cells In vitro through Its Interaction with Ezrin
Authors: Sizemore Steven , Cicek Muzaffer , Sizemore Nywana , Ng Kwok Peng , Casey Graham 
Published: July 2007

Abstract
Podocalyxin is an anti-adhesive transmembrane sialomucin that has been implicated in the development of more aggressive forms of breast and prostate cancer. The mechanism through which podocalyxin increases cancer aggressiveness remains poorly understood but may involve the interaction of podocalyxin with ezrin, an established mediator of metastasis. Here, we show that overexpression of podocalyxin in MCF7 breast cancer and PC3 prostate cancer cell lines increased their in vitro invasive and migratory potential and led to increased expression of matrix metalloproteases 1 and 9 (MMP1 and MMP9). Podocalyxin expression also led to an increase in mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) activity. To determine the role of ezrin in these podocalyxin-dependent phenotypic events, we first confirmed that podocalyxin formed a complex with ezrin in MCF7 and PC3 cells. Furthermore, expression of podocalyxin was associated with a changed ezrin subcellular localization and increased ezrin phosphorylation. Transient knockdown of ezrin protein abrogated MAPK and PI3K signaling as well as MMP expression and invasiveness in cancer cells overexpressing podocalyxin. These findings suggest that podocalyxin leads to increased in vitro migration and invasion, increased MMP expression, and increased activation of MAPK and PI3K activity in MCF7 and PC3 cells through its ability to form a complex with ezrin. [Cancer Res 2007;67(13):6183–91]
Tumor Suppressor 101F6 and Ascorbate Synergistically and Selectively Inhibit Non–Small Cell Lung Cancer Growth by Caspase-Independent Apoptosis and Autophagy
Authors: Ohtani Shoichiro , Iwamaru Arifumi , Deng Wuguo , Ueda Kentaro , Wu Guanglin , Jayachandran Gitanjali , Kondo Seiji , Atkinson Edward N. , Minna John D. , Roth Jack A. , Ji Lin 
Published: July 2007

Abstract
101F6 is a candidate tumor suppressor gene harbored on chromosome 3p21.3, a region with frequent and early allele loss and genetic alterations in many human cancers. We previously showed that enforced expression of wild-type 101F6 by adenoviral vector–mediated gene transfer significantly inhibited tumor cell growth in 3p21.3-deficient non–small cell lung cancer (NSCLC) cells in vitro and in vivo. The molecular mechanism of 101F6-mediated tumor suppression is largely unknown. A computer-aided structural and functional model predicts the 101F6 protein to be a member of the cytochrome b561 protein family that is involved in the regeneration of the antioxidant ascorbate. 101F6 protein is expressed in normal lung bronchial epithelial cells and fibroblasts but is lost in most lung cancers. Treatment with 101F6 nanoparticle–mediated gene transfer in combination with a subpharmacologic dose (200–500 μmol/L) of ascorbate synergistically and selectively inhibited lung cancer cell growth in vitro. Systemic injection of 101F6 nanoparticles plus the i.p. injection of ascorbate synergistically inhibited both tumor formation and growth in human NSCLC H322 orthotopic lung cancer mouse models (P &lt; 0.001). Furthermore, exogenous expression of 101F6 enhanced intracellular uptake of ascorbate, leading to an accumulation of cytotoxic H2O2 and a synergistic killing of tumor cells through caspase-independent apoptotic and autophagic pathways. The antitumor synergism showed by the combination treatment with systemic administration of 101F6 nanoparticles and ascorbate on lung cancer offers an attractive therapeutic strategy for future clinical trials in cancer prevention and treatment. [Cancer Res 2007;67(13):6293–303]
Inhibition of Tumor Metastasis by a Growth Factor Receptor Bound Protein 2 Src Homology 2 Domain–Binding Antagonist
Authors: Giubellino Alessio , Gao Yang , Lee Sunmin , Lee Min-Jung , Vasselli James R. , Medepalli Sampath , Trepel Jane B. , Burke Terrence R. , Bottaro Donald P. 
Published: July 2007

Abstract
Metastasis, the primary cause of death in most forms of cancer, is a multistep process whereby cells from the primary tumor spread systemically and colonize distant new sites. Blocking critical steps in this process could potentially inhibit tumor metastasis and dramatically improve cancer survival rates; however, our understanding of metastasis at the molecular level is still rudimentary. Growth factor receptor binding protein 2 (Grb2) is a widely expressed adapter protein with roles in epithelial cell growth and morphogenesis, as well as angiogenesis, making it a logical target for anticancer drug development. We have previously shown that a potent antagonist of Grb2 Src homology-2 domain–binding, C90, blocks growth factor–driven cell motility in vitro and angiogenesis in vivo. We now report that C90 inhibits metastasis in vivo in two aggressive tumor models, without affecting primary tumor growth rate. These results support the potential efficacy of this compound in reducing the metastatic spread of primary solid tumors and establish a critical role for Grb2 Src homology-2 domain–mediated interactions in this process. [Cancer Res 2007;67(13):6012–6]
Superoxide Signaling Mediates N-acetyl-l-cysteine–Induced G1 Arrest: Regulatory Role of Cyclin D1 and Manganese Superoxide Dismutase
Authors: Menon Sarita G. , Sarsour Ehab H. , Kalen Amanda L. , Venkataraman Sujatha , Hitchler Michael J. , Domann Frederick E. , Oberley Larry W. , Goswami Prabhat C. 
Published: July 2007

Abstract
Thiol antioxidants, including N-acetyl-l-cysteine (NAC), are widely used as modulators of the intracellular redox state. We investigated the hypothesis that NAC-induced reactive oxygen species (ROS) signaling perturbs cellular proliferation by regulating the cell cycle regulatory protein cyclin D1 and the ROS scavenging enzyme Mn–superoxide dismutase (MnSOD). When cultured in media containing NAC, mouse fibroblasts showed G1 arrest with decreased cyclin D1 protein levels. The absence of a NAC-induced G1 arrest in fibroblasts overexpressing cyclin D1 (or a nondegradable mutant of cyclin D1-T286A) indicates that cyclin D1 regulates this G1 arrest. A delayed response to NAC exposure was an increase in both MnSOD protein and activity. NAC-induced G1 arrest is exacerbated in MnSOD heterozygous fibroblasts. Results from electron spin resonance spectroscopy and flow cytometry measurements of dihydroethidine fluorescence showed an approximately 2-fold to 3-fold increase in the steady-state levels of superoxide (O2•−) in NAC-treated cells compared with control. Scavenging of O2•− with Tiron reversed the NAC-induced G1 arrest. These results show that an O2•− signaling pathway regulates NAC-induced G1 arrest by decreasing cyclin D1 protein levels and increasing MnSOD activity. [Cancer Res 2007;67(13):6392–9]
Delivery of 5-Aza-2′-Deoxycytidine to Cells Using Oligodeoxynucleotides
Authors: Yoo Christine B. , Jeong Shinwu , Egger Gerda , Liang Gangning , Phiasivongsa Pasit , Tang Chunlin , Redkar Sanjeev , Jones Peter A. 
Published: July 2007

Abstract
The major goal of epigenetic therapy is to reverse aberrant promoter hypermethylation and restore normal function of tumor suppressor genes by the use of chromatin-modifying drugs. Decitabine, or 5-aza-2′-deoxycytidine (5-aza-CdR), is a well-characterized drug that is now Food and Drug Administration approved for the treatment of myelodysplastic syndrome. Although 5-aza-CdR is an extremely potent inhibitor of DNA methylation, it is subject to degradation by hydrolytic cleavage and deamination by cytidine deaminase. We show that short oligonucleotides containing a 5-aza-CdR can also inhibit DNA methylation in cancer cells at concentrations comparable with 5-aza-CdR. Detailed studies with S110, a dinucleotide, showed that it works via a mechanism similar to that of 5-aza-CdR after incorporation of its aza-moiety into DNA. Stability of the triazine ring in aqueous solution was not improved in the S110 dinucleotide; however, deamination by cytidine deaminase was dramatically decreased. This is the first demonstration of the use of short oligonucleotides to provide effective delivery and cellular uptake of a nucleotide drug and protection from enzymatic degradation. This approach may pave the way for more stable and potent inhibitors of DNA methylation as well as provide means for improving existing therapeutics. [Cancer Res 2007;67(13):6400–8]
Spontaneous Mammary Tumors Differ Widely in Their Inherent Sensitivity to Adoptively Transferred T Cells
Authors: Wall Erika M. , Milne Katy , Martin Michele L. , Watson Peter H. , Theiss Patty , Nelson Brad H. 
Published: July 2007

AbstractImmunotherapy of cancer can lead to the selection of antigen loss variants, which provides strong rationale to target oncogenes that are essential for tumor growth or viability. To investigate this concept, we tagged the HER2/neu oncogene with epitopes from ovalbumin to confer recognition by T-cell receptor transgenic CD8+ (OT-I) and CD4+ (OT-II) T cells. Transgenic mice expressing neuOT-I/OT-II developed mammary adenocarcinomas at 6 to 10 months of age. Adoptively transferred naive OT-I cells (with or without OT-II cells) proliferated vigorously on encountering neuOT-I/OT-II-expressing tumors. This was followed by the complete regression of 37% of tumors, whereas others showed partial/stable responses (40%) or progressive disease (23%). Those tumors undergoing complete regression never recurred. In mice with multiple primary tumors, simultaneous regressions and nonregressions were often seen, indicating that immune evasion occurred at a local rather than systemic level. The majority of nonregressing tumors expressed NeuOT-I/OT-II and MHC class I, and many avoided rejection through a profound block to T-cell infiltration. Thus, T cells directed against an essential oncogene can permanently eradicate a subset of spontaneous, established mammary tumors. However, in other tumors, local barriers severely limit the therapeutic response. To maximize the efficacy of immunotherapy against spontaneous cancers, predictive strategies that take into account the heterogeneity of the tumor microenvironment will be required. [Cancer Res 2007;67(13):6442–50]
Positive Cross-Regulatory Loop Ties GATA-3 to Estrogen Receptor α Expression in Breast Cancer
Authors: Eeckhoute Jérôme , Keeton Erika Krasnickas , Lupien Mathieu , Krum Susan A. , Carroll Jason S. , Brown Myles 
Published: July 2007

Abstract
The transcription factor GATA-3 is required for normal mammary gland development, and its expression is highly correlated with estrogen receptor α (ERα) in human breast tumors. However, the functional role of GATA-3 in ERα-positive breast cancers is yet to be established. Here, we show that GATA-3 is required for estradiol stimulation of cell cycle progression in breast cancer cells. The role of GATA-3 in estradiol signaling requires the direct positive regulation of the expression of the ERα gene itself by GATA-3. GATA-3 binds to two cis-regulatory elements located within the ERα gene, and this is required for RNA polymerase II recruitment to ERα promoters. Reciprocally, ERα directly stimulates the transcription of the GATA-3 gene, indicating that these two factors are involved in a positive cross-regulatory loop. Moreover, GATA-3 and ERα regulate their own expression in breast cancer cells. Hence, this transcriptional coregulatory mechanism accounts for the robust coexpression of GATA-3 and ERα in human breast cancers. In addition, these results highlight the crucial role of GATA-3 for the response of ERα-positive breast cancers to estradiol. Moreover, they identify GATA-3 as a critical component of the master cell-type–specific transcriptional network including ERα and FoxA1 that dictates the phenotype of hormone-dependent breast cancer. [Cancer Res 2007;67(13):6477–83]
Neutrophil activation via β2 integrins (CD11/CD18): Molecular mechanisms and clinical implications
Authors: Schymeinsky Jürgen , Mócsai Attila , Walzog Barbara 
Published: July 2007

SummaryPolymorphonuclear neutrophils (PMN) are key components of the innate immunity and their efficient recruitment to the sites of lesion is a prerequisite for acute inflammation. Signaling via adhesion molecules of the β2 integrin family (CD11/CD18) plays an essential role for PMN recruitment and activation during inflammation. In this review, we will focus on the non-receptor tyrosine kinase Syk, an important downstream signaling component of β2 integrins that is required for the control of different PMN functions including adhesion,migration and phagocytosis. The exploration of β2 integrin-mediated Syk activation provided not only novel insights into the control of PMN functions but also led to the identification of Syk as a new molecular target for therapeutic intervention during inflammatory diseases.
A thromboxane A2/prostaglandin H2 receptor antagonist (S18886) shows high antithrombotic efficacy in an experimental model of stent-induced thrombosis
Authors: Vilahur Gemma , Casaní Laura , Badimon Lina 
Published: July 2007

SummaryAcute thrombosis is a threat in patients undergoing percutaneous coronary intervention with stent implantation. Our objective was to determine if stent-induced thrombus formation could be inhibited by oral treatment with a thromboxane A2/prostaglandin H2 receptor antagonist (TPr; S18886) as an alternative to standard therapy. Pigs were allocated in the following treatment (p.o) groups: I) clopidogrel (CLOP); II) ASA; III) S18886; IV) ASA+CLOP; and V) placebo-control. Damaged vessel was placed in the Badimon chamber containing a stent and perfused at 212/s.Antithrombotic effects were assessed as 111In-platelet deposition (PD) in two series (60 and 180 min after drug intake). Fibrin(ogen) deposition, light transmittance aggregometry (LTA; collagen, U46619, and ADP), and bleeding time (BT) were also evaluated. After 60 min S18886 reduced PD ≤48%, 40%, and 35% vs placebo, CLOP-, and ASA-treated ani mals, respectively (P<0.05), while ASA+CLOP showed a 58% reduction versus placebo (P<0.01).After 3 hours, ASA+CLOP decreased PD by 55%, S18886 by 40%, CLOP alone by 28% (P>0.05), and ASA showed no inhibition versus placebo. Similar effects were found in S18886– and ASA+CLOP-treated animals at both times. Fibrin(ogen) deposition followed the same pattern. Collagen-induced LTA was significantly reduced by ASA, ASA+CLOP, and S18886; S18886 abolished U46619-induced LTA; and, CLOP±ASA reduced ADP-induced LTA in a time-dependent manner. TPr blockade did not prolong BT, whereas CLOP±ASA significantly did (P<0.0001). In conclusion, blockade of theTPr provided a fast and potent platelet inhibitory effect in a porcine model of in-stent thrombosis comparable to that of blocking both the ADP receptor and cyclooxygenase activation; in addition,TPr provided a more favorable bleeding risk profile.
Rabbi Hayyim of Volozhin's Non-Messianic Vision of the Present and Future
Authors: Shapiro Harvey 
Published: July 2007

AbstractRecent studies have characterized R. Hayyim of Volozhin (1749–1821) as actively preparing for the messianic redemption. Contrary to this, I maintain that R. Hayyim was concerned with the immediate potential of the world in the context of historical time (divre ha-yamim), rather than with a world-to-come, in the context of messianic time (aharit ha-yamim). To R. Hayyim, the existence of the cosmos and the stability of a dynamic life-giving universe are fraught with contingency because of the interdependent organic naturality shared by man and world. This contingency is constant, placing man's conduct as the central determinant of the world's future. R. Hayyim's theory and practice attest to a concern for the immanent and transcendent aspects of this world and for the meanings of our everyday experienced relationship to its variegated pragmata.
Serial personal digital assistant data capture of health-related quality of life: A randomized controlled trial in a prostate cancer clinic
Authors: Matthew Andrew G , Currie Kristen L , Irvine Jane , Ritvo Paul , Santa Mina Daniel , Jamnicky Leah , Nam Robert , Trachtenberg John 
Published: July 2007

Abstract

Background
In clinical and research practice linked to prostate cancer treatment, frequent monitoring of patient health-related quality of life (HRQOL) is essential. Practical and analytic limitations of paper questionnaire data capture may be overcome with the use of self-administered personal digital assistant (PDA) data collection. The objective of this study was to assess the reliability, validity, and feasibility of using PDA in place of paper versions of the International Prostate Symptom Score (IPSS), the Patient Oriented Prostate Cancer Utility Survey (PORPUS), and the International Index of Erectile Function-5 (IIEF-5) in a prostate cancer clinic setting.

Methods
152 participants were randomly assigned to one of three conditions: 1) paper followed by PDA survey; 2) PDA followed by paper survey; or 3) PDA followed by PDA survey. Evaluation included an assessment of data quality (internal consistency, test-retest reliability, response correlation, completeness of data), and feasibility (participation rates, time to completion, preference and difficultly/ease of using PDA).

Results
Internal consistency was similar for both PDA and paper applications. Test-retest reliability was confirmed for PDA repeated administration. Data from paper and PDA questionnaires were strongly correlated. Lower missed item rates were found in PDA administration. 82.8% of participants preferred using the PDA or had no preference. Mean difficulty/ease ratings indicated that participants found the PDA easy to use. Age did not significantly correlate with preference or difficulty.

Conclusion
The results confirm the adaptability of the IPSS, IIEF-5, and the PORPUS to PDA administration. Similarly, the findings of this study support the feasibility of using PDA technology for HRQOL serial data capture in the prostate cancer patient population.
Identification of 9 uterine genes that are regulated during mouse pregnancy and exhibit abnormal levels in the cyclooxygenase-1 knockout mouse
Authors: Zhao Baohui , Koon Deanna , Curtis Allyson L , Soper Jessica , Bethin Kathleen E 
Published: July 2007

Abstract

Background
Preterm birth is the leading cause of all infant mortality. In 2004, 12.5% of all births were preterm. In order to understand preterm labor, we must first understand normal labor. Since many of the myometrial changes that occur during pregnancy are similar in mice and humans and mouse gestation is short, we have studied the uterine genes that change in the mouse during pregnancy. Here, we used microarray analysis to identify uterine genes in the gravid mouse that are differentially regulated in the cyclooxygenase-1 knockout mouse model of delayed parturition.

Methods
Gestational d18.0 uteri (n = 4) were collected from pregnant wild-type and cyclooxygenase-1 knockout mice. Part of the uterus was used for frozen sections and RNA was isolated from the remainder. Microarray analysis was performed at the Indiana University School of Medicine Genomic Core and analyzed using the Microarray Data Portal. Northern analysis was performed to confirm microarray data and the genes localized in the gravid uterus by in situ hybridization.

Results
We identified 277 genes that are abnormally expressed in the gravid d18.0 cyclooxygenase-1 knockout mouse. Nine of these genes are also regulated in the normal murine uterus during the last half of gestation. Many of these genes are involved in the immune response, consistent with an important role of the immune system in parturition. Expression of 4 of these genes; arginase I, IgJ, Tnfrsf9 and troponin; was confirmed by Northern analysis to be mis-regulated during pregnancy in the knockout mouse. In situ hybridization of these genes demonstrated a similar location in the gravid wild-type and Cox-1 knockout mouse uteri.

Conclusion
To our knowledge, this is the first work to demonstrate the uterine location of these 4 genes in the mouse during late pregnancy. There are several putative transcription factor binding sites that are shared by many of the 9 genes identified here including; estrogen and progesterone response elements and Ets binding sites. In summary, this work identifies 9 uterine murine genes that may play a role in parturition. The function of these genes is consistent with an important role of the immune system in parturition.