bluuebunny/crossref_metadata_2025 huggingface dataset:
SEMICLASSICAL (QUANTUM FIELD THEORY) AND QUANTUM (STRING) DE SITTER REGIMES: NEW RESULTS
Authors: BOUCHAREB A. , RAMÓN MEDRANO M. , SÁNCHEZ N. G.
Published: July 2007

We compute the quantum string entropy S s (m, H) from the microscopic string density of states ρ s (m, H) of mass m in de Sitter space–time. We find for high m (high Hm → c/α') a new phase transition at the critical string temperature T s = (1/2πk B )L cl c2/α', higher than the flat space (Hagedorn) temperature t s (L cl = c/H, the Hubble constant H acts at the transition, producing a smaller string constant α' and thus, a higher tension). T s is the precise quantum dual of the semiclassical (QFT Hawking–Gibbons) de Sitter temperature T sem = ħ c/(2πk B L cl ). By precisely identifying the semiclassical and quantum (string) de Sitter regimes, we find a new formula for the full de Sitter entropy S sem (H), as a function of the usual Bekenstein–Hawking entropy [Formula: see text]. For L cl ≫ ℓ Planck , i.e. for low [Formula: see text] is the leading term, but for high H near c/ℓ Planck , a new phase transition operates and the whole entropy S sem (H) is drastically different from the Bekenstein–Hawking entropy [Formula: see text]. We compute the string quantum emission cross-section σ string by a black hole in de Sitter (or asymptotically de Sitter) space–time (bhdS). For T sem bhdS ℓ T s (early evaporation stage), it shows the QFT Hawking emission with temperature T sem bhdS (semiclassical regime). For T sem bhdS → T s , σ string exhibits a phase transition into a string de Sitter state of size [Formula: see text], [Formula: see text], and string de Sitter temperature T s . Instead of featuring a single pole singularity in the temperature (Carlitz transition), it features a square root branch point (de Vega–Sanchez transition). New bounds on the black hole radius r g emerge in the bhdS string regime: it can become r g = L s /2, or it can reach a more quantum value, r g = 0.365 ℓ s .
CONFORMAL STRUCTURES AND TWISTORS IN THE PARAVECTOR MODEL OF SPACETIME
Authors: DA ROCHA R. , VAZ J.
Published: July 2007

Some properties of the Clifford algebras [Formula: see text] and [Formula: see text] are presented, and three isomorphisms between the Dirac–Clifford algebra [Formula: see text] and [Formula: see text] are exhibited, in order to construct conformal maps and twistors, using the paravector model of spacetime. The isomorphism between the twistor space inner product isometry group SU(2,2) and the group $pin+(2,4) is also investigated, in the light of a suitable isomorphism between [Formula: see text] and [Formula: see text]. After reviewing the conformal spacetime structure, conformal maps are described in Minkowski spacetime as the twisted adjoint representation of $pin+(2,4), acting on paravectors. Twistors are then presented via the paravector model of Clifford algebras and related to conformal maps in the Clifford algebra over the Lorentzian ℝ4,1 spacetime. We construct twistors in Minkowski spacetime as algebraic spinors associated with the Dirac–Clifford algebra [Formula: see text] using one lower spacetime dimension than standard Clifford algebra formulations, since for this purpose, the Clifford algebra over ℝ4,1 is also used to describe conformal maps, instead of ℝ2,4. Our formalism sheds some new light on the use of the paravector model and generalizations.
COHOMOLOGY OF LAGRANGE COMPLEXES INVARIANT UNDER PSEUDOGROUPS OF LOCAL TRANSFORMATIONS
Authors: SPIRO ANDREA
Published: July 2007

The inverse problem of the Calculus of Variations for Lagrangians and Euler–Lagrange equations invariant under a pseudogroup [Formula: see text] of local transformations of the base manifold is considered. Exploiting some ideas of Krupka, a theorem is proved showing that, if the configuration space consists of sections of tensor bundles or of local maps of a manifold into another, then such inverse problem is solvable whenever a certain cohomology class of [Formula: see text]-invariant forms on the configuration space is vanishing. In addition, for a few pseudogroups, the cohomology groups considered in the main result are explicitly determined in terms of the de Rham cohomology of the configuration space.
PPARs and Adipose Cell Plasticity
Authors: Casteilla Louis , Cousin Béatrice , Carmona Mamen
Published: July 2007

Due to the importance of fat tissues in both energy balance and in the associated disorders arising when such balance is not maintained, adipocyte differentiation has been extensively investigated in order to control and inhibit the enlargement of white adipose tissue. The ability of a cell to undergo adipocyte differentiation is one particular feature of all mesenchymal cells. Up until now, the peroxysome proliferator-activated receptor (PPAR) subtypes appear to be the keys and essential players capable of inducing and controlling adipocyte differentiation. In addition, it is now accepted that adipose cells present a broad plasticity that allows them to differentiate towards various mesodermal phenotypes. The role of PPARs in such plasticity is reviewed here, although no definite conclusion can yet be drawn. Many questions thus remain open concerning the definition of preadipocytes and the relative importance of PPARs in comparison to other master factors involved in the other mesodermal phenotypes.
Proteomics-Based Identification of Proteins Secreted in Apical Surface Fluid of Squamous Metaplastic Human Tracheobronchial Epithelial Cells Cultured by Three-Dimensional Organotypic Air-Liquid Interface Method
Authors: Kim Seung-Wook , Cheon Kyounga , Kim Chang-Hoon , Yoon Joo-Heon , Hawke David H. , Kobayashi Ryuji , Prudkin Ludmila , Wistuba Ignacio I. , Lotan Reuben , Hong Waun Ki , Koo Ja Seok
Published: July 2007

Squamous cell carcinoma in the lung originates from bronchial epithelial cells that acquire increasingly abnormal phenotypes. Currently, no known biomarkers are clinically efficient for the early detection of premalignant lesions and lung cancer. We sought to identify secreted molecules produced from squamous bronchial epithelial cells cultured with organotypic culture methods. We analyzed protein expression patterns in the apical surface fluid (ASF) from aberrantly differentiated squamous metaplastic normal human tracheobronchial epithelial (NHTBE) and mucous NHTBE cells. Comparative two-dimensional PAGE analysis revealed 174 unique proteins in the ASF of squamous NHTBE cells compared with normal mucociliary differentiated NHTBE cells. Among them, 64 well-separated protein spots were identified by liquid chromatography-tandem mass spectrometry, revealing 22 different proteins in the ASF from squamous NHTBE cells. Expression of six of these proteins [SCC antigen 1 (SCCA1), SCC antigen 2 (SCCA2), S100A8, S100A9, Annexin I, and Annexin II] in the squamous NHTBE cells was further confirmed with immunoblot analysis. Notably, SCCA1 and SCCA2 were verified as being expressed in squamous metaplastic NHTBE cells but not in normal mucous NHTBE or normal bronchial epithelium. Moreover, SCCA1 and SCCA2 expression increased in in vitro lung carcinogenesis model cell lines with increasing malignancy. In summary, we identified proteins that are uniquely secreted from squamous metaplastic primary human bronchial epithelial cells cultured by the organotypic air-liquid interface method. These ASF proteins may be used to detect abnormal lesions in the lung without collecting invasive biopsy specimens. [Cancer Res 2007;67(14):6565–73]
Cancer Cells and Normal Cells Differ in Their Requirements for Thoc1
Authors: Li Yanping , Lin Athena W. , Zhang Xiaojing , Wang Yanqing , Wang Xiaoling , Goodrich David W.
Published: July 2007

The evolutionarily conserved TREX (Transcription/Export) complex physically couples transcription, messenger ribonucleoprotein particle biogenesis, RNA processing, and RNA export for a subset of genes. HPR1 encodes an essential component of the S. cerevisiae TREX complex. HPR1 loss compromises transcriptional elongation, nuclear RNA export, and genome stability. Yet, HPR1 is not required for yeast viability. Thoc1 is the recently discovered human functional orthologue of HPR1. Thoc1 is expressed at higher levels in breast cancer than in normal epithelia, and expression levels correlate with tumor size and metastatic potential. Depletion of Thoc1 protein (pThoc1) in human cancer cell lines compromises cell proliferation. It is currently unclear whether Thoc1 is essential for all mammalian cells or whether cancer cells may differ from normal cells in their dependence on Thoc1. To address this issue, we have compared the requirements for Thoc1 in the proliferation and survival of isogenic normal and oncogene-transformed cells. Neoplastic cells rapidly lose viability via apoptotic cell death on depletion of pThoc1. Induction of apoptotic cell death is coincident with increased DNA damage as indicated by the appearance of phosphorylated histone H2AX. In contrast, the viability of normal cells is largely unaffected by pThoc1 loss. Normal cells lacking Thoc1 cannot be transformed by forced expression of E1A and Ha-ras, suggesting that Thoc1 may be important for neoplastic transformation. In sum, our data are consistent with the hypothesis that cancer cells require higher levels of pThoc1 for survival than normal cells. If true, pThoc1 may provide a novel molecular target for cancer therapy. [Cancer Res 2007;67(14):6657–64]
CytochromeP450 Epoxygenase Promotes Human Cancer Metastasis
Authors: Jiang Jian-Gang , Ning Yao-Gui , Chen Chen , Ma Ding , Liu Zhen-Jun , Yang Shilin , Zhou Jianfeng , Xiao Xiao , Zhang Xin A. , Edin Matthew L. , Card Jeffrey W. , Wang Jianing , Zeldin Darryl C. , Wang Dao Wen
Published: July 2007

Cytochrome P450 (CYP) epoxygenases convert arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EET), which exert diverse biological activities in a variety of systems. We previously reported that the CYP2J2 epoxygenase is overexpressed in human cancer tissues and cancer cell lines and that EETs enhance tumor growth, increase carcinoma cell proliferation, and prevent apoptosis of cancer cells. Herein, we report that CYP epoxygenase overexpression or EET treatment promotes tumor metastasis independent of effects on tumor growth. In four different human cancer cell lines in vitro, overexpression of CYP2J2 or CYP102 F87V with an associated increase in EET production or addition of synthetic EETs significantly induced Transwell migration (4.5- to 5.5-fold), invasion of cells (3- to 3.5-fold), cell adhesion to fibronectin, and colony formation in soft agar. In contrast, the epoxygenase inhibitor 17-ODYA or infection with the antisense recombinant adeno-associated viral vector (rAAV)-CYP2J2 vector inhibited cell migration, invasion, and adhesion with an associated reduction in EET production. CYP overexpression also enhanced metastatic potential in vivo in that rAAV-CYP2J2–infected MDA-MB-231 human breast carcinoma cells showed 60% more lung metastases in athymic BALB/c mice and enhanced angiogenesis in and around primary tumors compared with control cells. Lung metastasis was abolished by infection with the antisense rAAV-CYP2J2 vector. CYP epoxygenase overexpression or EET treatment up-regulated the prometastatic matrix metalloproteinases and CD44 and down-regulated the antimetastatic genes CD82 and nm-23. Together, these data suggest that CYP epoxygenase inhibition may represent a novel approach to prevent metastasis of human cancers. [Cancer Res 2007;67(14):6665–74]
A Polyepitope DNA Vaccine Targeted to Her-2/ErbB-2 Elicits a Broad Range of Human and Murine CTL Effectors to Protect against Tumor Challenge
Authors: Scardino Antonio , Alimandi Maurizio , Correale Pierpaolo , Smith Steven G. , Bei Roberto , Firat Hüseyin , Cusi Maria Grazia , Faure Olivier , Graf-Dubois Stephanie , Cencioni Giulia , Marrocco Jordan , Chouaib Salem , Lemonnier François A. , Jackson Andrew Michael , Kosmatopoulos Kostas
Published: July 2007

A cDNA vaccine (pVax1/pet-neu) was designed to encode 12 different Her-2/ErbB-2–derived, HLA-A*0201–restricted dominant and high-affinity heteroclitic cryptic epitopes. Vaccination with pVax1/pet-neu triggered multiple and ErbB-2–specific CTL responses in HLA-A*0201 transgenic HHD mice and in HLA-A*0201 healthy donors in vitro. Human and murine CTL specific for each one of the 12 ErbB-2 peptides recognized in vitro both human and murine tumor cells overexpressing endogenous ErbB-2. Furthermore, vaccination of HHD mice with pVax1/pet-neu significantly delayed the in vivo growth of challenged ErbB-2–expressing tumor (EL4/HHD/neu murine thymoma) more actively when compared with vaccination with the empty vector (pVax1) or vehicle alone. These data indicate that the pVax1/pet-neu cDNA vaccine coding for a poly-ErbB-2 epitope is able to generate simultaneous ErbB-2–specific antitumor responses against dominant and cryptic multiple epitopes. [Cancer Res 2007;67(14):7028–36]
EWS/FLI1 Regulates Tumor Angiogenesis in Ewing's Sarcoma via Suppression of Thrombospondins
Authors: Potikyan Gary , Savene Rupert O.V. , Gaulden Julie M. , France Kelly A. , Zhou Zhichao , Kleinerman Eugenie S. , Lessnick Stephen L. , Denny Christopher T.
Published: July 2007

Suppression of the expression of antiangiogenic factors has been closely associated with multiple malignancies. Thrombospondins 1 and 2 are members of a family of angiogenic inhibitors that are regulated by several oncogenes. In this study, we investigate the role of thrombospondins in Ewing's sarcoma and their regulation by EWS/ETS fusion oncoproteins. We show that the EWS/FLI1 fusion suppresses the expression of thrombospondins in both NIH3T3 fibroblasts and Ewing's sarcoma tumor–derived cell lines. This regulation depends on an intact EWS/FLI1 DNA-binding domain and may involve direct interactions between EWS/FLI1 and thrombospondin promoter regions. Forced expression of thrombospondins in Ewing's sarcoma cell lines inhibited the rate of tumor formation in vivo and markedly decreased the number of microvessels present in the tumors. These findings suggest that thrombospondins play a biologically significant role in tumor vascularization in Ewing's sarcoma and suggest potential therapeutic strategies for future therapeutic intervention. [Cancer Res 2007;67(14):6675–84]
HER4 D-Box Sequences Regulate Mitotic Progression and Degradation of the Nuclear HER4 Cleavage Product s80HER4
Authors: Strunk Karen E. , Husted Carty , Miraglia Leah C. , Sandahl Melissa , Rearick William A. , Hunter Debra M. , Earp H. Shelton , Muraoka-Cook Rebecca S.
Published: July 2007

Heregulin-mediated activation of HER4 initiates receptor cleavage (releasing an 80-kDa HER4 intracellular domain, s80HER4, containing nuclear localization sequences) and results in G2-M delay by unknown signaling mechanisms. We report herein that s80HER4 contains a functional cyclin B–like sequence known as a D-box, which targets proteins for degradation by anaphase-promoting complex (APC)/cyclosome, a multisubunit ubiquitin ligase. s80HER4 ubiquitination and proteasomal degradation occurred during mitosis but not during S phase. Inhibition of an APC subunit (APC2) using short interfering RNA knockdown impaired s80HER4 degradation. Mutation of the s80HER4 D-box sequence stabilized s80HER4 during mitosis, and s80HER4-dependent growth inhibition via G2-M delay was significantly greater with the D-box mutant. Polyomavirus middle T antigen–transformed HC11 cells expressing s80HER4 resulted in smaller, less proliferative, more differentiated tumors in vivo than those expressing kinase-dead s80HER4 or the empty vector. Cells expressing s80HER4 with a disrupted D-box did not form tumors, instead forming differentiated ductal structures. These results suggest that cell cycle–dependent degradation of s80HER4 limits its growth-inhibitory action, and stabilization of s80HER4 enhances tumor suppression, thus providing a link between HER4-mediated growth inhibition and cell cycle control. [Cancer Res 2007;67(14):6582–90]
BCR-Tyrosine 177 Plays an Essential Role in Ras and Akt Activation and in Human Hematopoietic Progenitor Transformation in Chronic Myelogenous Leukemia
Authors: Chu Su , Li Liang , Singh Harjeet , Bhatia Ravi
Published: July 2007

Chronic myelogenous leukemia (CML) results from the transformation of a primitive hematopoietic cell by the BCR/ABL gene. BCR/ABL signaling has been studied in cell lines and murine models, but the transforming effects of BCR/ABL are highly dependent on cellular context, and mechanisms responsible for the transformation of primitive human hematopoietic cells remain poorly understood. Current targeted therapies fail to eliminate malignant CML progenitors, and improved understanding of crucial molecular mechanisms of progenitor transformation may facilitate the development of improved therapeutic approaches. We investigated the role of BCR/ABL tyrosine 177 (BCR/ABL-Y177) in CML progenitor transformation by comparing the effects of expression of Y177-mutated BCR/ABL, wild-type BCR/ABL, or green fluorescent protein alone on normal CD34+ cells. We show that BCR/ABL-Y177 plays a critical role in CML progenitor expansion, proliferation, and survival. BCR/ABL expression results in enhanced Ras and Akt activity but reduced mitogen-activated protein kinase activity in human hematopoietic cells, which is reversed by BCR/ABL-Y177 mutation. Blocking BCR/ABL-Y177–mediated signaling enhances targeting of CML progenitors by imatinib mesylate. Our studies indicate that BCR/ABL-Y177 plays an essential role in Ras and Akt activation and in human hematopoietic progenitor transformation in CML. [Cancer Res 2007;67(14):7045–53]
S100A4 Contributes to the Suppression of BNIP3 Expression, Chemoresistance, and Inhibition of Apoptosis in Pancreatic Cancer
Authors: Mahon Patrick C. , Baril Patrick , Bhakta Vipul , Chelala Claude , Caulee Krishna , Harada Tomohiko , Lemoine Nicholas R.
Published: July 2007

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that is characterized by a particularly marked resistance to chemotherapy. We previously showed an association between decreased expression of BNIP3 and chemoresistance in PDAC cell lines. To further explore the molecular basis of chemoresistance in PDAC, we analyzed microarray data obtained from normal pancreas and PDAC tumor samples to identify genes exhibiting a negative correlation with the expression profile of BNIP3. This analysis identified several S100 family proteins, of which two, S100A2 and S100A4, showed in vitro the ability to repress exogenous BNIP3 promoter activity. We subsequently showed that RNA interference–mediated S100A4 knockdown resulted in an elevated expression of BNIP3 in PDAC cell lines that possess an unmethylated BNIP3 promoter, suggesting that, in addition to hypermethylation, S100A4 overexpression may represent an alternative mechanism for inhibiting BNIP3 function in PDAC. S100A4 knockdown also resulted in an increased sensitivity of PDAC cell lines to gemcitabine treatment, which was coupled with an increase in apoptosis and cell cycle arrest. To investigate the underlying mechanisms mediating these effects, we studied the effect of silencing the expression of S100A4 on the induction of apoptosis, cell cycle arrest, and the activation of apoptotic mediators. Knockdown of S100A4 clearly induced apoptosis with increased fragmentation of DNA and phosphatidyl serine externalization; activation of caspase-3, caspase-9, and poly(ADP-ribose) polymerase; and release of cytochrome c into the cytosol. These findings provide evidence that supports a novel role for S100A4 as a prosurvival factor in pancreatic cancer. [Cancer Res 2007;67(14):6786–95]
Gene Expression Profiling of Liposarcoma Identifies Distinct Biological Types/Subtypes and Potential Therapeutic Targets in Well-Differentiated and Dedifferentiated Liposarcoma
Authors: Singer Samuel , Socci Nicholas D. , Ambrosini Grazia , Sambol Elliot , Decarolis Penelope , Wu Yuhsin , O'Connor Rachael , Maki Robert , Viale Agnes , Sander Chris , Schwartz Gary K. , Antonescu Cristina R.
Published: July 2007

Classification of liposarcoma into three biological types encompassing five subtypes, (a) well-differentiated/dedifferentiated, (b) myxoid/round cell, and (c) pleomorphic, based on morphologic features and cytogenetic aberrations, is widely accepted. However, diagnostic discordance remains even among expert sarcoma pathologists. We sought to develop a more systematic approach to liposarcoma classification based on gene expression analysis and to identify subtype-specific differentially expressed genes that may be involved in liposarcoma genesis/progression and serve as potential therapeutic targets. A classifier based on gene expression profiling was able to distinguish between liposarcoma subtypes, lipoma, and normal fat samples. A 142-gene predictor of tissue class was derived to automatically determine the class of an independent validation set of lipomatous samples and shows the feasibility of liposarcoma classification based entirely on gene expression monitoring. Differentially expressed genes for each liposarcoma subtype compared with normal fat were used to identify histology-specific candidate genes with an in-depth analysis of signaling pathways important to liposarcoma pathogenesis and progression in the well-differentiated/dedifferentiated subset. The activation of cell cycle and checkpoint pathways in well-differentiated/dedifferentiated liposarcoma provides several possible novel therapeutic strategies with MDM2 serving as a particularly promising target. We show that Nutlin-3a, an antagonist of MDM2, preferentially induces apoptosis and growth arrest in dedifferentiated liposarcoma cells compared with normal adipocytes. These results support the development of a clinical trial with MDM2 antagonists for liposarcoma subtypes which overexpress MDM2 and show the promise of using this expression dataset for new drug discovery in liposarcoma. [Cancer Res 2007;67(14):6626–36]
Blockade of β-Catenin Signaling by Plant Flavonoid Apigenin Suppresses Prostate Carcinogenesis in TRAMP Mice
Authors: Shukla Sanjeev , MacLennan Gregory T. , Flask Chris A. , Fu Pingfu , Mishra Anil , Resnick Martin I. , Gupta Sanjay
Published: July 2007

Deregulation of β-catenin signaling is an important event in the genesis of several human malignancies including prostate cancer. We investigated the effects of apigenin, a naturally occurring plant flavone, on prostate carcinogenesis in TRAMP mice and further elucidated its mechanism of action. Oral intake of apigenin by gavage at doses of 20 and 50 μg/mouse/d, 6 days per week for 20 weeks, significantly decreased tumor volumes of the prostate as well as completely abolished distant-site metastases to lymph nodes, lungs, and liver in TRAMP mice. Apigenin-treated mice had significantly diminished weights of their genitourinary apparatuses and dorsolateral and ventral prostate lobes, compared with the control group, and showed reduced proliferation and increased apoptosis in the dorsolateral prostates, which correlated with elevated plasma apigenin levels. Continuous intake of apigenin up to 50 weeks by TRAMP mice significantly improved their overall survival. P.o. administration of apigenin further resulted in increased levels of E-cadherin and decreased levels of nuclear β-catenin, c-Myc, and cyclin D1 in the dorsolateral prostates of TRAMP mice. Similar effects were noted in TRAMP mice with established tumors. Treatment of DU145 human prostate cancer cells with 10 and 20 μmol/L apigenin also increased protein levels of E-cadherin by 27% to 74%, inhibited nuclear translocation of β-catenin and its retention in the cytoplasm, and decreased c-Myc and cyclin D1 levels, an effect similar to the exposure of cells to β-catenin small interfering RNA. Our results indicate that apigenin effectively suppressed prostate carcinogenesis in TRAMP mice, at least in part, by blocking β-catenin signaling. [Cancer Res 2007;67(14):6925–35]
Breast Cancer Expressing the Activated HER2/neu Is Sensitive to Gefitinib In vitro and In vivo and Acquires Resistance through a Novel Point Mutation in the HER2/neu
Authors: Piechocki Marie P. , Yoo George H. , Dibbley Susan K. , Lonardo Fulvio
Published: July 2007

The HER2/neu oncogene is an important diagnostic and prognostic factor and therapeutic target in breast and other cancers. We developed and characterized a breast cancer cell line (Bam1a) that overexpresses the activated HER2/neu and ErbB-3 and has a gene expression profile consistent with the ErbB-2 genetic signature. We evaluated the effects of the epidermal growth factor receptor (EGFR)/HER2 inhibitor, gefitinib, on this breast tumor line in vitro and in vivo. We characterized the effects of gefitinib on EGFR, HER2, and ErbB-3 phosphorylation by Western blot and determined the effects on downstream signaling through growth, survival, and stress pathways and the effect on proliferation, cell cycle, and apoptosis. Gefitinib treatment diminished phosphorylation of the ErbB-3 > EGFR > HER2/neu and signal transducers and activators of transcriptions in a dose-dependent fashion. Downstream mitogenic signaling through mitogen-activated protein (MAP)/extracellular signal regulated kinase kinase, p44/42 MAP kinase (MAPK) and stress signaling through c-Jun-NH2-kinase (JNK) 1 and c-Jun was impaired (1 μmol/L, 4–24 h), leading to cytostasis and cell cycle arrest within 24 h by decreased cyclin D1, cyclin B1, and pSer795Rb and increased p27. Proliferation and colony formation were inhibited at 0.5 and 1 μmol/L, respectively, and correlated with altered gene expression profiles. Diminished survival signaling through Akt, induction of bim, loss of connexin43, and decreased production of vascular endothelial growth factor-D preceded caspase-3 and poly(ADP)ribose polymerase (PARP) cleavage and apoptosis (>50% 2 μmol/L, 48 h). Oral administration of gefitinib was able to prevent the outgrowth of Bam1a tumor cells from palpable lesions, shrink established tumors, eliminate HER2 and HER3 phosphorylation, and decrease MAPK and Akt signaling in vivo. A variant of the Bam1a cell line, IR-5, with acquired ability to grow in 5 μmol/L gefitinib was developed and characterized. IR-5 bears a novel point mutation in the HER2/neu that corresponds to a L726I in the ATP-binding pocket and correlates with a log decrease in sensitivity to gefitinib, increased heterodimerization with EGFR and HER3, and impaired down-regulation. Gene expression profiling of IR-5 showed increased expression of EMP-1, NOTCH-1, FLT-1, PDGFB, and several other genes that may contribute to the resistant phenotype and sustain signaling through MAPK and Akt. This model will be useful in understanding the differences between intrinsic drug sensitivity and acquired resistance in the context of therapeutic strategies that target oncogene addicted diseases. [Cancer Res 2007;67(14):6825–43]
Development of Vaccines for High-Risk Ductal Carcinoma In situ of the Breast
Authors: Czerniecki Brian J. , Roses Robert E. , Koski Gary K.
Published: July 2007

Certain ductal carcinoma in situ (DCIS) lesions overexpress the HER-2/neu receptor at this early stage of breast cancer development. Recently, we showed that a HER-2–targeted dendritic cell vaccine could be used to eliminate HER-2–overexpressing cells in patients that harbor these high-risk DCIS lesions. Our findings suggest that vaccinating such patients might diminish the risk of recurrence, protect against the development of invasive breast cancer, and minimize morbidity associated with current treatments. We discuss several implications of this work for developing effective cancer vaccines. [Cancer Res 2007;67(14):6531–4]
Outcomes of Left Ventricular Assist Device Implantation as Destination Therapy in the Post-REMATCH Era
Authors: Lietz Katherine , Long James W. , Kfoury Abdallah G. , Slaughter Mark S. , Silver Marc A. , Milano Carmelo A. , Rogers Joseph G. , Naka Yoshifumi , Mancini Donna , Miller Leslie W.
Published: July 2007

Background—

The landmark Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial first demonstrated that implantation of left ventricular assist devices (LVADs) as destination therapy (DT) can provide survival superior to any known medical treatment in patients with end-stage heart failure who are ineligible for transplantation. In the present study, we describe outcomes of DT in the post-REMATCH era in the United States.

Methods and Results—

The present study included 280 patients who underwent HeartMate XVE LVAD implantation between November 2001 and December 2005. A preoperative risk score for in-hospital mortality after LVAD implantation was established in 222 patients with complete data. All patients were followed up until death or December 2006. The 1-year survival after LVAD implantation was 56%. The in-hospital mortality after LVAD surgery was 27%. The main causes of death included sepsis, right heart failure, and multiorgan failure. The most important determinants of in-hospital mortality were poor nutrition, hematological abnormalities, markers of end-organ or right ventricular dysfunction, and lack of inotropic support. Stratification of DT candidates into low (n=65), medium (n=111), high (n=28), and very high (n=18) risk on the basis of the risk score calculated from these predictors corresponded with 1-year survival rates of 81%, 62%, 28%, and 11%, respectively.

Conclusions—

Appropriate selection of candidates and timing of LVAD implantation are critical for improved outcomes of DT. Patients with advanced heart failure who are referred for DT before major complications of heart failure develop have the best chance of achieving an excellent 1-year survival with LVAD therapy.
Adenoassociated Virus–Mediated Prostacyclin Synthase Expression Prevents Pulmonary Arterial Hypertension in Rats
Authors: Ito Takayuki , Okada Takashi , Mimuro Jun , Miyashita Hiroshi , Uchibori Ryosuke , Urabe Masashi , Mizukami Hiroaki , Kume Akihiro , Takahashi Masafumi , Ikeda Uichi , Sakata Yoichi , Shimada Kazuyuki , Ozawa Keiya
Published: July 2007

Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway of prostacyclin production. The therapeutic option of intravenous prostacyclin infusion in patients with pulmonary arterial hypertension is limited by the short half-life of the drug and life-threatening catheter-related complications. To develop a better delivery system for prostacyclin, we examined the feasibility of intramuscular injection of an adenoassociated virus (AAV) vector expressing PGIS for preventing monocrotaline-induced pulmonary arterial hypertension in rats. We developed an AAV serotype 1–based vector carrying a human PGIS gene (AAV-PGIS). AAV-PGIS or the control AAV vector expressing enhanced green fluorescent protein was injected into the anterior tibial muscles of 3-week–old male Wistar rats; this was followed by the monocrotaline administration at 7 weeks. Eight weeks after injecting the vector, the plasma levels of 6-keto-prostaglandin F
1α
increased in a vector dose-dependent manner. At this time point, the PGIS transduction (1×10
10
genome copies per body) significantly decreased mean pulmonary arterial pressure (33.9±2.4 versus 46.1±3.0 mm Hg;
P
<0.05), pulmonary vascular resistance (0.26±0.03 versus 0.41±0.03 mm Hg · mL
−1
· min
−1
· kg
−1
;
P
<0.05), and medial thickness of the peripheral pulmonary artery (14.6±1.5% versus 23.5±0.5%;
P
<0.01) as compared with the controls. Furthermore, the PGIS-transduced rats demonstrated significantly improved survival rates as compared with the controls (100% versus 50%;
P
<0.05) at 8 weeks postmonocrotaline administration. An intramuscular injection of AAV-PGIS prevents monocrotaline-pulmonary arterial hypertension in rats and provides a new therapeutic alternative for preventing pulmonary arterial hypertension in humans.
Role of Renal Cortical Neovascularization in Experimental Hypercholesterolemia
Authors: Chade Alejandro R. , Krier James D. , Galili Offer , Lerman Amir , Lerman Lilach O.
Published: July 2007

Hypercholesterolemia induces renal inflammation and neovascularization, associated with renal endothelial dysfunction and injury. Neovascularization might conceivably represent a defense mechanism to sustain renal perfusion. Therefore, the present study was designed to test the hypothesis that preventing neovascularization using thalidomide, a potent anti-inflammatory and antiangiogenic agent, would impair basal renal hemodynamics in experimental hypercholesterolemia. Single-kidney function and hemodynamic responses to endothelium-dependent challenge were assessed in pigs after 12 weeks of hypercholesterolemia, hypercholesterolemia chronically supplemented with thalidomide (4 mg/kg per day), and normal controls. Renal microvascular architecture was then studied ex vivo using 3D microcomputed tomography imaging and inflammation, angiogenesis, and oxidative stress explored in renal tissue. The density of larger microvessels (200 to 500 μm) was selectively decreased in hypercholesterolemia plus thalidomide and accompanied by a decreased fraction of angiogenic, integrin β
3
-positive microvessels (9.9%±0.9% versus 25.5%±1.7%;
P
<0.05 versus hypercholesterolemia), implying decreased angiogenic activity. Furthermore, thalidomide increased renal expression of endothelial NO synthase and decreased tumor necrosis factor-α and renal inflammation but did not decrease oxidative stress. Thalidomide also decreased basal renal blood flow and glomerular filtration rate but normalized the blunted renal hemodynamic responses in hypercholesterolemia. Attenuated inflammation and pathological angiogenesis achieved in hypercholesterolemia by thalidomide are accompanied by restoration of renovascular endothelial function but decreased basal renal hemodynamics. This study, therefore, suggests that neovascularization in the hypercholesterolemic kidney is a compensatory mechanism that sustains basal renal vascular function.
Pitfalls in the Diagnosis of Immune Thrombocytopenic Purpura in Children: 4 Case Reports
Authors: Biner Betül , Devecioğlu Ömer , Demir Muzaffer
Published: July 2007

Acute idiopathic thrombocytopenic purpura is the most common cause of thrombocytopenia in childhood, and diagnosis of idiopathic thrombocytopenic purpura is made clinically based on the exclusion of other causes of thrombocytopenia. Patients with diverse causes of thrombocytopenia are sometimes erroneously diagnosed as having idiopathic thrombocytopenic purpura. However, for the prevention of misdiagnoses, careful inspection of peripheral blood smear is of utmost importance. This report presents 4 cases presumed as acute idiopathic thrombocytopenic purpura that were finally identified as pseudothrombocytopenia, inherited macrothrombocytopenia (MHY9 disorders) possibly Epstein syndrome, Bernard-Soulier syndrome, and drug-induced thrombocytopenia. They draw attention to the importance of platelet morphology to exclude inherited macrothrombocytopenia and history to exclude drug-induced thrombocytopenia. Better diagnostic approaches would be possible by the awareness of these relatively rare causes of isolated thrombocytopenia.
Ph+/VE-cadherin+ identifies a stem cell–like population of acute lymphoblastic leukemia sustained by bone marrow niche cells
Authors: Wang Lin , O'Leary Heather , Fortney James , Gibson Laura F.
Published: July 2007

Although leukemic stem cells (LSCs) show a symbiotic relationship with bone marrow microenvironmental niches, the mechanism by which the marrow microenvironment contributes to self-renewal and proliferation of LSCs remains elusive. In the present study, we identified a unique subpopulation of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) cells coexpressing markers of endothelial cells (including VE-cadherin, PECAM-1, and Flk-1) and committed B-lineage progenitors. After long-term coculture with bone marrow stromal cells, tumor cells formed hematopoietic colonies and cords, expressed early stem- cell markers, and showed endothelial sprouting. Gene expression profiles of LSCs were altered in the presence of stromal cell contact. Stromal cell contact promoted leukemic cell VE-cadherin expression, stabilized β-catenin, and up-regulated Bcr-abl fusion gene expression. Our study indicates that these specific tumor cells are uniquely positioned to respond to microenvironment-derived self-renewing and proliferative cues. Ph+/VE-cadherin+ tumor subpopulation circumvents the requirement of exogenous Wnt signaling for self-renewal through stromal cell support of leukemic cell VE-cadherin expression and up-regulated Bcr-abl tyrosine kinase activity. These data suggest that strategies targeting signals in the marrow microenvironment that amplify the Bcr-abl/VE-cadherin/β-catenin axis may have utility in sensitizing drug-resistant leukemic stem cells.
Cotransplantation of ex vivo–expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation
Authors: Ball Lynne M. , Bernardo Maria Ester , Roelofs Helene , Lankester Arjan , Cometa Angela , Egeler R. Maarten , Locatelli Franco , Fibbe Willem E.
Published: July 2007

Haploidentical hematopoietic stem-cell transplantation (HSCT) is associated with an increased risk of graft failure. Adult bone marrow–derived mesenchymal stromal cells (MSCs) have been shown to support in vivo normal hematopoiesis and to display potent immune suppressive effects. We cotransplanted donor MSCs in 14 children undergoing transplantation of HLA-disparate CD34+ cells from a relative. While we observed a graft failure rate of 15% in 47 historic controls, all patients given MSCs showed sustained hematopoietic engraftment without any adverse reaction. In particular, children given MSCs did not experience more infections compared with controls. These data suggest that MSCs, possibly thanks to their potent immunosuppressive effect on alloreactive host T lymphocytes escaping the preparative regimen, reduce the risk of graft failure in haploidentical HSC transplant recipients.
The Laminin 511/521–binding site on the Lutheran blood group glycoprotein is located at the flexible junction of Ig domains 2 and 3
Authors: Mankelow Tosti J. , Burton Nicholas , Stefansdottir Fanney O. , Spring Frances A. , Parsons Stephen F. , Pedersen Jan S. , Oliveira Cristiano L. P. , Lammie Donna , Wess Timothy , Mohandas Narla , Chasis Joel Anne , Brady R. Leo , Anstee David J.
Published: July 2007

The Lutheran blood group glycoprotein, first discovered on erythrocytes, is widely expressed in human tissues. It is a ligand for the α5 subunit of Laminin 511/521, an extracellular matrix protein. This interaction may contribute to vaso-occlusive events that are an important cause of morbidity in sickle cell disease. Using x-ray crystallography, small-angle x-ray scattering, and site-directed mutagenesis, we show that the extracellular region of Lutheran forms an extended structure with a distinctive bend between the second and third immunoglobulin-like domains. The linker between domains 2 and 3 appears to be flexible and is a critical determinant in maintaining an overall conformation for Lutheran that is capable of binding to Laminin. Mutagenesis studies indicate that Asp312 of Lutheran and the surrounding cluster of negatively charged residues in this linker region form the Laminin-binding site. Unusually, receptor binding is therefore not a function of the domains expected to be furthermost from the plasma membrane. These studies imply that structural flexibility of Lutheran may be essential for its interaction with Laminin and present a novel opportunity for the development of therapeutics for sickle cell disease.
Whole genome expression profiling reveals a significant role for immune function in human abdominal aortic aneurysms
Authors: Lenk Guy M , Tromp Gerard , Weinsheimer Shantel , Gatalica Zoran , Berguer Ramon , Kuivaniemi Helena
Published: July 2007

Background

Abdominal aortic aneurysms are a common disorder with an incompletely understood etiology. We used Illumina and Affymetrix microarray platforms to generate global gene expression profiles for both aneurysmal (AAA) and non-aneurysmal abdominal aorta, and identified genes that were significantly differentially expressed between cases and controls.

Results

Affymetrix and Illumina arrays included 18,057 genes in common; 11,542 (64%) of these genes were considered to be expressed in either aneurysmal or normal abdominal aorta. There were 3,274 differentially expressed genes with a false discovery rate (FDR) ≤ 0.05. Many of these genes were not previously known to be involved in AAA, includingSOSTandRUNX3, which were confirmed using Q-RT-PCR (Pearson correlation coefficient for microarray and Q-RT-PCR data = 0.89; p-values for differences in expression between AAA and controls forSOST: 4.87 × 10-4and forRUNX3: 4.33 × 10-5). Analysis of biological pathways, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), indicated extreme overrepresentation of immune related categories. The enriched categories included the GO category Immune Response (GO:0006955; FDR = 2.1 × 10-14), and the KEGG pathwaysnatural killer cell mediated cytotoxicity(hsa04650; FDR = 5.9 × 10-6) andleukocyte transendothelial migration(hsa04670; FDR = 1.1 × 10-5).

Conclusion

Previous studies have provided evidence for the involvement of the immune system in AAA. The current expression analysis extends these findings by demonstrating broad coordinate gene expression in immunological pathways. A large number of genes involved in immune function were differentially expressed in AAA, and the pathway analysis gave these results a biological context. The data provide valuable insight for future studies to dissect the pathogenesis of human AAA. These pathways might also be used as targets for the development of therapeutic agents for AAA.
The distribution of sexually-transmitted Human Papillomaviruses in HIV positive and negative patients in Zambia, Africa
Authors: Ng'andwe Christopher , Lowe John J , Richards Paula J , Hause Lara , Wood Charles , Angeletti Peter C
Published: July 2007

Background

Human Papillomaviruses (HPV) are double-stranded DNA viruses, considered to be the primary etiological agents in cervical intraepithelial neoplasias and cancers. Approximately 15–20 of the 40 mucosal HPVs confer a high-risk of progression of lesions to invasive cancer. In this study, we investigated the prevalence of sexually transmitted HPVs in Human Immunodeficiency Virus (HIV) positive and negative patients in Zambia, Africa. The rate of high-risk HPV genotypes worldwide varies within each country. Thus, we sought to investigate the rates of HPV infection in sub-Saharan Africa and the potential role of HIV in affecting the HPV genotype distribution.

Methods

This retrospective cross-sectional study reports findings on the association and effects of HIV on HPV infections in an existing cohort of patients at University Teaching Hospital (UTH) Lusaka, Zambia. The objective of this study was to assess HPV prevalence, genotype distribution and to identify co-factors that influence HPV infection. Polymerase chain reaction (PCR) with two standard consensus primer sets (CpI/II and GP5+/6+) was used to test for the presence of HPV DNA. Primers specific for β-actin were used to monitor DNA quality. Vaginal lavage samples, collected between 1998-1999 from a total of 70 women, were part of a larger cohort that was also analyzed for HIV and human herpesvirus infection. Seventy of the samples yielded usable DNA. HIV status was determined by two rapid assays, Capillus and Determine. The incidence of HIV and HPV infections and HPV genotype distributions were calculated and statistical significance was determined by Chi-Squared test.

Results

We determined that most common HPV genotypes detected among these Zambian patients were types 16 and 18 (21.6% each), which is approximately three-fold greater than the rates for HPV16, and ten-fold greater than the rates for HPV18 in the United States. The worldwide prevalence of HPV16 is approximately 14% and HPV18 is 5%. The overall ratio of high-risk (HR) to low-risk (LR) HPVs in the patient cohort was 69% and 31% respectively; essentially identical to that for the HR and LR distributions worldwide. However, we discovered that HIV positive patients were two-times as likely to have an HR HPV as HIV negative individuals, while the distribution of LR HPVs was unaffected by HIV status. Interestingly, we observed a nine-fold increase in HPV18 infection frequency in HIV positive versus HIV negative individuals.

Conclusion

The rate of oncogenic HPVs (type 16 and 18) in Zambia was much higher than in the U.S., potentially providing an explanation for the high-rates of cervical cancer in Zambia. Surprisingly, we discovered a strong association between positive HIV status and the prevalence of HR HPVs, and specifically HPV18.
RF tumor ablation with internally cooled electrodes and saline infusion: what is the optimal location of the saline infusion?
Authors: Burdío Fernando , Berjano Enrique J , Navarro Ana , Burdío José M , Güemes Antonio , Grande Luis , Sousa Ramón , Subiró Jorge , Gonzalez Ana , Cruz Ignacio , Castiella Tomás , Tejero Eloy , Lozano Ricardo , de Gregorio Miguel A
Published: July 2007

Background

Radiofrequency ablation (RFA) of tumors by means of internally cooled electrodes (ICE) combined with interstitial infusion of saline may improve clinical results. To date, infusion has been conducted through outlets placed on the surface of the cooled electrode. However, the effect of infusion at a distance from the electrode surface is unknown. Our aim was to assess the effect of perfusion distance (PD) on the coagulation geometry and deposited power during RFA using ICE.

Methods

Experiments were performed on excised bovine livers. Perfusion distance (PD) was defined as the shortest distance between the infusion outlet and the surface of the ICE. We considered three values of PD: 0, 2 and 4 mm. Two sets of experiments were considered: 1) 15 ablations of 10 minutes (n ≥ 4 for each PD), in order to evaluate the effect of PD on volume and diameters of coagulation; and 2) 20 additional ablations of 20 minutes. The effect of PD on deposited power and relative frequency of uncontrolled impedance rises (roll-off) was evaluated using the results from the two sets of experiments (n ≥ 7 for each PD). Comparisons between PD were performed by analysis of variance or Kruskal-Wallis test. Additionally, non-linear regression models were performed to elucidate the best PD in terms of coagulation volume and diameter, and the occurrence of uncontrolled impedance rises.

Results

The best-fit least square functions were always obtained with quadratic curves where volume and diameters of coagulation were maximum for a PD of 2 mm. A thirty per cent increase in volume coagulation was observed for this PD value compared to other values (P < 0.05). Likewise, the short coagulation diameter was nearly twenty five per cent larger for a 2 mm PD than for 0 mm. Regarding deposited power, the best-fit least square function was obtained by a quadratic curve with a 2 mm PD peak. This matched well with the higher relative frequency of uncontrolled impedance rises for PD of 0 and 4 mm.

Conclusion

Saline perfusion at around 2 mm from the electrode surface while using an ICE in RFA improves deposition of energy and enlarges coagulation volume.