bluuebunny/crossref_metadata_2025_split huggingface dataset:
CALCULUS ON FRACTAL SUBSETS OF REAL LINE — I: FORMULATION
Authors: PARVATE ABHAY , GANGAL A. D. 
Published: January 2009

A new calculus based on fractal subsets of the real line is formulated. In this calculus, an integral of order α, 0 < α ≤ 1, called Fα-integral, is defined, which is suitable to integrate functions with fractal support F of dimension α. Further, a derivative of order α, 0 < α ≤ 1, called Fα-derivative, is defined, which enables us to differentiate functions, like the Cantor staircase, "changing" only on a fractal set. The Fα-derivative is local unlike the classical fractional derivative. The Fα-calculus retains much of the simplicity of ordinary calculus. Several results including analogues of fundamental theorems of calculus are proved. The integral staircase function, which is a generalization of the functions like the Cantor staircase function, plays a key role in this formulation. Further, it gives rise to a new definition of dimension, the γ-dimension. Spaces of Fα-differentiable and Fα-integrable functions are analyzed. Analogues of Sobolev Spaces are constructed on F and Fα-differentiability is generalized using Sobolev-like construction. Fα-differential equations are equations involving Fα-derivatives. They can be used to model sublinear dynamical systems and fractal time processes, since sublinear behaviors are associated with staircase-like functions which occur naturally as their solutions. As examples, we discuss a fractal-time diffusion equation, and one-dimensional motion of a particle undergoing friction in a fractal medium.
Melanoma Antigen-11 Inhibits the Hypoxia-Inducible Factor Prolyl Hydroxylase 2 and Activates Hypoxic Response
Authors: Aprelikova Olga , Pandolfi Silvia , Tackett Sean , Ferreira Mark , Salnikow Konstantin , Ward Yvona , Risinger John I. , Barrett J. Carl , Niederhuber John 
Published: January 2009

Abstract
Activation of hypoxia-inducible factors (HIF), responsible for tumor angiogenesis and glycolytic switch, is regulated by reduced oxygen availability. Normally, HIF-α proteins are maintained at low levels, controlled by site-specific hydroxylation carried out by HIF prolyl hydroxylases (PHD) and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitin ligase. Using a yeast two-hybrid screen, we identified an interaction between melanoma antigen-11 (MAGE-11) cancer-testis antigen and the major HIF-α hydroxylating enzyme PHD2. The interaction was confirmed by a pull-down assay, coimmunoprecipitation, and colocalization in both normoxic and hypoxic conditions. Furthermore, MAGE-9, the closest homologue of MAGE-11, was also found to interact with PHD2. MAGE-11 inhibited PHD activity without affecting protein levels. This inhibition was accompanied by stabilization of ectopic or endogenous HIF-1α protein. Knockdown of MAGE-11 by small interfering RNA results in decreased hypoxic induction of HIF-1α and its target genes. Inhibition of PHD by MAGE-11, and following activation of HIFs, is a novel tumor-associated HIF regulatory mechanism. This finding provides new insights into the significance of MAGE expression in tumors and may provide valuable tools for therapeutic intervention because of the restricted expression of the MAGE gene family in cancers, but not in normal tissues. [Cancer Res 2009;69(2):616–24]
Identification of Nuclear Export Inhibitors with Potent Anticancer Activity In vivo
Authors: Mutka Sarah C. , Yang Wen Qing , Dong Steven D. , Ward Shannon L. , Craig Darren A. , Timmermans Pieter B.M.W.M. , Murli Sumati 
Published: January 2009

Abstract
The export protein CRM1 is required for the nuclear export of a wide variety of cancer-related “cargo” proteins including p53, c-Abl, and FOXO-3A. Leptomycin B (LMB) is a highly specific inhibitor of CRM1 with significant in vitro potency but limited in vivo efficacy due to toxicity. We now report a series of semisynthetic LMB derivatives showing substantially improved therapeutic windows. Exposure of cancer cells to these compounds leads to a rapid and prolonged block of nuclear export and apoptosis. In contrast to what is observed in cancer cells, these agents induce cell cycle arrest, but not apoptosis, in normal lung fibroblasts. These new nuclear export inhibitors (NEI) maintain the high potency of LMB, are up to 16-fold better tolerated than LMB in vivo, and show significant efficacy in multiple mouse xenograft models. These NEIs show the potential of CRM1 inhibitors as novel and potent anticancer agents. [Cancer Res 2009;69(2):510–7]
Reversal of P-glycoprotein–Mediated Multidrug Resistance by the Murine Double Minute 2 Antagonist Nutlin-3
Authors: Michaelis Martin , Rothweiler Florian , Klassert Denise , von Deimling Andreas , Weber Kristoffer , Fehse Boris , Kammerer Bernd , Doerr Hans Wilhelm , Cinatl Jindrich 
Published: January 2009

Abstract
Murine double minute 2 (MDM2) negatively regulates the activity of the tumor suppressor protein p53. Nutlin-3 is a MDM2 inhibitor under preclinical investigation as nongenotoxic activator of the p53 pathway for cancer therapy. Here, nutlin-3 was evaluated for its activity alone or in combination with established chemotherapeutic drugs for antitumor action in chemosensitive and chemoresistant neuroblastoma and rhabdomyosarcoma cell lines. Effects of nutlin-3 single treatment were much more pronounced in p53 wild-type cell lines (IC50s &lt;3 μmol/L) than in p53-mutated cell lines (IC50s &gt;17 μmol/L). In sharp contrast to the expectations, nutlin-3 concentrations that did not affect viability of p53-mutated cell lines strongly increased the efficacy of vincristine in p53-mutated, P-glycoprotein (P-gp)–overexpressing cell lines (decrease in IC50s 92- to 3,434-fold). Similar results were obtained for other P-gp substrates. Moreover, nutlin-3 reduced efflux of rhodamine 123 and other fluorescence dyes that are effluxed by P-gp. Investigation of Madin-Darby canine kidney (MDCK) II cells stably transfected with plasmids encoding for P-gp (MDCKII MDR1) or multidrug resistance protein 1 (MRP-1, MDCKII MRP1) revealed that nutlin-3 not only interferes with P-gp but also affects MRP-1–mediated efflux. Kinetic studies and investigation of P-gp-ATPase activity showed that nutlin-3 is likely to act as a P-gp transport substrate. Examination of the nutlin-3 enantiomers nutlin-3a and nutlin-3b revealed that, in contrast to MDM2-inhibitory activity that is limited to nutlin-3a, both enantiomers similarly interfere with P-gp–mediated drug efflux. In conclusion, nutlin-3–induced inhibition of P-gp and MRP-1 was discovered as a novel anticancer mechanism of the substance in this report. [Cancer Res 2009;69(2):416–21]
Genome-Wide Linkage Analysis of TMPRSS2-ERG Fusion in Familial Prostate Cancer
Authors: Hofer Matthias D. , Kuefer Rainer , Maier Christiane , Herkommer Kathleen , Perner Sven , Demichelis Francesca , Paiss Thomas , Vogel Walter , Rubin Mark A. , Hoegel Josef 
Published: January 2009

Abstract
Fusion of the 5′-untranslated region of androgen-regulated TMPRSS2 promoter with ETS transcription factor family members is found frequently in prostate cancers, and recent work suggests that the most common TMPRSS2-ERG fusion is associated with an aggressive clinical phenotype compared with fusion-negative prostate cancer. Thus far, analysis of the fusion has been limited to sporadic cases of prostate cancer. In the current study, we explore for an enrichment of TMPRSS2-ERG fusion in familial prostate cancer. TMPRSS2-ERG fusion was identified using a break-apart fluorescence in situ hybridization assay on tissue microarrays. Presence of TMPRSS2-ERG fusion was associated with higher Gleason scores (P = 0.027). Of 75 patients with established history of prostate cancer, we detected the TMPRSS2-ERG fusion in 44 (59%) patients. Almost three quarters (73%) of fusion-positive patients accumulated within 16 specific families whereas only 27% were single fusion-positive cases within one family. Based on reported prevalence rates, we calculated a sibling recurrence risk ratio of up to 18.9. A subset (63%) of families with uniformly TMPRSS2-ERG–positive prostate cancer underwent a genome-wide linkage scan at 500 markers. This revealed several loci located on chromosomes #9, #18, and X that were suggestive of linkage to the TMPRSS2-ERG fusion-positive prostate cancer phenotype with linkage-of-disease scores up to 2.16 and nonparametric linkage scores up to 2.77. This suggests the presence of an inherited susceptibility to developing the TMPRSS2-ERG fusion. Given the association of TMPRSS2-ERG fusion and aggressive prostate cancer, close surveillance of relatives of patients with established fusion-positive prostate cancer or a family history of prostate cancer in general would be warranted. [Cancer Res 2009;69(4):640–6]
Thyroid Hormone Receptor β1 Acts as a Potent Suppressor of Tumor Invasiveness and Metastasis
Authors: Martínez-Iglesias Olaia , Garcia-Silva Susana , Tenbaum Stephan P. , Regadera Javier , Larcher Fernando , Paramio Jesus M. , Vennström Bjorn , Aranda Ana 
Published: January 2009

Abstract
Loss of thyroid hormone receptors (TR) is a common feature in some tumors, although their role in tumor progression is currently unknown. We show here that expression of TRβ1 in hepatocarcinoma and breast cancer cells reduces tumor growth, causes partial mesenchymal-to-epithelial cell transition, and has a striking inhibitory effect on invasiveness, extravasation, and metastasis formation in mice. In cultured cells, TRβ1 abolishes anchorage-independent growth and migration, blocks responses to epidermal growth factor, insulin-like growth factor-I, and transforming growth factor β, and regulates expression of genes that play a key role in tumorigenicity and metastatic growth. The receptor disrupts the mitogenic action of growth factors by suppressing activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling pathways that are crucial for cell proliferation and invasiveness. Furthermore, increased aggressiveness of skin tumors is found in genetically modified mice lacking TRs, further demonstrating the role of these receptors as inhibitors of tumor progression. These results define a novel role for the thyroid hormone receptor as a metastasis suppressor gene, providing a starting point for the development of novel therapeutic strategies for the treatment of human cancer. [Cancer Res 2009;69(2):501–9]
Inhibition of Peroxisome Proliferator-Activated Receptor γ Increases Estrogen Receptor–Dependent Tumor Specification
Authors: Yin Yuzhi , Yuan Hongyan , Zeng Xiao , Kopelovich Levy , Glazer Robert I. 
Published: January 2009

Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that regulates gene transcription associated with intermediary metabolism, adipocyte differentiation, and tumor suppression and proliferation. To understand the role of PPARγ in tumorigenesis, transgenic mice were generated with mammary gland–directed expression of the dominant-negative transgene Pax8PPARγ. Transgenic mice were phenotypically indistinguishable from wild-type (WT) mice, but mammary epithelial cells expressed a greater percentage of CD29hi/CD24neg, CK5+, and double-positive CK14/CK18 cells. These changes correlated with reduced PTEN and increased Ras and extracellular signal-regulated kinase (ERK) and AKT activation. Although spontaneous tumorigenesis did not occur, transgenic animals were highly susceptible to progestin/7,12-dimethylbenz(a)anthracene–induced mammary carcinogenesis, which in contrast to WT mice resulted in a high tumor multiplicity and, most importantly, in the appearance of predominantly estrogen receptor α–positive (ER+) ductal adenocarcinomas. Tumors expressed a similar PTENlo/pERKhi/pAKThi phenotype as mammary epithelium and exhibited high activation of estrogen response element–dependent reporter gene activity. Tumorigenesis in MMTV-Pax8PPARγ mice was insensitive to the chemopreventive effect of a PPARγ agonist but was profoundly inhibited by the ER antagonist fulvestrant. These results reveal important new insights into the previously unrecognized role of PPARγ in the specification of mammary lineage and the development of ER+ tumors. [Cancer Res 2009;69(2):687–94]
Morelloflavone, a Biflavonoid, Inhibits Tumor Angiogenesis by Targeting Rho GTPases and Extracellular Signal-Regulated Kinase Signaling Pathways
Authors: Pang Xiufeng , Yi Tingfang , Yi Zhengfang , Cho Sung Gook , Qu Weijing , Pinkaew Decha , Fujise Ken , Liu Mingyao 
Published: January 2009

Abstract
Morelloflavone, a biflavonoid extracted from Garcinia dulcis, has shown antioxidative, antiviral, and anti-inflammatory properties. However, the function and the mechanism of this compound in cancer treatment and tumor angiogenesis have not been elucidated to date. In this study, we postulated that morelloflavone might have the ability to inhibit angiogenesis, the pivotal step in tumor growth, invasiveness, and metastasis. We showed that morelloflavone could inhibit vascular endothelial growth factor (VEGF)–induced cell proliferation, migration, invasion, and capillary-like tube formation of primary cultured human umbilical vascular endothelial cells in a dose-dependent manner. Morelloflavone effectively inhibited microvessel sprouting of endothelial cells in the mouse aortic ring assay and the formation of new blood microvessels induced by VEGF in the mouse Matrigel plug assay. Furthermore, morelloflavone inhibited tumor growth and tumor angiogenesis of prostate cancer cells (PC-3) in xenograft mouse tumor model in vivo, suggesting that morelloflavone inhibited tumorigenesis by targeting angiogenesis. To understand the underlying mechanism of morelloflavone on the inhibitory effect of tumor growth and angiogenesis, we showed that morelloflavone could inhibit the activation of both RhoA and Rac1 GTPases but have little effect on the activation of Cdc42 GTPase. Additionally, morelloflavone inhibited the phosphorylation and activation of Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase/ERK pathway kinases without affecting VEGF receptor 2 activity. Together, our results indicate that morelloflavone exerts antiangiogenic action by targeting the activation of Rho-GTPases and ERK signaling pathways. These findings are the first to reveal the novel functions of morelloflavone in tumor angiogenesis and its molecular basis for the anticancer action. [Cancer Res 2009;69(2):518–25]
Glycosaminoglycans as Potential Regulators of Osteoprotegerin Therapeutic Activity in Osteosarcoma
Authors: Lamoureux Francois , Picarda Gaëlle , Garrigue-Antar Laure , Baud'huin Marc , Trichet Valerie , Vidal André , Miot-Noirault Elisabeth , Pitard Bruno , Heymann Dominique , Rédini Françoise 
Published: January 2009

AbstractOsteosarcoma is the most frequent primary bone malignant tumor that develops mainly in children and adolescents. Despite recent improvements in chemotherapy and surgery, survival rate is ∼50% after 5 years. Osteoprotegerin (OPG) is a potent inhibitor of osteoclast differentiation and activation, but its use as therapeutic agent in cancer-associated osteolysis remains controversial due to its ability to bind and inhibit the apoptotic effect of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) on tumor cells. The therapeutic effects of full-length OPG (1-401) and OPG 1-194 lacking its heparin-binding domain delivered by nonviral gene therapy were compared in a murine model of osteolytic osteosarcoma. Tumor incidence, progression, and associated bone lesions were significantly diminished in the OPG 1-194 group, but not in the OPG 1-401 group, compared with controls. As receptor activator of nuclear factor-κB ligand (RANKL), TRAIL, and glycosaminoglycans (GAG) were shown to be overexpressed in osteosarcoma environment compared with control tissue, OPG 1-401 bioactivity may be modulated by one of these protagonists. Surface plasmon resonance analyses performed with OPG, TRAIL, and GAGs revealed that TRAIL binds both forms of OPG with the same affinity. In addition, as OPG 1-194 and OPG 1-401 similarly inhibit TRAIL-induced apoptosis, it suggests that TRAIL is not involved in the modulation of OPG bioactivity. However, as GAGs inhibit OPG 1-401 but not OPG 1-194 binding to TRAIL or to RANKL, they may represent potent regulators of OPG availability and antitumor activity in bone tumor microenvironment. [Cancer Res 2009;69(2):526–36]
Transforming Growth Factor β Induces Clustering of HER2 and Integrins by Activating Src-Focal Adhesion Kinase and Receptor Association to the Cytoskeleton
Authors: Wang Shizhen Emily , Xiang Bin , Zent Roy , Quaranta Vito , Pozzi Ambra , Arteaga Carlos L. 
Published: January 2009

Abstract
It has been proposed that cross talk between integrin and growth factor receptor signaling such as ErbB2 (HER2) is required for activation of downstream effectors and ErbB2-mediated mammary tumorigenesis. Here we show that transforming growth factor β (TGF-β) induced focal adhesion kinase (FAK)–dependent clustering of HER2 and integrins α6, β1, and β4 in HER2-overexpressing mammary epithelial cells without altering the total and surface levels of HER2 receptors. This effect was mediated by ligand-induced epidermal growth factor receptor (EGFR) activation and the subsequent phosphorylation of Src and FAK. We have previously reported that TGF-β up-regulates EGFR ligand shedding through a mechanism involving the phosphorylation of tumor necrosis factor-α–converting enzyme (TACE/ADAM17). Knockdown of TACE, FAK, or integrin α6 by siRNA or inhibition of EGFR or Src by specific inhibitors abrogated TGF-β–induced receptor clustering and signaling to phosphatidylinositol 3-kinase-Akt. Finally, inhibition of Src-FAK reversed TGF-β–induced resistance to the therapeutic HER2 inhibitor trastuzumab in HER2-overexpressing breast cancer cells. Taken together, these data suggest that, by activating Src-FAK, TGF-β integrates ErbB receptor and integrin signaling to induce cell migration and survival during breast cancer progression. [Cancer Res 2009;69(2):475–82]
Pretreatment with Statin Attenuates the Cardiotoxicity of Doxorubicin in Mice
Authors: Riad Alexander , Bien Sandra , Westermann Dirk , Becher Peter M. , Loya Komal , Landmesser Ulf , Kroemer Heyo K. , Schultheiss Heinz P. , Tschöpe Carsten 
Published: January 2009

Abstract
Cardiotoxicity, which may result from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anticancer therapy using doxorubicin. Because statins might exert beneficial pleiotropic cardiovascular effects, among other things, by anti-inflammatory and antioxidative mechanisms, we investigated whether or not fluvastatin pretreatment can attenuate doxorubicin-induced cardiotoxicity. Five days after a single injection of doxorubicin (20 mg/kg; i.p.), left ventricular (LV) function was measured in fluvastatin-treated (DoxStatin; 100 mg/kg/day, p.o.) and saline-treated (doxorubicin) mice (n = 8 per group) by a micro conductance catheter. Untreated mice served as controls (placebo; n = 8 per group). After measurement of cardiac function, LV tissues were analyzed by molecular biological and immunohistologic methods. Injection resulted in significantly impaired LV function (LV pressure, −29%; dp/dtmax, −45%; cardiac output, −68%; P &lt; 0.05) when compared with placebo. This was associated with a significant increase in cardiac oxidative stress, inflammation and apoptotic mechanisms, as indicated by significant increased cardiac lipid peroxidation activity, protein expression of nitrotyrosine, tumor necrosis factor α and Bax (P &lt; 0.05). In contrast, DoxStatin mice showed improved LV function (LV pressure, +24%; dp/dtmax, +87%; cardiac output, +87%; P &lt; 0.05) when compared with untreated doxorubicin mice. This was associated with reduced cardiac expression of nitrotyrosine, enhanced expression of the mitochondrial located antioxidative SOD 2, attenuated mitochondrial apoptotic pathways, and reduced cardiac inflammatory response. Statin pretreatment attenuates doxorubicin-induced cardiotoxicity via antioxidative and anti-inflammatory effects. [Cancer Res 2009;69(2):695–9]
Mammary Epithelial-Specific Ablation of the Focal Adhesion Kinase Suppresses Mammary Tumorigenesis by Affecting Mammary Cancer Stem/Progenitor Cells
Authors: Luo Ming , Fan Huaping , Nagy Tamas , Wei Huijun , Wang Chenran , Liu Suling , Wicha Max S. , Guan Jun-Lin 
Published: January 2009

Abstract
Focal adhesion kinase (FAK) has been implicated in the development of cancers, including those of the breast. Nevertheless, the molecular and cellular mechanisms by which FAK promotes mammary tumorigenesis in vivo are not well understood. Here, we show that targeted deletion of FAK in mouse mammary epithelium significantly suppresses mammary tumorigenesis in a well-characterized breast cancer model. Ablation of FAK leads to the depletion of a subset of bipotent cells in the tumor that express both luminal marker keratin 8/18 and basal marker keratin 5. Using mammary stem/progenitor markers, including aldehyde dehydrogenase, CD24, CD29, and CD61, we further revealed that ablation of FAK reduced the pool of cancer stem/progenitor cells in primary tumors of FAK-targeted mice and impaired their self-renewal and migration in vitro. Finally, through transplantation in NOD-SCID mice, we found that cancer stem/progenitor cells isolated from FAK-targeted mice have compromised tumorigenicity and impaired maintenance in vivo. Together, these results show a novel function of FAK in maintaining the mammary cancer stem/progenitor cell population and provide a novel mechanism by which FAK may promote breast cancer development and progression. [Cancer Res 2009;69(2):466–74]
Combined Transductional Untargeting/Retargeting and Transcriptional Restriction Enhances Adenovirus Gene Targeting and Therapy for Hepatic Colorectal Cancer Tumors
Authors: Li Hua-Jung , Everts Maaike , Yamamoto Masato , Curiel David T. , Herschman Harvey R. 
Published: January 2009

Abstract
Unresectable hepatic colorectal cancer (CRC) metastases are a leading cause of cancer mortality. These tumors and other epithelial tumors often express both cyclooxygenase-2 (COX-2) and carcinoembryonic antigen (CEA). Because adenovirus (Ad) vectors infect the liver and lack tumor tropism, they cannot be used for systemic therapy of hepatic metastases. We used COX-2 transcriptional restriction, in combination with transductional Ad hepatic untargeting and tumor retargeting by a bispecific adapter, sCARhMFE, composed of sCAR [the coxsackie/Ad receptor (CAR) ectodomain] and MFE-23 (a single-chain anti-CEA antibody), to untarget liver after i.v. administration of Ad vectors expressing firefly luciferase and to retarget virus to hepatic colorectal tumor xenografts and non–small cell lung tumor xenografts. To improve both liver untargeting and tumor retargeting, we developed sCARfMFE, a trimerized sCARhMFE adapter. Trimerization greatly improves both untargeting of CAR-dependent Ad infection and CEA-dependent virus retargeting in culture and in vivo. Combining sCARfMFE bispecific adapter transductional liver untargeting and transductional tumor retargeting with COX-2 transcriptional tumor-restricted transgene expression increases systemically administered Ad therapeutic efficacy for hepatic CRC tumors, using herpes virus type 1 thymidine kinase (HSV1-tk) as a therapeutic gene in conjunction with the prodrug ganciclovir (GCV). Both transductional untargeting and COX-2 transcriptional restriction also reduce HSV1-tk/GCV hepatic toxicity. In addition, transductional sCARfMFE untargeting reduces the innate immune response to systemic Ad administration. Combined transductional liver Ad untargeting, transductional tumor retargeting, and transcriptional transgene restriction suggests a means to engineer practical, effective therapeutic agents for hepatic CRC metastases in particular, as well as hepatic metastases of other epithelial cancers. [Cancer Res 2009;69(2):554–64]