bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dissecting the Role of Matrix Metalloproteinases (MMP) and Integrin αvβ3 in AngiogenesisIn vitro: Absence of Hemopexin C Domain Bioactivity, but Membrane-Type 1-MMP and αvβ3 Are Critical
Authors: Nisato Riccardo E. , Hosseini Ghamartaj , Sirrenberg Christian , Butler Georgina S. , Crabbe Thomas , Docherty Andrew J.P. , Wiesner Matthias , Murphy Gillian , Overall Christopher M. , Goodman Simon L. , Pepper Michael S. 
Published: October 2005

AbstractMatrix metalloproteinase (MMP)-2 and its hemopexin C domain autolytic fragment (also called PEX) have been proposed to be crucial for angiogenesis. Here, we have investigated the dependency of in vitro angiogenesis on MMP-mediated extracellular proteolysis and integrin αvβ3–mediated cell adhesion in a three-dimensional collagen I model. The hydroxamate-based synthetic inhibitors BB94, CT1399, and CT1847 inhibited endothelial cell invasion, as did neutralizing anti–membrane-type 1-MMP (MT1-MMP) antibodies and tissue inhibitor of MMP (TIMP)-2 and TIMP-3 but not TIMP-1. This confirmed the pivotal importance of MT1-MMP over other MMPs in this model. Invasion was also inhibited by a nonpeptidic antagonist of integrin αvβ3, EMD 361276. Although PEX strongly inhibited pro-MMP-2 activation, when contaminating lipopolysaccharide was neutralized, PEX neither affected angiogenesis nor bound integrin αvβ3. Moreover, no specific binding of pro-MMP-2 to integrin αvβ3 was found, whereas only one out of four independently prepared enzymatically active MMP-2 preparations could bind integrin αvβ3, and this in a PEX-independent manner. Likewise, integrin αvβ3–expressing cells did not bind MMP-2-coated surfaces. Hence, these findings show that endothelial cell invasion of collagen I gels is MT1-MMP and αvβ3- dependent but MMP-2 independent and does not support a role for PEX in αvβ3 integrin binding or in modulating angiogenesis in this system.
Increases of Amphiregulin and Transforming Growth Factor-α in Serum as Predictors of Poor Response to Gefitinib among Patients with Advanced Non–Small Cell Lung Cancers
Authors: Ishikawa Nobuhisa , Daigo Yataro , Takano Atsushi , Taniwaki Masaya , Kato Tatsuya , Hayama Satoshi , Murakami Haruyasu , Takeshima Yukio , Inai Kouki , Nishimura Hitoshi , Tsuchiya Eiju , Kohno Nobuoki , Nakamura Yusuke 
Published: October 2005

AbstractSerum levels of amphiregulin and transforming growth factor-α (TGF-α), which were identified previously to be expressed at high levels in non–small cell lung cancer (NSCLC) with poor response to gefitinib, were examined by ELISA using blood samples taken from 50 patients with advanced NSCLCs. Of 14 cases that revealed above the cutoff line for amphiregulin in serum, 12 responded poorly to gefitinib, whereas 18 of the 36 cases showing below the cutoff revealed partial response (PR) or stable disease (SD; P = 0.026). Thirteen of 15 patients who were positive for TGF-α responded poorly to gefitinib, whereas 18 of the 35 patients with negative TGF-α levels turned out to be relatively good responders (P = 0.014). Of 22 patients with positive values for either or both markers, 19 were poor responders. On the other hand, among 28 patients negative for both markers, 17 were classified into the PR or SD groups (P = 0.001). Gefitinib-treated NSCLC patients whose serum amphiregulin or TGF-α was positive showed a poorer tumor-specific survival (P = 0.037 and 0.002, respectively, by univariate analysis) compared with those whose serum amphiregulin or TGF-α concentrations were negative. Multivariate analysis showed an independent association between positivity for TGF-α and shorter survival times among NSCLC patients treated with gefitinib (P = 0.034). Amphiregulin or TGF-α positivity in NSCLC tissues was significantly higher in male, nonadenocarcinomas, and smokers. Our data suggest that the status of amphiregulin and TGF-α in serum can be an important predictor of the resistance to gefitinib among patients with advanced NSCLC.
Low-Density Lipoprotein Receptor–Related Protein Contributes to the Antiangiogenic Activity of Thrombospondin-2 in a Murine Glioma Model
Authors: Fears Constance Y. , Grammer J. Robert , Stewart Jerry E. , Annis Douglas S. , Mosher Deane F. , Bornstein Paul , Gladson Candece L. 
Published: October 2005

Abstract
Host antiangiogenesis factors defend against tumor growth. The matricellular protein, thrombospondin-2 (TSP-2), has been shown to act as an antiangiogenesis factor in a carcinogen-induced model of skin cancer. Here, using an in vivo malignant glioma model in which the characteristics of the tumors formed after intracerebral implantation of GL261 mouse glioma cells are assessed, we found that tumor growth and microvessel density were significantly enhanced in tumors propagated in TSP-2−/− mice. Mechanistically, matrix metalloproteinase (MMP)-2 has been associated with neoangiogenesis and it has been proposed that the levels of available MMP-2 may be down-regulated by formation of a complex with TSP-2 that is internalized by low-density lipoprotein receptor–related protein 1 (LRP1). We found elevated expression of MMP-2 and MMP-9 in tumors propagated in TSP-2−/− mice, with a preferential localization in the microvasculature. In wild-type mice, MMP-2 was coexpressed with TSP-2 in the tumor microvasculature. In vitro, addition of recombinant (rec) TSP-2 to mouse brain microvessel endothelial cells reduced MMP-2 levels and invasion through mechanisms that could be inhibited by a competitive inhibitor of ligand binding to LRP1 or by siLRP1. Thus, the antiangiogenic activity of TSP-2 is capable of inhibiting the growth of gliomas in part by reducing the levels of MMP-2 in the tumor microvasculature. This mechanism is mediated by LRP1.
A Potential Synergistic Anticancer Effect of Paclitaxel and Amifostine on Endometrial Cancer
Authors: Dai Donghai , Holmes Anna M. , Nguyen Tan , Davies Suzy , Theele Daniel P. , Verschraegen Claire , Leslie Kimberly K. 
Published: October 2005

Abstract
Although paclitaxel is one of the most effective chemotherapeutic agents, its usefulness is still limited in advanced and recurrent endometrial cancer. Amifostine protection of normal tissues against the side effects of chemotherapeutic agents has been clinically proven in cancer patients; however, its application in endometrial cancer has not been fully evaluated. We have investigated the use of paclitaxel and amifostine in controlling the growth of poorly differentiated endometrial cancer cells, Hec50co, in vitro and in vivo. Our studies show that amifostine had direct anticancer effects on endometrial cancer cells in vitro by arresting the cell cycle at the G1 phase and inducing apoptosis. Amifostine also inhibited s.c. tumor growth in athymic mice. Paclitaxel IC50 value was reduced from 14 to 2 nmol/L with pretreatment of a single dose of 178 μmol/L of amifostine for 72 hours. Amifostine also synergized with paclitaxel in the arrest of the cell cycle at the G2-M phase and in the induction of apoptosis. This two-drug regimen inhibited s.c. tumor growth as well as improved mouse survival significantly more than paclitaxel alone. Amifostine also significantly improved paclitaxel-induced cytotoxic effects on peripheral blood profiles. Our studies show that amifostine has direct anticancer effects on endometrial cancer. Our data have also shown a potential anticancer synergy between amifostine and paclitaxel in vitro and in vivo, whereas amifostine maintained a protective role in peripheral blood profiles. The dual specificity of amifostine action should be further investigated.
Continuous MLL-ENL Expression Is Necessary to Establish a “Hox Code” and Maintain Immortalization of Hematopoietic Progenitor Cells
Authors: Horton Sarah J. , Grier David G. , McGonigle Glenda J. , Thompson Alexander , Morrow Michelle , De Silva Inusha , Moulding Dale A. , Kioussis Dimitris , Lappin Terence R.J. , Brady Hugh J.M. , Williams Owen 
Published: October 2005

Abstract
The t[(11;19)(p22;q23)] translocation, which gives rise to the MLL-ENL fusion protein, is commonly found in infant acute leukemias of both the myeloid and lymphoid lineage. To investigate the molecular mechanism of immortalization by MLL-ENL we established a Tet-regulatable system of MLL-ENL expression in primary hematopoietic progenitor cells. Immortalized myeloid cell lines were generated, which are dependent on continued MLL-ENL expression for their survival and proliferation. These cells either terminally differentiate or die when MLL-ENL expression is turned off with doxycycline. The expression profile of all 39 murine Hox genes was analyzed in these cells by real-time quantitative PCR. This analysis showed that loss of MLL-ENL was accompanied by a reduction in the expression of multiple Hoxa genes. By comparing these changes with Hox gene expression in cells induced to differentiate with granulocyte colony-stimulating factor, we show for the first time that reduced Hox gene expression is specific to loss of MLL-ENL and is not a consequence of differentiation. Our data also suggest that the Hox cofactor Meis-2 can substitute for Meis-1 function. Thus, MLL-ENL is required to initiate and maintain immortalization of myeloid progenitors and may contribute to leukemogenesis by aberrantly sustaining the expression of a “Hox code” consisting of Hoxa4 to Hoxa11.
Association between Large-scale Genomic Homozygosity without Chromosomal Loss and Nonseminomatous Germ Cell Tumor Development
Authors: Lu Yong-Jie , Yang Jinshu , Noel Elodie , Skoulakis Spyros , Chaplin Tracy , Raghavan Manoj , Purkis Trisha , Mcintyre Alan , Kudahetti Sakunthala C. , Naase Mahmoud , Berney Dan , Shipley Janet , Oliver R. Timothy D. , Young Bryan D. 
Published: October 2005

Abstract
The genotype of a tumor determines its biology and clinical behavior. The genetic alterations associated with the unique embryonal morphology of nonseminomatous subtypes of testicular germ cell tumors remain to be established. Using single nucleotide polymorphism microarray analysis, we found in all of the 15 nonseminomas analyzed, large-scale chromosomal homozygosities, most of which were not associated with relative chromosome loss. This unusual genotype, distinguishing nonseminoma from seminomas and other human tumors, may be associated with the special embryonal development morphologic transition of this malignancy. Based on these genetic data, we hypothesized a new potential origin of nonseminomas through sperm fusion. Nonrandom involvement of certain chromosomes also suggests that genes on these chromosome regions may play an important role in nonseminoma development.
Action of the Src Family Kinase Inhibitor, Dasatinib (BMS-354825), on Human Prostate Cancer Cells
Authors: Nam Sangkil , Kim Donghwa , Cheng Jin Q. , Zhang Shumin , Lee Ji-Hyun , Buettner Ralf , Mirosevich Janni , Lee Francis Y. , Jove Richard 
Published: October 2005

Abstract
Src family kinases (SFK) are currently being investigated as targets for treatment strategies in various cancers. The novel SFK/Abl inhibitor, dasatinib (BMS-354825), is a promising therapeutic agent with oral bioavailability. Dasatinib has been shown to inhibit growth of Bcr-Abl–dependent chronic myeloid leukemia xenografts in nude mice. Dasatinib also has been shown to have activity against cultured human prostate and breast cancer cells. However, the molecular mechanism by which dasatinib acts on epithelial tumor cells remains unknown. In this study, we show that dasatinib blocks the kinase activities of the SFKs, Lyn, and Src, in human prostate cancer cells at low nanomolar concentrations. Moreover, focal adhesion kinase and Crk-associated substrate (p130CAS) signaling downstream of SFKs are also inhibited at similar concentrations of dasatinib. Consistent with inhibition of these signaling pathways, dasatinib suppresses cell adhesion, migration, and invasion of prostate cancer cells at low nanomolar concentrations. Therefore, dasatinib has potential as a therapeutic agent for metastatic prostate cancers harboring activated SFK and focal adhesion kinase signaling.
Ionizing Radiation Activates Late Herpes Simplex Virus 1 Promoters via the p38 Pathway in Tumors Treated with Oncolytic Viruses
Authors: Mezhir James J. , Advani Sunil J. , Smith Kerrington D. , Darga Thomas E. , Poon Alice P.W. , Schmidt Hank , Posner Mitchell C. , Roizman Bernard , Weichselbaum Ralph R. 
Published: October 2005

Abstract
Ionizing radiation potentiates the oncolytic activity of attenuated herpes simplex viruses in tumors exposed to irradiation at specific time intervals by inducing higher virus yields. Cell culture studies have shown that an attenuated virus lacking the viral γ134.5 genes underproduces late proteins whose synthesis depends on sustained synthesis of viral DNA. Here we report that ionizing radiation enhances gene expression from late viral promoters in transduced cells in the absence of other viral gene products. Consistent with this result, we show that in tumors infected with the attenuated virus, ionizing radiation increases 13.6-fold above baseline the gene expression from a late viral promoter as early as 2 hours after virus infection, an interval too short to account for viral DNA synthesis. The radiation-dependent up-regulation of late viral genes is mediated by the p38 pathway, inasmuch as the enhancement is abolished by p38 inhibitors or a p38 dominant-negative construct. The p38 pathway is not essential for wild-type virus gene expression. The results suggest that ionizing radiation up-regulates late promoters active in the course of viral DNA synthesis and provide a rationale for use of radiation to up-regulate cytotoxic genes introduced into tumor cells by viral vectors for cytoreductive therapy.
GlutathioneS-Transferase π1 Promotes Tumorigenicity in HCT116 Human Colon Cancer Cells
Authors: Dang Duyen T. , Chen Fang , Kohli Manu , Rago Carlo , Cummins Jordan M. , Dang Long H. 
Published: October 2005

AbstractGSTP1 is a member of the glutathione S-transferase enzyme superfamily, which catalyzes the conjugation of electrophiles with glutathione in the process of detoxification. GSTP1 is widely overexpressed in colorectal cancer, from aberrant crypt foci to advanced carcinomas. Increased expression of GSTP1 is associated with multidrug resistance and a worse clinical prognosis. However, GSTP1-null mice have an increased risk of tumor formation. Thus, the biological function of GSTP1 in colorectal cancer biology remains speculative. In an effort to gain further insights into the role of GSTP1 in tumorigenesis, we disrupted the GSTP1 gene in HCT116 human colorectal cancer cells using targeted homologous recombination. We find that loss of GSTP1 resulted in impaired clonogenic survival and proliferation. Specifically, under growth-limiting conditions, (a) GSTP1 protected HCT116 cells from oxidative stress and associated apoptosis and (b) promoted mitogen-activated protein kinase-extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase–mediated G1-S cell cycle progression. In vivo, GSTP1 was critical for engraftment and growth of HCT116 tumor xenografts. These studies directly show that GSTP1 promotes clonogenic survival and proliferation in HCT116 human colon cancer cells.
The Scatter Factor/Hepatocyte Growth Factor: c-Met Pathway in Human Embryonal Central Nervous System Tumor Malignancy
Authors: Li Yunqing , Lal Bachchu , Kwon Sherwin , Fan Xing , Saldanha Usha , Reznik Thomas E. , Kuchner Eric B. , Eberhart Charles , Laterra John , Abounader Roger 
Published: October 2005

Abstract
Embryonal central nervous system (CNS) tumors, which comprise medulloblastoma, are the most common malignant brain tumors in children. The role of the growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its tyrosine kinase receptor c-Met in these tumors has been until now completely unknown. In the present study, we show that human embryonal CNS tumor cell lines and surgical tumor specimens express SF/HGF and c-Met. Furthermore, c-Met mRNA expression levels statistically significantly correlate with poor clinical outcome. Treatment of medulloblastoma cells with SF/HGF activates c-Met and downstream signal transduction as evidenced by c-Met, mitogen-activated protein kinase, and Akt phosphorylation. SF/HGF induces tumor cell proliferation, anchorage-independent growth, and cell cycle progression beyond the G1-S checkpoint. Using dominant-negative Cdk2 and a degradation stable p27 mutant, we show that cell cycle progression induced by SF/HGF requires Cdk2 function and p27 inhibition. SF/HGF also protects medulloblastoma cells against apoptosis induced by chemotherapy. This cytoprotective effect is associated with reduction of proapoptotic cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 proteins and requires phosphoinositide 3-kinase activity. SF/HGF gene transfer to medulloblastoma cells strongly enhances the in vivo growth of s.c. and intracranial tumor xenografts. SF/HGF-overexpressing medulloblastoma xenografts exhibit increased invasion and morphologic changes that resemble human large cell anaplastic medulloblastoma. This first characterization establishes SF/HGF:c-Met as a new pathway of malignancy with multifunctional effects in human embryonal CNS tumors.
Nox4 Is Critical for Hypoxia-Inducible Factor 2-α Transcriptional Activity in von Hippel-Lindau–Deficient Renal Cell Carcinoma
Authors: Maranchie Jodi K. , Zhan Ye 
Published: October 2005

Abstract
Inactivation of the von Hippel-Lindau tumor suppressor (VHL) is an early event in &gt;60% of sporadic clear cell renal cell carcinoma (RCC). Loss of VHL E3 ubiquitin ligase function results in accumulation of the α-subunit of the hypoxia-inducible heterodimeric transcription factor (HIF-α) and transcription of an array of genes including vascular endothelial growth factor, transforming growth factor-α, and erythropoietin. Studies have shown that HIF-α can be alternatively activated by reactive oxygen species. Nox4 is an NADP(H) oxidase that generates signaling levels of superoxide and is found in greatest abundance in the distal renal tubules. To determine if Nox4 contributes to HIF activity in RCC, we examined the impact of Nox4 expression on HIF-α expression and transactivation. We report here that small inhibitory RNA (siRNA) knockdown of Nox4 in 786-0 human renal tumor cells expressing empty vector (PRC) or wild-type VHL (WT) results in 50% decrease in intracellular reactive oxygen species as measured by a fluorescent 2′,7′-dichlorofluorescin diacetate assay, and &gt;85% reduction in HIF2-α mRNA and protein levels by quantitative reverse transcription-PCR and Western blot analysis. Furthermore, expression of the HIF target genes, vascular endothelial growth factor, transforming growth factor-α, and Glut-1 was abrogated by 93%, 74%, and 99%, respectively, after stable transfection with Nox4 siRNA relative to nontargeting siRNA, as determined by quantitative reverse transcription-PCR. Thus, renal Nox4 expression is essential for full HIF2-α expression and activity in 786-0 renal tumor cells, even in the absence of functional VHL. We propose the use of Nox4 as a target in the treatment of clear cell RCC.
Recent Advances in Understanding the Antineoplastic Mechanisms of Farnesyltransferase Inhibitors
Authors: Pan Jingxuan , Yeung Sai-Ching Jim 
Published: October 2005

Abstract
Farnesyltransferase (FTase) inhibitors (FTI) have broad antineoplastic actions targeting both cancer cells and mesenchymal cells involved in tumor angiogenesis. The small GTPases H-Ras, Rheb, and RhoB and the centromere proteins CENP-E and CENP-F are relevant targets of farnesylation inhibition; however, their relative importance in the antineoplastic effect of FTIs may vary in different cell types at different stages of the cell cycle and at different stages in oncogenesis. Three recent studies argue that Ras-independent and perhaps even FTase-independent properties are important to the antineoplastic action of this class of drugs. In mice, genetic ablation of FTase does not abolish the oncogenic activity of Ras, limiting the original conception of FTIs as an effective means to target Ras in cancer cells. FTase may not be the sole molecular target of these agents, and one study has suggested that FTIs act by targeting geranylgeranyl transferase II. Lastly, we have obtained evidence that induction of reactive oxygen species and reactive oxygen species–mediated DNA damage by FTIs may be critical for their antineoplastic action as a class. Together, these findings may alter thinking about how to apply FTIs in the clinic.
Targeting Myelomonocytic Cells to Revert Inflammation-Dependent Cancer Promotion
Authors: Colombo Mario P. , Mantovani Alberto 
Published: October 2005

Abstract
Tumor development and progression are strongly linked to inflammation and the presence of tumor-associated macrophages (TAMs). In murine tumors, antitumor activity can be achieved by targeting TAM recruitment, survival, activation, polarization, effector signaling, or extracellular matrix interactions. Thus, it may be possible to increase the efficacy of conventional cancer therapeutic strategies by targeting TAMs.
Venous thromboembolism and fractured neck of femur
Authors: Hitos Kerry , Fletcher John 
Published: October 2005

SummaryThe post-operative incidence of venous thromboembolism (VTE) is high for patients undergoing hip fracture surgery. Proven prophylactic measures are available although underutilized due to concern on post-operative bleeding with use of anticoagulants. This study retrospectively reviewed the clinical incidence of VTE and utilisation of thromboprophylactic protocols over an eight year period. Demographic details, mechanism of injury, VTE risk factors, prophylactic modalities (mechanical and pharmacological), operation duration, mode of anaesthesia, hospital length of stay (LOS) and post-operative complications with particular attention to suspected deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were analysed. Male to female ratio was 1: 2.7 with a median age of 78 years (IQR: 70–86 years) and 83 years (IQR: 77–87 years) respectively (p<0.001). Median hospital LOS was 8 days (IQR: 5–13 days) and differed with mechanism of injury. The in-hospital incidence of VTE was 1.6% (95% CI:1.1–2.5%) with a probably underestimated three month rate of 8.2% (95% CI:5.3–12.4%). Non fatal PE was 0.5% (95% CI: 0.2–1.0%) in-hospital and 2.6% (95% CI: 1.2–5.5%) at three months. Fatal PE was 0.5% (95% CI: 0.2–1.0%) with a three month incidence of 0.4% (95% CI: 0.1–2.4%). The in-hospitalVTE incidence was kept relatively low with use of prophylactic protocols with almost all patients receiving prophylaxis by the end of the study period. Given the five-fold out of hospital increase in incidence, consideration should be given to continue prophylaxis beyond hospital discharge in this high risk group of patients.