bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4354: Celecoxib reduces MGMT expression and potentiates the effect of temozolomide in childhood medulloblastoma
Authors: Baryawno Ninib , Milosevic Jelena , Wickström Malin , Sveinbjörnsson Baldur , Eksborg Staffan , Kogner Per , Johnsen John I. 
Published: February 2011

Abstract
Background: O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that protects DNA from the biological effects of alkylating agents. MGMT has been implicated in resistance to alkylating drugs such as temozolomide used in the clinic against brain tumors. Temozolomide has been shown to be ineffective in tumors expressing MGMT and in medulloblastoma high expression of MGMT is correlated with poor prognosis. Therefore, the demand to find agents that deplete MGMT is warranted.
Methods: medulloblastoma cell cytotoxicity of chemotherapeutic drugs in combination with Celecoxib was examined in MGMT positive cell lines using fluorometric microculture cytotoxicity assay. In vivo, nude NMRI mice carrying MGMT positive D283 MED xenografts were treated with celecoxib in combination with temozolomide. For mechanistic studies, western blot and quantitative PCR were used.
Results: the clinically available COX-2 inhibitor Celecoxib induced a synergistic or an additive cytotoxic effect in combination with Temozolomide, Cyclophosphamide, Doxorubicin, Irinotecan, Vincristine, Rapamycin or CCI-779 in vitro. In vivo, Celecoxib synergistically potentiates the effect of Temozolomide through downregulation of MGMT expression.
Conclusions: this study shows that Celecoxib reduces the DNA repair capacity of MGMT in medulloblastoma and increases the susceptibility to temozolomide. These findings support the use of pharmacological MGMT depletion as a rational approach for intensification of temozolomide therapy in the treatment of medulloblastoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4354.
Abstract 436: Cell surface HSPA8/HSc70 influences invasive tumor cell phenotype
Authors: Watanabe Takafumi , Goodison Steve , Rosser Charles J. , Urquidi Virginia 
Published: February 2011

Abstract
The mechanisms involved in tumor dissemination and metastasis are potential targets for therapeutic intervention. In this study, we used a subtractive immunization approach to generate monoclonal antibodies (mAbs) against proteins preferentially expressed by the highly metastatic human cell line, M4A4. In vitro selection assays selected an antibody that significantly inhibited the migration of this cell line. This antibody was used to immunopurify, and identify the specific target as heat shock 70kDa protein 8 (HSPA8/ HSc70).
Protein expression levels of HSPA8 correlated with different cell clones metastatic ability. Fluorescent immunocytochemistry revealed a cell surface location of HSPA8. The migratory potential of M4A4 cells was similarly reduced by knocking down HSPA8 using siRNA technology, confirming a potential role for this protein in an aggressive tumor cell phenotype. Analysis of gene expression profiles of several clones with reduced HSPA8 expression revealed approximately 200 genes as being regulated by HSPA8, including several that code for putative metastatic factors.
Heat shock proteins are primarily implicated in a cytoprotective role when cells are exposed to stressful stimuli. They are intracellular molecular chaperones but are also found in the surface of embryonic stem cells and a variety of tumor cells.
HSPA8 is moderately induced by heat shock, in response to which it translocates from the cytosol to the nucleus. Immune modulators (like IFN-γ and IL-10) stimulate the release of intracellular HSPA8 from tumors. Extracellular heat shock proteins have recently been shown to mediate a range of powerful effects in inflammatory, neuronal and immune cells through a number of cell surface receptors. The mechanism by which blocking cell surface HSPA8 protein inhibits tumor cell migration and influences the invasive phenotype is currently under investigation.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 436.
Abstract 4364: Mechanism of promotion effect of diphenylarsenic acid on rat liver carcinogenesis
Authors: Yamada Takanori , Wei Min , Suga Naoto , Wanibuchi Hideki 
Published: February 2011

Abstract
Diphenylarsinic acid (DPAA) is an enviromental degradation of product of diphenylarsine chloride or diphenylarsine cyanide, which were chemical warfare agents produced by Japan during the World War II. DPAA is now considered a dangerous environmental pollution in Kamisu, Japan, where it is suspected of inducing health effect that include articulation disorders, involuntary movements, and sleep disorders. We previously showed that GST-P (Glutathione S-transferase P) positive foci which is precancerous condition increased the number and the area at DPAA 20 ppm but not at below on rat liver carcinogenesis in medium-term bioassay (Ito test), suggesting that DPAA had promotion activities. However, the mechanism of its promotion activities is unclear. The purpose of present study is to clarify the mechanism of DPAA-induced promotion activity in rat liver carcinogenesis. We found that DPAA at 20 ppm but not at below increased significantly in oxidative DNA damage, mRNA expression of CYP1B1, cyclin D1, and c-Myc, and protein level and transcriptional activity of AhR (Arylhydrocarbon receptor) which is implicated in most of the biological responses to the environmental contaminant (e.g. TCDD). Proteome analysis showed that 69 proteins were differentially up or down-regulated in DEN-DPAA 20ppm group compared with DEN alone including 18 proteins of AhR pathway. These results suggested that activity of AhR pathway and oxidative DNA damage on rat liver carcinogenesis involved in promotion activity of DPAA.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4364.
Abstract 437: A putative role of hypoxia in development of de novo chemoresistance
Authors: Silva Ariosto S. , Gatenby Robert A. 
Published: February 2011

Abstract
In this work we built a computational model that explores the concept of hypoxia induced de novo chemoresistance. We propose that the hypoxic regions of solid tumors not only protect tumor cells from chemotherapy (environmental resistance) but also are the birthplace of de novo multidrug phenotypically chemoresistant cells.
These phenotypically resistant cells would be rare in an untreated tumor due to hypoxia and low external pH (pHe) induced quiescence in the environment where they grow. These cells, however, would be subject to a selective pressure for survival by disruption of apoptotic pathways and overexpression of hypoxia-inducible factors which are known to activate multidrug resistance genes, among other pro-survival mechanisms.
Tumor cells under chronic hypoxic conditions are also subject to higher genetic instability than tumor cells in normoxia, due in part to the decrease in the expression of homologous recombination proteins, what could also increase the rate of evolution towards a multi-drug chemoresistant phenotype.
In the presence of therapy, the sensitive cells (environmentally or phenotypically) are removed from the tumor, reducing hypoxia, normalizing pHe and allowing the phenotypically chemoresistant subpopulation of cells to grow and re-populate the tumor.
This work extends our recent chemoresistance model by adding a representation of HIF-1alpha gene, whose response to hypoxia may change due to mutation from varying thresholds until constant activation or deactivation. The expression of this gene is linked to survival in low pHe, expression of multidrug resistance gene (MDR-1) and glycolysis.
Our simulations show that HIF-1alpha expression is selected towards constitutive activation due to its increase in glycolysis and low pHe resistance, which in turn increase tumor survival and invasion. Multi-drug resistance is also increased in such cells as a consequence of the selection for these two phenotypes.
This work proposes a mechanism for development of chemoresistance in absence of drug which is different from acquired resistance since the selection for this phenotype is not imposed by the drug itself but as side effect of the selection for survival in hypoxia and low pHe.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 437.
Abstract 4379: Involvement of phosphatidylserine externalization and DNA damage in arsenic-induced toxicity to hepatocellular carcinoma (HepG2) cells
Authors: Brown Erika , Yedjou Clement G. , Tchounwou Paul B. 
Published: February 2011

Abstract
Arsenic is a naturally occurring element that is widely distributed in nature, air, water and soil. A well-known toxic and carcinogenic agent, arsenic has been associated with various human malignancies, including skin, lung, liver, kidney and bladder cancers. It has been shown to induce apoptosis in a variety of malignant cell lines, but the precise mechanisms involved in arsenic toxicity and carcinogenicity are not well elucidated. In this study, we used hepatocellular carcinoma (HepG2) cells as a model to determine whether DNA damage and phosphatidylserine externalization are involved in arsenic trioxide (ATO) toxicity. The MTT, single cell gel electrophoresis and annexin-V assays were used to assess cell viability, DNA damage and apoptosis, respectively. The results of the MTT assay demonstrated that ATO significantly reduced the viability of HepG2 cells in a dose-dependent fashion, showing a LD50 value of about 8.5 μg/mL, upon 24 hours of exposure. Data generated from the comet assay showed a significant time and dose-dependent increase in DNA damage, with respect to comet tail-length, tail arm and tail moment, as a result of ATO exposure. In regard to annexin V assay experiment, we observed an increase in annexin V positive cells undergoing early apoptosis in ATO-treated cells compared to the control, upon 2 hr of exposure. However, there was not a detection of annnexin V positive cells in ATO-treated cells compared to the control at 24 hr exposure. Based on the 24 hr cytotoxic effect of ATO to HepG2 cells, further studies are needed to elucidate the apoptotic potential of ATO to HepG2 cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4379.
Abstract 439: Evaluation of hypoxia in a feline model of head and neck squamous cell carcinoma using 64Cu-ATSM positron emission tomography
Authors: McNiel Elizabeth A. , Erfourth Todd M. , Madrill Nicole J. , Agnew Dalen W. , Nelson Nathan C. , Ballegeer Elizabeth A. , Berger Kevin L. 
Published: February 2011

Abstract
Tumor hypoxia substantially impacts the prognosis of cancer patients by impairing the response to therapy and by promoting the acquisition of a malignant cellular phenotype. A variety human tumors exhibit hypoxia including head and neck squamous cell carcinoma (HNSCC) where it is considered a barrier to successful management of these patients. In the feline, HNSCC is a common and aggressive malignancy that shares morphologic, clinical and molecular features with human HNSCC. Therefore, feline HNSCC may serve as an informative model. To date, there are no data concerning the occurrence of hypoxia in feline HNSCC. We hypothesized that like its human counter part, feline HNSCC would demonstrate regions of intratumoral hypoxia and that hypoxia would be a feature of malignant rather than benign oral tumors. To test this hypothesis, cats with spontaneously occurring oral tumors (N=7) were administered 2 mCi 64Cu- diacetyl-bis(N4-methylthiosemicarbazone) (ATSM) IV 20 minutes prior to PET-CT scan (Discovery ST, GE Healthcare). Histologically, 4 cats had invasive squamous cell carcinoma, 1 had osteosarcoma and 2 had inflammatory lesions (1 polyp and 1 granuloma). All four squamous cell carcinomas and both inflammatory lesions demonstrated strong diffuse uptake of 64Cu within the tumor. Two cats with metastases to regional lymph nodes also demonstrated significant 64Cu uptake. Tumor hypoxia was confirmed by fluorescent lifetime probe measurements (Oxylab pO2), Oxford Optronix) in 4 cats and pimonidazole (HypoxyporbeTM-1, Hypoxyprobe Inc) uptake in biopsy samples in 4 cats. These data indicate that HNSCC in the cat exhibits significant, diffuse hypoxia. Hypoxia was also significant in inflammatory lesions and thus was not a marker of malignancy, but could indicate that inflammatory disease may provide a selective microenvironement to promote tumorigenesis in the cat. The feline model may provide an important tool for studying clinical methods to modulate hypoxia and to study the role of hypoxia on oral carcinogenesis. We are currently evaluating the effect of vascular modulating agents on feline HNSCC and intratumoral hypoxia as a means to optimize this therapy for combination with irradiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 439.
Abstract 4392: Oxidative damage to placental DNA, air pollution, genetic polymorphisms and pregnancy outcomes
Authors: Rossner Pavel , Tabashidze Nana , Dostal Miroslav , Novakova Zuzana , Chvatalova Irena , Spatova Milada , Srám Radim J. 
Published: February 2011

Abstract
Oxidative stress to placenta DNA may result in negative pregnancy outcomes, including intrauterine growth retardation (IUGR) and low birth weight (LBW). The aim of our study was to investigate the association between the levels of 8-oxodeoxuanosine (8-oxodG), a marker of oxidative DNA damage, in placenta DNA, exposure to particulate matter &lt;2.5 µm (PM2.5) and benzo[a]pyrene (B[a]P) during pregnancy, genetic polymorphisms in 97 genes and pregnancy outcomes in a group of 891 newborns born between the years 1994 and 1999 in the Czech Republic in two districts with different levels of air pollution. We observed a borderline difference in oxidative stress levels between the IUGR and non-IUGR group (median 8-oxodG/105 dG (range): 2.03 (0.29-6.17) and 1.74 (0.20-6.50), p=0.055, for the IUGR and non-IUGR group, respectively) and higher oxidative stress in the LBW newborns (median 8-oxodG/105 dG (range): 2.25 (0.27-6.25) and 1.75 (0.20-6.50), p&lt;0.05, for the LBW and non-LBW group, respectively). Univariate regression analysis revealed single nucleotide polymorphisms (SNPs) in 12 genes (ADH1B, ALDH2, BCL6, CCL2, CTLA4, CXCL10, CYP1A2, CYP2D6, GATA3, IL13, MGMT, XPC) to be associated with 8-oxodG levels; IUGR was associated with SNPs in 6 genes (AHR, C5, CCL24, CTLA4, TLR4, XRCC3), while LBW with SNPs in 18 genes (ADH1C, CCL7, CCL8, CCL18, CYP1A1, ERCC3, HMOX1, IL10, LIG1, LTA, MBL2, STAT4, TOLLIP, TLR2, XPC, TP53, XRCC1, XRCC3). 8-oxodG levels were increased by exposure to PM2.5 in the first four moths of pregnancy; exposure to B[a]P had no effect. Multivariate-adjusted logistic regression revealed that newborns with above-median levels of 8-oxodG (&gt;1.80 8-oxodG/105 dG) had 64% higher probability of IUGR (OR (95% CI): 1.64 (1.12-2.42), p&lt;0.05) than newborns with below-median levels of oxidative DNA damage. Genetic polymorphisms in ADH1B, C5 and TLR4, as well as body mass index and the length of education of the mother also significantly affected the risk of IUGR. Oxidative DNA damage was not confirmed by multivariate-adjusted logistic regression to be a risk factor of LBW. Variables affecting LBW include genetic polymorphisms in CCL7, HMOX1 and STAT4, gender, mother's smoking and the length of gestation. In summary, our results suggest that oxidative DNA damage increases the risk of IUGR; exposure to air pollution during pregnancy is not a significant independent factor affecting 8-oxodG-related IUGR. Supported by the Czech Ministry of the Environment (SP/1b3/50/07).
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4392.
Abstract 4402: Fsn0503: A novel therapeutic antibody for the treatment of colorectal cancer
Authors: Gormley Julie A. , Olwill Shane A. , Hegarty Shauna M. , Scott Christopher J. , Burden Roberta E. , Johnston James A. , Kay Elaine W. 
Published: February 2011

Abstract
Local invasion and metastasis is the primary cause of death in many cancers. Extracellular matrix degradation by proteolytic enzymes facilitates tumour invasion into the surrounding tissue, eventually leading to metastatic spread of the disease. Cathepsin S (CTSS) is a lysosomal cysteine protease, which has been shown to play a role in promoting tumour invasion and angiogenesis. CTSS has been found to be overexpressed and secreted in a number of cancer tissues including astrocytoma and prostate. We have developed Fsn0503, a novel antibody that targets and inhibits the extracellular activity of CTSS. Fsn0503 specifically binds to and inhibits the activity of CTSS. It significantly attenuates invasion of a range of colorectal cancer cell (CRC) lines in vitro (e.g. HCT116 64% at 200nM). Fsn0503 also demonstrates anti-angiogenic effects; it significantly reduces microtubule formation by HUVEC cells in vitro and vessel outgrowth in the (ex vivo) rat aortic ring model. Fsn0503 also impairs tumour growth and vascularisaton in the HCT116 colorectal xenograft model and reduced metastatic burden in a 3LL metastatic model, with no signs of toxicity. As these data suggest a role for CTSS in CRC progression, we probed its expression pattern in a large-scale immunohistochemical study spanning five cohorts of patients (n=600). Greater than 90% of tumours show intense expression of CTSS compared with weak or undetectable expression in the normal colonic epithelium. Increased CTSS expression in lymph node metastatic tissue compared to normal tissue was also observed. These compelling results signify an important role for CTSS in malignant progression of CRC and accompanying metastases. Demonstration of in vivo efficacy highlights the therapeutic potential of targeting CTSS with an antibody. Overall, our data indicate that Fsn0503 is an exciting experimental therapeutic which has great clinical potential
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4402.
Abstract 4406: A monoclonal antibody targeting PAUF inhibits metastasis of pancreatic cancer
Authors: Lee Yangsoon , Kim Su Jin , Min Hye Jin , Yu Kyung Sook , Park Eun Hye , Koh Sang Seok 
Published: February 2011

Abstract
Pancreatic cancer is one of the deadliest human tumors and, due to lack of effective therapeutic agents and diagnostic tools, has a poor prognosis with approximately a five-year survival rate of less than 5%. This disease is characterized by early metastatic spread but the process of tumor cell dissemination is largely unknown. Recently, we have shown that a novel soluble protein named PAUF (Pancreatic Adenocarcinoma Up-regulated Factor) plays an important role in the metastasis and progression of the disease. The expression of CXCR4 is induced by PAUF, implicating a role of PAUF in the organ specific metastasis of pancreatic cancer. The tumorigenic and metastatic activity of PAUF suggests that PAUF could be a target for pancreatic cancer immunotherapy. To examine the therapeutic potential of PAUF, a human monoclonal antibody against PAUF (8F3) has been generated. The 8F3 antibody exerted inhibition of migration, invasion, adhesion and proliferation of pancreatic cancer cells in vitro. In combination with gemcitabine, 8F3 showed additive effect on reduction of cell growth. In orthotopically xenografted mouse model, these anti-tumor activities of 8F3 converted to growth retardation and repression of metastasis. The level of PAUF in tumor and serum from 8F3 treated mouse was lower than that of control mouse. The immunohistochemical analysis revealed that the treatment of 8F3 inhibited the proliferation and CXCR4 expression in both primary and metastasized tumors. The 8F3 antibody also alters intracellular signaling which was induced by PAUF. We will also discuss about the effect of 8F3 in tumor microenvironment, especially recruitment of immune cells. Collectively, these findings indicate that PAUF has a therapeutic potential for treatment of human pancreatic cancer and the 8F3 antibody can be developed for therapeutic agent for this disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4406.