bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment Choices Based on OncotypeDx in the Breast Oncology Care Setting
Authors: Malo Teri L. , Lipkus Isaac , Wilson Tobi , Han Hyo S. , Acs Geza , Vadaparampil Susan T.
Published: August 2012

Introduction. This study aimed to evaluate whether OncotypeDx test results predict receipt of adjuvant chemotherapy in breast cancer patients who received an OncotypeDx recurrence score (RS).Materials and Methods. Pathology records were used to identify breast cancer patients who had OncotypeDx testing between December 2004 and January 2009 (n=118). Patient sociodemographic information, tumor characteristics, RS, and treatment-specific data were collected via chart review. RS was classified as follows: low (RS≤17), intermediate (RS = 18–30), or high (RS≥31). Bivariate analyses were conducted to investigate the relationship between adjuvant chemotherapy receipt and each sociodemographic and clinical characteristic; significant sociodemographic and clinical variables were included in a multivariable logistic regression model.Results. In multivariable analysis controlling for tumor size, histologic grade, and nuclear grade, only RS remained significantly associated with chemotherapy uptake. Relative to low RS, an intermediate (adjusted odds ratio [AOR], 21.24; 95% confidence interval [CI], 3.62–237.52) or high (AOR, 15.07; 95% CI, 1.28–288.21) RS was associated with a greater odds of chemotherapy uptake.Discussion. Results indicate that RS was significantly associated with adjuvant chemotherapy uptake, suggesting that OncotypeDx results were used to inform treatment decision making, although it is unclear if and how the information was conveyed to patients.
Effects of Tocotrienol and Lovastatin Combination on Osteoblast and Osteoclast Activity in Estrogen-Deficient Osteoporosis
Authors: Abdul-Majeed Saif , Mohamed Norazlina , Soelaiman Ima-Nirwana
Published: August 2012

Statins are HMGCoA reductase inhibitors and had been demonstrated to stimulate bone formation in rodents after high oral doses. Observational studies on patients treated with oral statins were varied. Delta-tocotrienol had been found to stimulate the cleavage of HMGCoA reductase and inhibit its activity. Tocotrienols were found to have both catabolic and anabolic effects on bone in different animal models of osteoporosis. The current study aimed to ascertain the effects of delta–tocotrienol and lovastatin combination on biochemical and static bone histomorphometric parameters in a postmenopausal rat model at clinically tolerable doses. 48 Sprague Dawley female rats were randomly divided into 6 groups: (1) baseline control group; (2) sham-operated control group; (3) ovariectomised control group; (4) ovariectomised and 11 mg/kg lovastatin; (5) ovariectomised and 60 mg/kg delta-tocotrienol; (6) ovariectomised and 60 mg/kg delta-tocotrienol + 11 mg/kg lovastatin. These treatments were given daily via oral gavage for 8 weeks. Delta-tocotrienol plus lovastatin treatment significantly increased bone formation and reduced bone resorption compared to the other groups. Therefore, the combined treatment may have synergistic or additive effects and have the potential to be used as an antiosteoporotic agent in patients who are at risk of both osteoporosis and hypercholesterolemia, especially in postmenopausal women.
Synthesis and Characterization of Nanosized Fe2O3 Pigments
Authors: Fouda M. F. R. , El-Kholy M. B. , Moustafa S. A. , Hussien A. I. , Wahba M. A. , El-Shahat M. F.
Published: August 2012

The work in this paper was devoted to investigating some nanosized iron oxide pigments prepared by microemulsion technique. The role of concentration of iron salt and surfactant (cetyltrimethylammonium bromide) on the produced iron oxide was studied. The techniques employed to characterize the samples were thermogravimetric analysis, X-ray diffractometry, transmission electron microscope, infrared spectroscopy, and diffuse reflectance spectroscopy. The results revealed that the particle size of the prepared sample using 0.2 M iron sulfate and 3.2 wt% of surfactant was in the range 7–9 nm. Increasing the concentration of either iron salt or the surfactant increased the particle size of the obtained ferric oxide. The diffuse reflectance measurements showed that the charge transfer/electron pair transition absorption peak, which is closely related to the reddish color of the oxide, was shifted to a longer wavelength (blue shift) by decreasing the dimension of the particles. The samples were tested as pigments. They showed different tints of red color and were found to be promising for applications as pigments in the field of paint manufacturing.
Pre-Invasive Ovarian Mucinous Tumors Are Characterized by CDKN2A and RAS Pathway Aberrations
Authors: Hunter Sally M. , Gorringe Kylie L. , Christie Michael , Rowley Simone M. , Bowtell David D. ,   on behalf of the Australian Ovarian Cancer Study Group, Campbell Ian G.
Published: August 2012

Introduction: Mucinous tumors are the second most common form of epithelial ovarian tumor, yet the cell of origin for this histologic subtype remains undetermined. Although these tumors are thought to arise through a stepwise progression from benign cystadenoma to borderline tumor to invasive carcinoma, few studies have attempted to comprehensively characterize the genetic changes specific to this subtype or its precursors.

Methods: To explore the spectrum of genomic alterations common to mucinous tumors we carried out high-resolution genome-wide copy number analysis, mutation screening by Sanger sequencing and immunohistochemistry on a series of primary ovarian mucinous cystadenomas (n = 20) and borderline tumors (n = 22).

Results: Integration of copy number data, targeted mutation screening of RAS/RAF pathway members and immunohistochemistry reveals that p16 loss and RAS/RAF pathway alterations are highly recurrent events that occur early during mucinous tumor development. The frequency of concurrence of these events was observed in 40% of benign cystadenomas and 68% of borderline tumors.

Conclusions: This study is the largest and highest resolution analysis of mucinous benign and borderline tumors carried out to date and provides strong support for these lesions being precursors of primary ovarian mucinous adenocarcinoma. The high level of uniformity in the molecular events underlying the pathogenesis of mucinous ovarian tumors provides an opportunity for treatments targeting specific mutations and pathways. Clin Cancer Res; 18(19); 5267–77. ©2012 AACR.
Abstract 1094: MicroRNA-30a inhibits vimentin expression and as a prognostic marker in breast cancer
Authors: Chang Chia-Wei , Cheng Chun-Wen , Wang Hsiao-Wei , Chen Cheng-You , Chu Hou-Wei , Ding Shian-ling , Wang Hui-Chun , Yu Jyh-Cherng , Shen Chen-Yang
Published: August 2012

Recent studies have suggested a significant role of microRNAs (miRNAs) in the regulation of cancer development. This study examined whether they play a role in breast cancer progression.A miRNA microarray analysis was performed on laser-capture microdissected breast tumors of different lymph-node metastasis status showing different progression signatures, indicated by overexpression of cyclin D1 and β-catenin genes, to identify specific miRNAs that exhibit significant differences in expression. Functional interaction between the candidate miRNA (i.e. miR-30a) and the gene (i.e. Vim gene, coding for vimentin, a protein involved in epithelial-mesenchymal transition) possibly regulated by miR-30a was verified. We further examined whether decreased expression of miR-30a was associated with breast cancer progression.miR-30a negatively regulated vimentin expression, by binding to the 3′-untranslated region of Vim. Ectopic expression of miR-30a was found to suppress the migration and invasiveness phenotypes of breast cancer cell lines. More importantly, breast cancer patients with decreased miR-30a level in primary cancerous sites were found to be associated with poor clinical features (late tumor stage and lymph node metastasis) and worse progression, demonstrating an increased hazard ratio (HR) for recurrence or recurrence plus mortality during the follow-up period (P<0.05). These findings provide a support of clinical importance of miR-30a in mediating breast tumor progression. Identification of miR-30a-mediated regulation of vimentin might provide a promising therapeutic target in treating breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1094. doi:1538-7445.AM2012-1094
Abstract 1128: The role of peptide deformylase in the apoptosis of c-Myc overexpressing cancers
Authors: Sheth Aneesh , Escobar-Alvarez Sindy , Ran Leili , Gardner Jeffery , Scheinberg David A.
Published: August 2012

In prokaryotes, the removal of an N-terminal formyl group by the peptide deformylase is required for post-translational protein processing. Our identification of human mitochondrial PDF (HsPDF) and deformylated peptides in the mitochondria shows that a similar post-translational processing of the 13 human mitochondrial DNA-encoded, and formylated, proteins can occur. Inhibition of HsPDF reduced proliferation of many human cancer lines. We developed a monoclonal antibody to hsPDF; profiling of cancer and normal cell lines by three immunoassays, flow cytometry, immunoprecipitation and in-cell western, showed over-expression of HsPDF in cancer cell lines. This data was confirmed at the mRNA level by RT-PCR. As the c-myc oncogene regulates mitochondria and metabolism in cancer, we investigated its role in regulating HsPDF. In a tet-off c-myc cell line, the expression of HsPDF was regulated by c-myc; inhibiting this protein resulted in the selective inhibition of mitochondrial protein translation, and eventual death of myc-positive, but not myc-negative cells. Furthmore, knocking down c-myc in a Burkitt's Lymphoma cell line significantly reduced the expression of both the mRNA and the protein levels of HsPDF relative to beta-Actin. The mechanism of death by actinonin was apoptosis in two c-myc over-expressing cell lines. Death was initiated with mitochondrial membrane depolarization, followed by inhibition of mitochondrial translation, and eventually caspase-3 activation and apoptosis. To confirm the specificity of PDF in cell death, we used two other hydroxamic acid peptidomimetics that do not target HsPDF. These compounds did not result in apoptotic death. Furthermore, inhibition of translation of the mitochondrial DNA by chloramphenicol and tetracycline, two structurally different inhibitors of the mitochondrial ribosome, which is upstream of deformylation, followed by treatment with actinonin resulted in a delay and marked reduction in apoptosis by actinonin, but not by staurosporine and the HDAC inhibitors SAHA and Trichostatin A. Thus, death was not a result of ATP depletion, but a unique PDF-mediated mechanism.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1128. doi:1538-7445.AM2012-1128
Abstract 1132: Regulation of the glutamine-to-lipid pathway by HIF: Reductive TCA cycle is a metabolic signature of VHL deficiency
Authors: Yang Juanjuan , Gameiro Paulo A. , Stephanopoulos Gregory , Iliopoulos Othon
Published: August 2012

Cancer cells undergo fundamental changes in glucose and glutamine metabolism to support anabolic processes. Acetyl-CoA is a central precursor for lipid synthesis, being generated from glucose-derived citrate in well oxygenated cells. Cells exposed to hypoxia divert glucose to lactate, raising the question of how TCA cycle is maintained to support lipogenesis. We recently showed that, under hypoxia conditions, cancer cells primarily utilize glutamine for lipid synthesis through reductive TCA cycle (redTCA). To investigate the regulation of this metabolic switch, we studied the role of Hypoxia Inducible Factors (HIF1s) in renal cell carcinoma (RCC) cell lines that are deficient in the von Hippel-Lindau (VHL) tumor suppressor gene. These cells exhibit constitutive HIF activity irrespective of oxygen availability. Here, we show that loss-of-VHL engages RCC cells in redTCA even under normoxia conditions in a HIF-dependent manner. Reintroduction of VHL restores the glucose-to-lipid flux. Inactivation of HIF regulatory subunits dramatically attenuates redTCA in RCC cell lines. Inversely, exogenous expression of a VHL-insensitive HIF2α mutant (P564toA) in VHL proficient cell lines is sufficient to stimulate redTCA cycle and lipogenesis from glutamine, under conditions of normoxia. Importantly, loss of VHL rendered RCC cells sensitive to glutamine restriction. VHL-deficient RCC cells grow less than their VHL-replete isogenic counterparts when cultured under conditions of low glutamine availability. Our results elucidate the metabolic control of lipogenesis by the VHL-HIF signaling pathway and highlight novel therapeutic targets for RCC and HIF-overexpressing tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1132. doi:1538-7445.AM2012-1132
Abstract 1149: The expression of Ki-67, but not IGF1R, predicts a poor disease-free survival in patients with adenocarcinoma of the lung
Authors: Oka Soichi , Uramoto Hidetaka , Chikaishi Yasuhiro , Nakagawa Makoto , Shimokawa Hidehiko , Takenaka Masaru , Shigematu Yoshiki , So Tomoko , Hanagiri Takeshi , Tanaka Fumihiro
Published: August 2012

Background: Ki-67 expression has been established as a predictive marker for recurrence in breast cancer. The insulin-like growth factor 1 receptor (IGF1R) is a transmembrane heterotetrameric protein implicated in promoting the oncogenic transformation, growth and survival of cancer cells. However, no useful data are presently available regarding the biological significance of both molecules in lung cancer. Therefore, we investigated the relationship between the expression of Ki-67 and IGF1R. This is the first molecular analysis of the correlation between the expression of Ki-67 and IGF1R in a Japanese population of primary lung adenocarcinoma patients. Methods: Tumor specimens were collected from 183 consecutive patients who underwent a complete resection for lung adenocarcinoma from 2003 to 2007 in our department. We analyzed the Ki-67 and IGF1R expression levels in the primary lung adenocarcinomas by immunohistochemistry. Results: The positive expression of Ki-67 and IGF1R was identified in 41 (22.4%) and 43 (23.6%) patients, respectively. The positive expression of Ki-67 was identified in 14 (50.0%) of 28 patients and 27 (18.1%) of 155 patients with and without recurrence, respectively (p< 0.001). The positive expression of Ki-67 was associated with a poorer disease-free survival (DFS) according to the survival analysis. A multivariate analysis also demonstrated that Ki-67 expression was independently associated with an increased risk of a poor DFS. On the other hand, a significant relationship was also observed between the expression levels of Ki-67 and IGF1R in NSCLC. However, in the subgroup analysis, no significant correlation was not observed. Conclusions: The expression of Ki-67, but not IGF1R, may be a useful marker for predicting postoperative recurrence in patients with the primary lung adenocarcinoma following complete resection.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1149. doi:1538-7445.AM2012-1149
Abstract 1150: Genome-wide DNA methylation profiling of cell-free serum DNA in esophageal adenocarcinoma and Barrett's esophagus
Authors: Zhai Rihong , Zhao Yang , Su Li , Carssidy Lauren , Liu Geoffrey , Christiani David
Published: August 2012

Aberrant DNA methylation (DNAm) is a feature of most types of cancers. Genome-wide DNAm profiling has been performed successfully on DNA extracted from many types of tumor tissues. However, the invasive procedure and the likely existence of tissue heterogeneity limit the utility of tumor tissue for epidemiological studies. While recent data indicate that cell-free circulating DNA methylation (cfDNAm) profiles reflect DNAm profiles in matched tumor tissues, no studies have examined the association of cfDNAm with cancer or precursors on a genome-wide scale. The objective of this pilot study was to evaluate the putative significance of genome-wide cfDNAm profiles in esophageal adenocarcinoma (EA) and Barrett's esophagus (BE, EA precursor). We performed genome-wide DNAm profiling in EA tissue DNA (n=8) and matched serum DNA (n=8), in serum DNAs of BE (n=12) and healthy controls (n=12), using the Infinium Humanmethylation27 Beadchip that covers 27,578 CpG loci in 14,495 genes. We found that cfDNAm profiles were highly correlated to DNAm profiles in matched tumor tissue DNAs (r=0.92) in patients with EA. We selected the most differentially methylated loci (a β-value difference of >0.2 and a P-value of 6 x 10 −7 between groups) to perform hierarchical clustering analysis. We found that 911 loci can perfectly discriminate between EA and control samples; 554 loci can separate EA from BE samples; and 46 loci can distinguish BE from control samples. These results suggest that genome-wide cfDNAm profiles are highly consistent with DNAm profiles detected in corresponding tumor tissues. Differential cfDNAm profiling may be a useful approach for the non-invasive screening of EA and EA premalignant lesions. Supported by grants: Flight Attendant Medical Research Institute (FAMRI) grant# 062459; NIH grants CA92824, CA74386, CA90578, and CA119650); the Kevin Jackson Memorial Fund and Alan Brown Chair of Molecular Genomics.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1150. doi:1538-7445.AM2012-1150
Abstract 1156: Cell-surface marker discovery for colorectal cancer
Authors: Sewda Kamini , Wojtkowiak Jonathan W. , Enkemann Steven , Lopez Alexis S. , Coppola Domenico , Shibata David , Yeatman Timothy J. , Gillies Robert J. , Morse David L.
Published: August 2012

In the United States and Europe, colorectal cancer (CRC) has the second highest mortality rate of all cancers. Early diagnosis allows for treatment and improved survival. Currently, colonoscopy is the standard of care for detection of early-stage CRC, which is an invasive procedure that requires a cathartic bowel preparation and general anesthesia. Consequently, less invasive screening methods are highly desirable. The objective of this study is to develop a targeted molecular imaging technique termed “molecular colonography,” that can non-invasively detect dysplastic and neoplastic colonic lesions with high sensitivity and conspicuity by oral administration of ligand-targeted probes containing image contrast agents followed by clearance and non-invasive colonography with MRI, CT or Fluorescence imaging. The first step in the development of molecular colonography is identification of cell-surface markers for CRC. To accomplish this goal, gene expression profiling of DNA microarray data from 432 adenocarcinomas, 39 adenomas and 16 inflammatory bowel disease; and unaffected patient tissue samples (178 colon, 6 small intestine, 4 stomach, 4 esophagus, 4 trachea, 3 oral mucosa and 3 tonsil) was performed. Data were filtered using a previously compiled list of 3,800 cell surface genes from the NCBI Gene Expression Omnibus database. Of these, 1085 genes were broadly expressed in CRC and were ranked by differential expression in adenomas and adenocarcinomas vs. normal tissues. Six cell-surface markers were identified that are highly and broadly expressed as mRNA in adenomas and adenocarcinomas relative to unaffected tissues: TLR4, GPR56, GRM8, LY6G6D, CLDN1 and SLC01B3. TLR4 and/or GRM8 were shown to be expressed in 100% of the colon adenomas and adenocarcinomas in this dataset. To confirm protein expression, immunohistochemistry of normal (n=15) and CRC (16 adenoma and 60 adenocarcinoma) patient tissue samples and 26 CRC cell lines was performed. All six markers were highly and broadly expressed in adenomas and adenocarcinomas compared to normal colon. Further validations by mRNA (qRT-PCR) and protein expression (Western blot and immunocytochemistry) of these markers were also performed in nine colon tumor cell lines (COLO-205, DIFI, HCT15, HCT116, HT-29, KM12C, Km12SM, SW480 and SW620). Development of specific binding ligands for selected targets is underway.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1156. doi:1538-7445.AM2012-1156
Abstract 1158: Clinical significance of p53 codon 72 polymorphism in hepatocellular carcinomas
Authors: Council Leona N. , Shanmugam Chandrakumar , Katkoori Venkat R. , Sthanam Meenakshi , Hanna Alex , Manne Upender
Published: August 2012

Purpose: We recently demonstrated that, in colorectal carcinomas, the presence of a single nucleotide polymorphism (SNP) at codon 72 of the p53 gene was associated with a poor outcome for African American (AA) patients. Since such studies have not been performed for hepatocellular carcinomas (HCCs), we determined, for AAs and non-Hispanic Caucasians (NHCAs), the prevalence of p53 SNPs in codon 72 of HCCs and its association with adverse clinical and pathological features. Methods: DNA samples extracted from 48 archived, formalin-fixed, paraffin-embedded HCC tissues and from matching, uninvolved liver were analyzed for the mutational status of the p53 gene by sequencing exon 4 through exon 9. The results obtained were correlated with the demographic and clinicopathological features of the HCCs and with patient survival. Results: Overall, the frequency of missense point mutations in p53 of HCCs was low (6 of 48, 12%). Missense point mutations, however, were common in NHCAs (4 of 6). Genotyping of codon 72 of p53 demonstrated that the Arg/Arg phenotype had the highest frequency (27 of 48; 56%), followed by Arg/Pro (16 of 48; 33%) and Pro/Pro (5 of 48; 11%). Four of five patients with the Pro/Pro phenotype were AAs (χ2 p = 0.028). Of these, three of the four tumors had high proliferative (ki67) indices; two of the four were poorly differentiated. In contrast, poorly differentiated tumors were few in Arg/Arg (1 of 27, 4%) and Arg/Pro (1 of 16; 6%) (χ2p = 0.016) phenotype groups. For all patients, the Pro/Pro phenotype were associated with hepatitis C virus (HCV) infection (χ2 p = 0.048). Furthermore, AAs with the Pro/Pro phenotype had lower median survival (15.5 months) compared to those with the Arg/Arg and Arg/Pro (32 months) phenotypes. NHCA patients with missense point mutations had shorter median survival (22.5 months) relative to NHCAs with wild-type p53 (34 months).Conclusion: These preliminary findings suggest that, in AAs, the Pro/Pro phenotype at codon 72 of the p53 gene is associated with aggressive tumor behavior, shorter median survival, and HCV infection. These pilot studies were supported jointly by a Charles Barkley Award through the UAB Minority Health Disparities Research Center (MHRC) and the UAB Center for Clinical and Translational Science (5UL1 RR025777-04).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1158. doi:1538-7445.AM2012-1158
Abstract 1321: A novel prevention method against re-obstruction of titanium alloy stent for biliary malignancy using generation of hydroxyl radical under ultrasonic irradiation
Authors: Fujimura Tomonori , Itano Osamu , Matsuda Sachiko , Tatsuya Onishi , Kitago Minoru , Shinoda Masahiro , kawachi Shigeyuki , Tanabe Minoru , Ogino Chiaki , Shimizu Nobuaki , Kitagawa Yuko
Published: August 2012

[introduction] Palliative biliary drainage using a metallic stent is performed for biliary obstruction by unresectable biliary carcinoma.The most important problem of biliary stenting therapy is re-obstruction due to tumor ingrowth. The generation of hydroxyl radical was investigated during ultrasonic irradiation and in the presence of TiO2(Shimizu, etal.Ultrason.Sonochem.2008).The metal stent which is used for biliary drainage is made of titanium alloy, and it is thought that it could generate hydroxyl radicals under ultrasonic irradiation in the same way. The object of this study was to establish a novel prevention method of re-obstruction of the stent using generation of hydroxyl radical under ultrasonic irradiation. [method] {in vitro}Nickel titanium alloy was ultrasonically irradiated at frequency of 1MHz for 30 seconds and the amount of generated hydroxyl radical was measured when intensity was changed to 0.1-0.5 W/cm2 by APF method. To evaluate the cytotoxic effect of the generated radicals, trypan blue exclusion assay was used.The number of living cells were counted. {in vivo}A stent re-obstruction model was established.Nude mice(BALB c nu/nu) were given an injection of 1.0×107 of human squamous carcinoma A431 cells on the back.After Seven days, a stent was put in the neighborhood of tumor.The irradiation group(n=3) was given 10 minutes-ultrasonic irradiation of 0.3W /cm2 once a day.The non-irradiation group(n=3) was not irradiated. Tumors with stents were resected on the 14th day. Tumor ingrowth area was measured and histlogical examination of the tumors was performed. [result] {in vitro}The maximum amount of hydroxyl radical generation was measured under ultrasonic irradiation of 0.3W /cm2. The number of living cells with titanium alloy under ultrasonic irradiation(0.3W /cm2 30seconds) was 79% of that without ultrasonic irradiation. {in vivo}On the 14th day, tumor ingrowth to the stent was seen in the non-irradiation group of the stent re-obstruction model.Tumor ingrowth to the stent was clearly inhibited in the irradiation group. [conclusion] Hydroxyl radical was generated from a titanium alloy stent by ultrasonic irradiation and seemed to have therapeutic efficacy. Tumor ingrowth was inhibited, and preventive effect against re-obstruction was suggested.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1321. doi:1538-7445.AM2012-1321
Abstract 1324: Unraveling novel functions of the oncogene Astrocyte elevated gene-1 (AEG-1) contributing to hepatocarcinogenesis employing a transgenic mouse model
Authors: Srivastava Jyoti , Siddiq Ayesha , Emdad Luni , Santhekadur Prasanna Kumar , Chen Dong , Gredler Rachel , Shen Xue-Ning , Robertson Chadia L. , Stafflinger Jillian , Subler Mark A. , Dumur Catherine I. , Hylemon Phillip B. , Windle Jolene J. , Fisher Paul B. , Sarkar Devanand
Published: August 2012

In vitro tissue culture and nude mice xenograft models have firmly established the role of Astrocyte elevated gene-1 (AEG-1) as a positive regulator of tumorigenesis, including hepatocarcinogenesis. To better appreciate the role of AEG-1 in hepatocarcinogenesis and to dissect the underlying molecular mechanism, we have created a transgenic mouse with hepatocyte-specific expression of AEG-1 (Alb/AEG1). Wild-type (WT) and Alb/AEG-1 mice were challenged with a hepatocarcinogen, N-nitrosodiethylamine (DEN), at 2 weeks of age. At 28 weeks of age, Alb/AEG-1 mice, but not WT mice, developed multinodular HCC with steatotic features and highly elevated serum liver enzymes. Affymetrix microarray analyses identified modulation of expression of genes associated with invasion, metastasis, angiogenesis and fatty acid synthesis in DEN-treated Alb/AEG-1 mice versus their WT counterparts. Hepatocytes isolated from Alb/AEG-1 mice demonstrated profound chemoresistance and dramatically evaded reduction in cell viability upon growth factor deprivation, which was associated with activation of multiple pro-survival signaling pathways. Compared to the WT hepatocytes, Alb/AEG-1 hepatocytes demonstrated marked resistance towards senescence, which was associated with abrogation of activation of a DNA damage response. Conditioned media (CM) from Alb/AEG-1 hepatocytes, but not form WT hepatocytes, induced marked angiogenesis. Mass spectrometric analysis of CM revealed noticeable increases in coagulation factors by AEG-1, which are known to play a significant role in regulating tumor invasion, angiogenesis and metastasis. siRNA-mediated knockdown of coagulation factor XII resulted in profound inhibition of AEG-1-induced angiogenesis. Our studies reveal novel aspects of AEG-1 functions, such as induction of steatosis, inhibition of senescence, a known anti-cancer mechanism, and activation of coagulation pathway to augment an aggressive hepatocarcinogenic phenotype. The Alb/AEG-1 mouse will be a useful model to decipher AEG-1 function in the context of hepatocarcinogenesis and to evaluate the efficacy of novel therapeutic strategies directed towards HCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1324. doi:1538-7445.AM2012-1324
Abstract 1338: Knockdown of CD24 prevents colorectal polyp formation in APCmin/CD24 double knockout transgenic mice
Authors: Naumov Inna , Zilberberg Alona , Rosin-Arbesfeld Rina , Ilan Aroch , Kazanov Dina , Arber Nadir , Kraus Sarah R.
Published: August 2012

Background: Previous studies in our lab have shown that CD24 is a potential oncogene in the colon. CD24, a mucin-like glycoprotein, is overexpressed in 90% of colorectal cancer (CRC) tumors at a fairly early stage in the multistep process of CR carcinogenesis (Sagiv et al., Gastroenterology, 2006). We have also shown that CD24 downregulation by shRNA interference (Sagiv et al., Can Res, 2008) or anti-CD24 mAb targeting (Shapira et al., Gastroenterology, 2011) retarded tumorigenicity of human CRC cell lines and/or reduced tumor volume in nude mice. The APCmin/+ is a popular animal model for studies of human colon carcinogenesis and the molecular changes associated with neoplasia in this system have been partially characterized. These mice have a germline nonsense mutation at codon 850 of the APC gene and spontaneously develop hundreds of polyps, mostly in the small intestine at the age of 10-12 weeks. Aim: To validate the importance of CD24 in intestinal carcinogenesis using a transgenic mouse model with a double knockout (KO) of CD24−/+ /CD24+/− and APCMin/+ alleles. Methods: We generated the CD24−/+/APCMin/+ double KO by crossing the mice with each of the single gene knockouts, in order to obtain both CD24+/−/APCMin/+ and CD24−/+ APCMin/+ genotypes. The double KO mice were followed up thrice a week and sacrificed at 12 weeks of age. Tumors from the entire small and large intestine were counted and verified by histological analysis Results: There was almost a complete absence of polyps in the small intestine in APCMin/+/CD24+/− double heterozygotes compared to that of the parental APCMin/+, CD24+/+ animals: 273±55.4 vs. 6±1.7 polyps, respectively (P=0.0001). APCMin/+and CD24−/+ homozygotes showed a striking lack of polyps (P< 0.0001). This reduction occurred in all sections of the small intestine. Histophatological analysis confirmed the absence of malignant lesions in the double KO mice as compared to the parental mice. Conclusions: 1. A deficiency of only one CD24 allele is sufficient to suppress almost completely polyp formation in the APCMin/+ mice that normally develop hundreds of polyps. 2. Although the mechanism/s underlying the pathophysiologic role of CD24 in the development of CRC are still unknown, these studies suggest that CD24 plays a critical role in the proliferation and progression of CRC and is a potential important target for the prevention and treatment of intestinal neoplasia.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1338. doi:1538-7445.AM2012-1338
Abstract 134: miRNA-708 suppresses prostate cancer growth through Akt2 signaling pathways
Authors: Saini Sharanjot , Majid Shahana , Shahryari Varahram , Arora Sumit , Yamamura Soichiro , Chang Inik , Zaman Saif , Deng Guoren , Tanaka Yuichiro , Carroll Peter R. , Dahiya Rajvir
Published: August 2012

MicroRNAs have been implicated in the etiology, progression and metastasis of various malignancies. We identify miR-708, a little studied member of a set of microRNAs that have been implicated in stress control, as an important tumor suppressor in prostate cancer. In this study we identify that miR-708 expression is significantly attenuated in prostate cancer cell lines and human prostate clinical specimens. To evaluate the functional significance of decreased miR-708 expression, miR-708 was reintroduced in prostate cancer cell lines followed by functional assays. Restoration of miR-708 expression in prostate cancer cell lines decreased cell growth, clonability, invasion, migration and elicited a dramatic increase in apoptosis. Moreover, intratumoral delivery of miR-708 was sufficient to trigger in vivo regression of established tumors in a murine xenograft model of human prostate cancer. Further, analysis of putative miR-708 targets showed that miR-708 targets the serine/threonine kinase Akt2/PKBβ, a member of the PI3K/Akt signaling pathway that plays a key role in cellular survival. Phenocopy experiments in prostate cancer cell lines suggest that Akt2 is a functionally relevant target of miR-708 in prostate cancer. In conclusion, our data suggests that miR-708 is a tumor suppressor microRNA that inhibits prostate cancer growth both in vitro and in vivo through targeting Akt2 pathways.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 134. doi:1538-7445.AM2012-134
Abstract 1340: A mouse model of metastatic intestinal cancers associated with Fbw7- and p53-loss
Authors: Grim Jonathan E. , Knoblaugh Sue , Hagar Amanda , Hespelt Jessica , Swanger Jherek , Guthrie Katherine , Small Thomas , Grady William M. , Nakayama Keiichi , Clurman Bruce E.
Published: August 2012

Colon cancer is a leading cause of cancer deaths in the USA, where it accounts for up to 50,000 deaths per year. Mouse models that recapitulate the genetic changes seen in human colon cancers are useful tools for biological and preclinical applications, but most available models develop adenomatous lesions that rarely metastasize. The Fbw7 tumor suppressor is a core component of a ubiquitin ligase complex that negatively regulates a number of proteins associated with genomic instability and cancer, including cyclin E, c-myc, Mcl-1, and Notch. Our previous work shows that Fbw7 cooperates with the p53 tumor suppressor to control genetic instability in vitro, and both Fbw7 and p53 are frequently deregulated in human colon cancers. We hypothesized that coordinate deletion of these two tumor suppressors would promote intestinal cancers in mice. To accomplish intestine specific deletion of these pathways, we interbred genetically engineered mice encoding conditional Fbw7 and p53 alleles with the VillinCre strain. Examination of normal intestines from the resulting Fbw7(fl/fl); p53(fl/fl); villinCre (FPV) animals showed abnormal proliferation and differentiation along the crypt-villus axis compared to control animals. Strikingly, the majority (55%) of FPV mice developed adenocarcinomas in the small intestine and cecum (median survival 70 weeks of age), and these tumors frequently metastasized to the lymph nodes and liver (in 36% and 14% of tumor bearing animals, respectively). Analysis of cancer tissues showed clear evidence of genetic instability in the majority of tumors. Finally, FPV tumors were readily grown as cell lines in vitro which could, in turn, grow as allografts in both immunodeficient and immunocompetent recipients. Notably, comparison of primary tumors and allografted cell lines showed similar pathological features and patterns of metastasis. This work confirms the critical role of the Fbw7 and p53 pathways in suppressing genetic instability and cancer development. Furthermore, the described FPV models recapitulate critical features of human colon cancer and should prove useful for studies of cancer biology, prevention, and therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1340. doi:1538-7445.AM2012-1340
Abstract 1341: Mice expressing activated PI3K develop advanced colon cancer
Authors: Deming Dustin A. , Leystra Alyssa A. , Christopher Zahm D. , Farhoud Mohammed , Olson Terrah J. Paul , Hadac Jaime N. , Nettekoven Laura A. , Albrecht Dawn M. , Clipson Linda , Sullivan Ruth , Washington Mary Kay , Torrealba Jose R. , Weichert Jamey P. , Halberg Richard B.
Published: August 2012

Background: Mutations in PIK3CA are a common feature of human cancers and multiple new PI3K inhibitors are in clinical development. These mutations are present in 20-30% of colorectal cancers in humans; however, the effects of such mutations on the intestinal mucosa have not been previously studied in animal models. Here we demonstrate that the expression of a dominant active form of the PI3K protein in the mouse intestine results not only in hyperplasia but also advanced neoplasia. Methods: Mice carrying a transgene in which the fatty acid binding protein promoter is fused to Cre recombinase (FC) were crossed to mice carrying a transgene encoding a chimeric protein with the iSH2 domain of the p85 subunit fused to the N-terminus of p110 (PIK3ca*). Progeny carrying both transgenes (FC PIK3ca*) express this constitutively active form of p110 in epithelial cells of the distal small bowel and colon. Results: Invasive mucinous adenocarcinomas develop in the proximal colon by only 50 days of age. These tumors are very aggressive, spreading into the mesentery and adjacent organs, and their histological characteristics are strikingly similar to those of invasive colon cancers in humans. Neoplastic cells exhibit a high rate of cell proliferation as seen by increased Ki67 immunohistochemical staining and phosphorylation of AKT, pS6, and p4E-BP1 by western blot demonstrating downstream signaling of PI3K. Interestingly, these cells did not exhibit perturbations in ERK and WNT signaling. Consistent with the lack of aberrant WNT signaling, no benign polypoid intermediaries were identified. Together, the results indicate that tumors in this model form via a non-canonical mechanism. A cohort of FC PIK3ca* mice were imaged by FDG dual hybrid PET/CT colonography and mice with similar sized tumors were divided into control and experimental arms. The experimental arm was treated with rapamycin (6mg/kg/day) for 14 days. Both groups were re-imaged 14 days later. The full results of the rapamycin treatment will be presented. Conclusion: This unique model of advanced colonic invasive adenocarcinomas has the potential to further our understanding of human disease and facilitate the development of therapeutics, especially inhibitors targeting downstream of PI3K.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1341. doi:1538-7445.AM2012-1341
Abstract 1365: The PAMM (pulmonary assessment of metastatic morbidity) diagnostic: A novel non-invasive method for evaluating lung metastasis in murine models
Authors: Gharpure Radhika V. , Mendoza Arnulfo , Dennis John U. , Khanna Chand
Published: August 2012

Metastasis continues to be the most significant problem in the field of cancer. The biological complexity that characterizes metastasis requires relevant experimental systems for its study, necessitating the use of animal models. When using murine models for pulmonary metastasis, it is valuable to conduct longitudinal studies during which progression of metastatic burden in the lung occurs. Current methods for evaluating pulmonary metastatic burden in experimental mice are limited to advanced imaging approaches or to the development of morbidity linked to pulmonary metastasis. Unfortunately, clinical signs of morbidity are often vague and unpredictable. A novel, inexpensive, clinical method to detect advanced metastatic burden in mice before the development of significant morbidity or mortality would be beneficial to the study of metastasis in mice. With this goal in mind we have developed a novel, non-invasive technique for assessing pulmonary metastatic burden in laboratory mice. The PAMM (Pulmonary Assessment of Metastatic Morbidity) test is performed by restraining an awake mouse and gently applying pressure with the index finger under the xiphoid process. This pressure reduces the diaphragmatic component to respiration. Mice with advanced lung metastases will show signs of respiratory distress within 3 seconds of applying this pressure. Application of this method in 4 models of pulmonary metastasis (n=27 mice including sarcoma and mammary carcinoma histologies), amongst 3 independent “users,” yielded 100% positive and 100% negative predictive values that were validated by post mortem examination. In summary, the PAMM method is a simple, inexpensive, reproducible and efficient method to assist in the detection of advanced pulmonary metastasis. This method contributes to the humane care of mice included in longitudinal studies of pulmonary metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1365. doi:1538-7445.AM2012-1365
Abstract 1399: SRC-1 up-regulates CSF-1 expression to potentiate breast cancer metastasis
Authors: Qin Li , Wu Yelin , Li Dabing , Toneff Michael Joseph , Tien Jean Ching Yi , Xu Yixiang , Liao Lan , Feng Zhen , Li Yi , Xu Jianming
Published: August 2012

Steroid receptor coactivator-1 (SRC-1/NCOA1) has been reported to be overexpressed in a subset of human breast cancer (BC) and its overexpression correlates with Her2 expression, disease recurrence and endocrine therapy resistance. To determine the role and underlying mechanisms of SRC-1 overexpression in BC progression and metastasis, a transgenic mouse model with overexpression of human SRC-1 in mouse mammary epithelial cells was created. In vivo data revealed that overxpression of SRC-1 potentiated BC metastasis to lung in both MMTV/Neu and MMTV/TVA/PyMT tumor models. While SRC-1 overexpression did not obviously accelerate tumor growth in these BC mouse models, the number of tumor cells invaded into blood vessels and metastasis index in lung tissue significantly increased in these mice. In addition to the elevated Twist expression and activation of Her2 and AKT driven by SRC-1 overexpression in the tumors, CSF-1 level was significantly increased in SRC-1 overexpressed tumors. We also found that CSF-1 expression was decreased in two PyMT/SRC-1 KO tumor cell lines compared with the two PyMT/WT control cell lines. Knockdown of SRC-1 in PyMT/WT cells or human BC cells reduced CSF-1 levels, while adenoviral-mediated expression of SRC-1 in PyMT/SRC-1 KO cells or human BC cells significantly promoted CSF-1 expression. Furthermore SRC-1 was found to interact with transcription factors, c-jun and c-fos, to activate the csf-1 promoter. Both SRC-1 and c-fos were found to associate with the csf-1 promoter at AP-1 binding sites in human BC cells. This study provided compelling evidence that overexpression of SRC-1 promotes BC metastasis. Targeting SRC-1 might be a potential therapeutic strategy for controlling BC metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1399. doi:1538-7445.AM2012-1399
Abstract 1401: Dietary selenium and metastasis in a mouse model
Authors: Mastro Andrea M. , Chen Yu-Chi , Sosnoski Donna M. , Prabhu K Sandeep
Published: August 2012

The skeleton is a common site for breast cancer metastasis. Once breast cancer cells enter the bone microenvironment, they alter the homeostasis of the bone remodeling system in favor of osteoclasts, which results in osteolysis. Breast cancer cells induce an osteoblast inflammatory response resulting in the production of IL-6, IL-8, MCP-1, and COX-2, known to promote osteoclastogenesis. Therefore, down-regulation of the inflammatory response of the osteoblasts brought about by breast cancer cells may reduce the activation of osteoclasts and decrease osteolysis. IL-6, MCP-1, COX-2 are regulated by a common transcription factor, NF-κB which is sensitive to intracellular redox status; its activation can be inhibited by cellular antioxidant enzymes. Two major antioxidant enzymes, glutathione peroxidase and thioredoxin reductase are selenoenzymes. Their dependence on selenium (Se) offers a way to increase their expression and activity, block NF-κB activation and thus inhibit the expression of its target genes. The hypothesis was that inhibition of NF-κB through dietary selenium would prevent the osteoblast inflammatory response and metastasis. To test the effect of dietary selenium in breast cancer progression, one of five diets: three selenium supplementation diets (sodium selenite, selenomethionine, and methylseleninic acid) or a selenium-deficient or a selenium adequate diet was fed to Balb/c mice for 3 months before inoculation of a metastatic breast cancer cell line 4T1.2luc into the mammary gland. The growth and metastasis of the tumors were followed by IVIS imaging. After 4 weeks, organs were collected and prepared for Q-PCR analysis of the luciferase gene as an indicator of metastatic burden. There was no significant difference in the development or growth of the primary breast tumor and the metastatic patterns between mice receiving the selenium-deficient or selenium-adequate diets. On the other hand, selenium supplementation diets were shown to affect breast cancer progression differently. Mice with sodium selenite supplementation developed the most metastasis (15/15) and showed higher incidence of breast cancer kidney and bone metastasis. The selenomethionine supplementation diet (3ppm) reduced breast cancer primary tumor growth and decreased overall tumor burden in major organs, such as lung, liver, kidney and femur. Taken together, this study showed that dietary selenium affected tumor growth and metastasis and that the selenomethionine supplementation diet offered the most protective effect on breast cancer progression. Support: American Institute for Cancer Research with supplemental support from the National Foundation for Cancer Research.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1401. doi:1538-7445.AM2012-1401