bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2268: Systems analysis identified Thioredoxin family genes as a prognostic signature and novel therapeutic target for gastric cancer
Authors: Lim Jae Yun , Yoon Sun Och , Hong Soon Won , Kim Jong Won , Choi Seung Ho , Cho Jae Yong 
Published: June 2012

Abstract
Background: Gastric cancer is the second cause of cancer-related deaths worldwide. After curative surgery, relapse occurs in a large number of patients except for early gastric cancer patients. Even though within the same stage, gastric cancer patients present diverse clinical manifestations and prognosis. The clinical diversity of gastric cancer arises from the molecular biological diversity, which is caused by changes in different genes. This study aimed to identify potential biomarkers which could be used to classify patients according to prognosis and also become new therapeutic targets.
Procedures: We obtained whole genome expression microarray data of 65 primary gastric adenocarcinoma patients and the results were validated by quantitative reverse transcription polymerase chain reaction experiment of 68 gastric cancer tissues. We uncovered prognostic subgroups of gastric cancer and identified expressions of a limited number of genes are significantly associated with prognosis. Immunohistochemical assay using 328 gastric cancer tissues was performed to validate protein levels of biomarker gene.
Results: A gene encoding thioredoxin (TXN) was found to be markedly elevated in many gastric cancer tissues and strongly related to poor prognosis (p=0.009) in univariate analysis. Conversely, thioredoxin interacting protein (TXNIP), TXN inhibitor, was significantly decreased in patients with poor prognosis. Systems analysis revealed TXN and TXNIP were highly correlated with many oncogenes and tumor suppressors and also with energy and protein synthesis. It was validated that TXN and TXNIP expression were significant prognostic biomarker even in the same stage patients. When patients were classified into the three groups by expression level of TXN and TXNIP, TXN low and TXNIP high expression group showed better prognosis than others; recurrence free survival (p&lt;0.001) and overall survival (p=0.001). Hypoxia induced gene, ERO1-like (ERO1L), also highly correlated with TXN and this suggested that TXN and TXNIP were influenced by hypoxia in gastric cancer.
Conclusion: TXN and TXNIP are promising prognostic markers for gastric cancer and agents that target TXN or up modulate TXNIP could be used in target therapy for gastric cancer patients who are selected based on TXN and TXNIP gene signatures.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2268. doi:10.1158/1538-7445.AM2011-2268
Abstract 2270: ATM is hyperactivated in triple-negative breast cancer tissues
Authors: Guo Xiaojing , Lei Ting , Sun Mianen , Yang Chunying , Fu Li , Xu Bo 
Published: June 2012

Abstract
Triple-negative breast cancer (TNBC) represents a phenotype defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) expression. TNBCs are extremely aggressive and lack effective therapeutic targets. The DNA damage response is an active mechanism which prevents genetic instability and tumorigenesis. We have recently found the existence of active DNA damage responses in late stage breast cancer tissues. Here we report a critical role of the Ataxia-Telangiectasia-Mutated (ATM) kinase, a key transducer of DNA damage signals, in TNBC metastasis. By analyzing ATM activity in 169 cases of TNBC using immunohistochemistry, we found that ATM activity is enhanced in TNBCs, compared to 210 cases of non-TNBCs (P=0.003). Among the TNBC cases, 62.1% have lymph node metastasis, and ATM is hyperactive in these cases. As epithelial-mesenchymal transition (EMT) is associated with increased aggressiveness and metastatic potential, we also assessed the occurrence of EMT in these tissues. Interestingly, our results showed that tumors with higher ATM activity displayed increased expression levels of Snail, an early EMT marker (P=0.001). We also observed a strong correlation of ATM activity with up-regulation of another EMT marker, vimentin (P=0.015), and with reduction of characteristic epithelial markers, E-cadherin and cytokeratin (P=0.002 and P=0.036, respectively). Among the TNBC cases, the expression levels of activated ATM and Snail were significantly correlated with lymph node metastasis (P=0.008 and P=0.01, respectively). In our laboratory, we have extensively studied the molecular link between ATM and Snail, demonstrating that an active ATM-Snail pathway is essential for breast cancer metastasis. Taken together, our clinical data indicate that deficiency of ER, PR and HER2 may lead to hyperactive ATM and Snail, which contribute to high invasiveness and metastasis of TNBCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2270. doi:10.1158/1538-7445.AM2011-2270
Abstract 228: A comprehensive study to functionally classify the BRCA2 missense mutations found in Fanconi anemia patients
Authors: Biswas Kajal , Das Ranabir , Alter Blanche P. , Kuznetsov Sergey , North Susan L. , Stauffer Stacey , Burkett Sandra , Brody Lawrence C. , Meyer Stefan , Byrd Andrew R. , Sharan Shyam K. 
Published: June 2012

Abstract
Biallelic mutations in breast cancer susceptibility gene 2 (BRCA2) cause a severe Fanconi Anemia (FA) phenotype that is a rare recessive disorder and reflects the cellular and phenotypic consequences of genetic instability. A number of mutations found in FA patients are missense mutations in BRCA2 and classified as variants of unknown clinical significance. This study is aimed towards the evaluation of functional significance of a few BRCA2 unclassified variants.
In this study, six of the human mutations (L2510P, R2336H, I2490T, W2626C, K2729N and IVS7+2T&gt;G) were generated in human BRCA2 gene cloned in a bacterial artificial chromosome vector. The effect of these variants on BRCA2 function was examined by using a mouse embryonic stem (ES) cell-based assay. We have shown the ability of wild-type human BRCA2 and neutral BRCA2 variants to rescue the lethality of Brca2-null mouse ES cells and functionally complement the loss of endogenous mouse Brca2. W2626C and IVS 7+2T&gt;G mutations failed to restore the viability of ES cell colonies after deletion of the endogenous mouse Brca2. The K2729N BRCA2 rescued the ES cell lethality and appeared similar to wild-type BRCA2 in various functional assays. In contrast, L2510P and R2336H BRCA2 exhibited reduced ES cell viability. In addition, ES cells expressing L2510P BRCA2 are sensitive to DNA damaging agents. Furthermore, L2510P BRCA2 mutant ES cells are slow growing, have increased genomic instability, defective in G1-S checkpoint control and show upregulation of p53 and p21. These mutant cells are defective in homologous recombination mediated DNA repair. IVS7+2T&gt;G and R2336H mutations result in exon-skipping leading to premature protein truncation. Alterations in L2510P, I2490T, W2626C and K2729N map to a highly conserved region of BRCA2 and the homology based molecular modeling of the mutant proteins supports our ES-cell results. L2510P and W2626C mutations disrupt the BRCA2 structure and the interaction of BRCA2 with a highly conserved protein DSS1, whereas I2490T and K2729N mutations do not affect the BRCA2 structure and are neutral in nature. It is possible that the patients with the variant alleles that are neutral in this assay have other undetected mutation in that allele or have mutations in some other FA genes. In conclusion, this study provides functional classification of a few variants of unknown clinical significance that should help in counseling individuals carrying these alleles.
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Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 228. doi:10.1158/1538-7445.AM2011-228
Abstract 2291: Inhibition of c-Src restores estrogen stimulated growth in estrogen-deprivation resistant MCF-7 breast cancer cells
Authors: Fan Ping , Kim Helen , McDaniel Russell , Jordan V. Craig 
Published: June 2012

Abstract
Resistance to aromatase inhibitors used for the treatment of estrogen receptor (ER) positive breast cancer is an increasing clinical problem. Previously we showed that physiological concentrations estradiol (E2) could trigger apoptosis of long-term E2 deprived breast cancer cells (MCF-7:5C) (Lewis et al. JNCI 2005; 97:1746-59). This new targeted strategy provides novel therapeutic approaches to endocrine resistant breast cancer. A recent phase II clinical trial reported that E2 provided a clinical benefit for aromatase inhibitor-resistant advanced breast cancer patients. However, only 30% of patients receive clinical benefit (Ellis MJ et al. JAMA 2009;302:774-80). This prompted us to investigate strategies to increase the therapeutic responsiveness in aromatase inhibitor resistant breast cancer. c-Src is currently of interest, as it mediates survival pathways of breast cancer cells. Here, we investigate the therapeutic potential of combination c-Src inhibitor PP2 and E2 on the MCF-7:5C cells. In the short-term treatment, c-Src inhibitor could block both Akt and MAPK pathways and decreased growth rates of MCF-7:5C cells. c-Src inhibitor could continuously block phosphor-Akt, but phosphor-MAPK pathway was increased after long-term treatment. Long-term treatment with E2 alone initially caused massive apoptosis, but a small population of surviving cells subsequently re-grew. In contrast, a combination of PP2 and E2 actually blocked apoptosis and the resulting cell line (MCF-7:PF) was unique, as they grew vigorously in culture with physiological levels of E2, which could be blocked by the pure antiestrogen ICI182,780. The mechanistic change underlying the action of combination treatment was that the c-Src inhibitor blocked E2 initiated apoptosis and collaborate with E2 to up-regulate endogenous ERα target genes and insulin-like growth factor-1 receptor (IGF-1Rβ) in MCF-7:PF cells. Furthermore, the inhibitor of IGF-1Rβ, AG1024, completely blocked E2 stimulated growth. This provides the evidence that IGF-1Rβ plays an important role in E2 stimulated growth in MCF-7:PF cells. These data illustrate that caution must be exercised when considering the evaluation of c-Src inhibitors in clinical trial following the development of acquired resistance to aromatase inhibitors, especially in combination with physiological levels of E2.
Key words: c-Src, long-term estrogen deprivation, apoptosis, breast cancer
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2291. doi:10.1158/1538-7445.AM2011-2291
Abstract 2304: 2-DG inhibits of N-glycosylation in glioblastoma-derived cancer stem cells
Authors: Priebe Waldemar , Emmett Mark R. , Ji Yongjie , Fokt Izabela , Skora Stanislaw , Conrad Charles , Wang Xu , Marshall Alan G. 
Published: June 2012

Abstract
Cancer stem cells (CSCs) are capable of unlimited self-renewal and multi-lineage differentiation. We have shown that 2-deoxy-D-glucose (2-DG), a known inhibitor of glycolysis, that is also a 2-deoxy-D-mannose can inhibits the growth of glioma-derived stem cells (GSC11) under normoxic conditions, and we hypothesize that 2-DG can affect D-glucose and D-mannose metabolism in glioblastoma derived cancer stem. Our studies showed that 2-DG affects formation of N-glycans by replacing D-mannose in glycosylation processes. We have synthesized 2-DG, D-glucose, and D-mannose labeled with deuterium at C-2 and C-6 and treated GSC11 cells with these monosaccharides to measure their effects on global N-glycan formation. Our results demonstrated that deuterium labeled 2-DG was incorporated into the N-glycans leading to the termination of the extension of oligosaccharide chain. Comparative glycomic analysis of control, 2-DG-treated, and D-mannose-rescued GSC11cells revealed a distinct modulation of the N-glycan profile. The levels of all types of N-glycans were decreased (by ∼4-fold) in 2-DG-treated GSC11 cells compared with control cells. In contrast, N-glycan synthesis in GSC11 cells could be rescued to almost “normal control” levels by adding exogenous D-mannose. D-Mannose rescue of 2-DG-treated GSC11 cells drastically reduced the incorporation of 2-DG into the N-glycans. These results indicate that 2-DG can interfere with biochemical transformations of D-mannose and that such interference might contribute to the overall antitumor effects of 2-DG.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2304. doi:10.1158/1538-7445.AM2011-2304
Abstract 2319: Target selective drug delivery through liposomes labeled with tetra-branched neurotensin peptides
Authors: Bracci Luisa , Falciani Chiara , Pini Alessandro , Brunetti Jlenia , Lelli Barbara , Accardo Antonella , Tesauro Diego , Morelli Giancarlo 
Published: June 2012

Abstract
Aim of the study was to construct and test liposomes labeled with tetra-branched receptor-specific peptides for target selective drug delivery.
Membrane receptors for endogenous peptides, like neurotensin (NT), are over-expressed by different human cancers and can be targeted as tumor-specific antigens. We found that peptide sequences, when synthesized in an oligo-branched form, become resistant to proteolysis and thanks to their multimericity are more efficient than corresponding monomers in binding cellular antigens (1).
In previous works we developed tetra-branched NT peptides (NT4), which can be used as ‘theranostics’, by addition of different functional units to the tumor targeting sequence (2-4).
Here we describe the synthesis of liposomes filled with the cytotoxic drug doxorubicin (Doxo) and functionalized on the external surface with a tetra-branched neurotensin peptide. The new functionalized liposomes, DOPC/NT4Lys(C18)2 (NT4-liposomes), are obtained by co-aggregation of the DOPC phospholipid with a new synthetic amphiphilic molecule, NT4Lys(C18)2, containing a lysine scaffold derivatized with a lypophilic moiety and the tetrabranched hydrophilic NT peptide. Selective internalization and cytotoxicity of NT4-liposomes and DOPC nude liposome, both loaded with doxorubicin, were tested in different human cancer cell lines. Peptide-functionalized liposomes showed a clear advantage with respect to DOPC nude liposomes in drug internalization, as followed either by confocal microscopy or cytofluorimetry. Cytotoxicity of NT4-Doxo-liposomes is increased with respect to DOPC-Doxo liposomes. The higher rate of internalization of NT4-Doxo-liposomes, might be due to a lower dissociation constant of the NT4-liposomes that bind the membrane onto a specific protein, differently to the DOPC liposomes that approach the plasma membrane unselectively.
These results are highly encouraging for an in vivo use of NT4-liposomes, considering that we already proved that, thanks to their cell selectivity, drug armed NT4 are much more effective in mice cancer models than in in vitro cytotocity experiments.
References.
1. Bracci et al. J Biol Chem. 2003, 278, 46590-5.
2. Falciani et al. Mol. Cancer Ther. 2007, 6, 2441-8.
3. Falciani et al. Curr. Cancer Drug Targets, 2010, 10, 695-04.
4. Falciani et al. ChemMedChem 2010, 5, 567-74.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2319. doi:10.1158/1538-7445.AM2011-2319
Abstract 232: Targeting HER3 mRNA by a locked nucleic antisense molecule enhances the antitumor activity of gefitinib in vivo
Authors: Wu Yaming , Wang Maoliang , Kraft Patricia , Qu Zhengxing , Zhang Yixian , Shi Victoria , Greenberger Lee M. , Horak Ivan D. 
Published: June 2012

Abstract
Background: The HER family consists of four tyrosine kinase receptors designated as EGFR, HER2, HER3 and HER4. HER3 is a unique member that plays a critical role in tumor growth since it 1) can heterodimerize with EGFR or HER2 and is the main link to the downstream PI3K/Akt signaling axis, 2) can mediate resistance to HER1/2-targeted therapeutics, and 3) unlike EGFR or HER2, is not typically overexpressed but still hyperphosphorylated in a variety of tumors. Resistance to the EGFR-tyrosine kinase inhibitors, such as gefitinib, can be associated with EGFR mutations and/or activation of HER3 ultimately leading to activation of the PI3K/AKT axis. We have used an RNA antagonist of HER3, designated EZN-3920, to explore the ability of this compound to inhibit tumor growth and overcome resistance to HER1/2 therapeutics. Methods: Tissue culture cells were treated with EZN-3920, a locked nucleic acid (LNA)-based oligonucleotide complementary to HER3. Compound was either added to tissue culture media (i.e. no transfection) in vitro or prepared in saline and given IV in vivo. Endpoints were measured by qRT-PCR, MTT, Western Blot analysis, Immunohistochemistry, and tumor size. Results: EZN-3920 down modulated HER3 mRNA, protein expression, PI3K/AKT signaling, and inhibited tumor cell proliferation. In vivo, systemic administration of EZN-3920, prepared in saline, resulted in specific down- modulation of HER3 mRNA and protein expression, as well as blockade in PI3K/AKT signaling pathways in NSCLC HCC827 associated with tumor growth inhibition. Similar results were also shown in tumor derived from BT-474-M1 breast carcinoma xenograft models. Interestingly, in the HCC827 tumor model, EZN-3920 at 30 mg/kg (biweekly for 4 weeks, i.v.) and gefitinib at 15 mg/kg (5 times a week for two weeks) completely shrank established tumors while either treatment alone only delayed tumor growth by 40-60%. Conclusions: The studies suggest that down regulation of HER3 by antisense molecule EZN-3920 inhibits human tumor growth in mice. Beyond this, antitumor effects of gefitinib can be enhanced by HER3 down modulation in gefitinib-sensitive tumors. On-going studies will determine if tumors that are resistant to HER1/2 therapeutics will either have enhanced sensitivity to EZN-3920 and/or the compound can restore sensitivity to such agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 232. doi:10.1158/1538-7445.AM2011-232
Abstract 2325: The crystal structure of the ERK2/norathyriol complex
Authors: Malakhova Margarita , Kurinov Igor , Li Jixia , Reddy Srinivasa , Bode Ann M. , Dong Zigang 
Published: June 2012

Abstract
Norathyriol is an active metabolite of mangiferin, one of the mango polyphenolic compounds that have been demonstrated to have anti-proliferative and pro-apoptotic activities against human leukemia, as well as human lung, breast, colon and prostate cancer cells. Norathyriol has been reported to inhibit the PMA-induced respiratory burst and aggregation of rat neutrophils by suppressing protein kinase C activity. We show that norathyriol targets extracellular signal-regulated kinase 2 (ERK2), which is activated in response to growth factors and cytokines, and is a key kinase in the Ras/Raf/MAPK signaling pathway, which is deregulated in many cancers. We determined the crystal structure of ERK2 complexed with norathyriol at 1.6 Å resolution. Human recombinant ERK2 was expressed, purified from E.coli and successfully crystallized. The protein crystals were soaked with norathyriol solution prior to the data collection. The norathyriol molecule is clearly visible in the electron density map inside the ATP-binding site below the phosphate-binding loop. Norathyriol is anchored to the ERK2 hinge region that connects the kinase N- and C-lobes by several hydrogen bonds. The side chain carboxyl of the gatekeeper residue Gln105 hydrogen bonded with the 7-OH group of norathyriol. The backbone of Asp106 and Met108 form hydrogen bonds with 6-OH group of norathyriol. We mutated Gln105 to alanine to weaken the norathyriol interaction with ERK2, and showed that the recombinant Q105A mutant exhibited impaired in vitro binding affinity to norathyriol compared with wild type. The Ile31, Val39, and Ala52 residues from the N-lobe contribute to the hydrophobic interactions with the xanthone moiety of norathyriol. These results indicate that norathyriol directly binds to the ATP-binding site of ERK2. The Ras/Raf mutation in many cancers causes the hyperactivation of ERK2 and unregulated cell proliferation. Recent reports indicate that knockdown of ERK2 inhibits growth of tumor cells, suggesting that ERK2 inhibition is a potential approach for the treatment of cancer. Norathyriol thus might be a potential therapeutic and chemopreventive lead compound targeting ERK2 in cancer cells where activation of the ERK2 pathway mediates the anti-apoptotic response.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2325. doi:10.1158/1538-7445.AM2011-2325