bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5336: Change in pattern of relapse following anti-angiogenic therapy in high grade gliomas
Authors: Narayana Ashwatha , Kunnakkat Saroj , Medabalmi Praveen , Golfinos John , Parker Erik , Knopp Edmond , Zagzag David , Gruber Deborah , Gruber Michael L. 
Published: February 2011

Abstract
Purpose:. Local recurrence (LR) accounts for &gt;90% at the time of relapse in high grade glioma (HGG) following conventional therapy. Anti-angiogenic therapy with bevacizumab has shown impressive radiological and clinical responses in HGG. However, an apparent increase in diffuse invasive relapse (DIR) following therapy necessitated a detailed analysis of pattern of recurrence following therapy.
Methods: One hundred and sixty five consecutive patients with HGG, either newly diagnosed (n=75) or recurrent (n= 90) received therapy with bevacizumab at 10 mg/kg every two weeks along with conventional chemotherapy ± involved field radiotherapy. The treatment was continued till the time of disease progression or the patient developed dose limiting toxicity. Treatment evaluation was done with neurological examination and magnetic resonance imaging at base line and every 8 weeks subsequently. Pattern of recurrence and time to relapse were the primary aims of the study. DIR was defined as involvement of multiple lobes ± crossing the midline. Survival was calculated from the start of bevacizumab therapy.
Results: With a mean follow-up of 6.8 months (range 1-58), 100 of the 165 patients (60.6%) have relapsed with 76 as DIR and 70 have died. The median progression free survival (PFS) and overall survival (OS) were 5 and 9 months respectively. Of the 62 patients who failed initially as LR, 38 (61.3%) patients subsequently developed DIR. 38/75 (50.7%) patients with newly diagnosed and 38/90 (42.2%) of recurrent HGG failed ultimately as DIR. All 9 patients who presented with multicentric HGG relapsed as DIR. The median OS for the patients who failed as DIR was 9 months Vs 6 months for patients with LR alone (p=0.06). While the hazard risk for LR remained linear over time, the risk of DR increased exponentially with time (R2 = 0.933). Biopsies done on eight of these patients at the time of recurrence showed decreased expression of Olig-2 in 6, increased expression of SDF-1 in 5 and a variable expression of CXCR-4 in 6 patients. No change in expression of HIF-1, p53, PDGF or CD163 was seen.
Conclusion: Invasion remains a dominant process in HGG as demonstrated by both imaging and pathology. Angiogenic blockade that results in increased invasiveness of HGG is worrisome and needs to be addressed in future clinical trials.
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 5336.
Abstract 5342: Phage display selelction on tumor histological specimens
Authors: sun yujing , Shukla Girja , Pero Stephanie , Peletskaya Elena , Krag David 
Published: February 2011

Abstract
A method was developed to obtain phage displayed ligands that bind to a select population of cells in histological specimens of freshly harvested solid human cancers. It combines phage display panning with laser capture microdissection (LCM). This method allows selection of phage ligands bound to subpopulations of specific cells contained in tumor tissue on histological sections. Naïve phage scFv library was incubated directly on a histological section of human breast cancer that was snap frozen immediately after surgical resection. Tumor stromal cells were captured by LCM and bound phages were recovered by bacterial infection. Individual phage clones selected after three rounds of panning were evaluated for their binding ability by immunofluorescence staining on tumor tissue from the same patient. Based on DNA analysis, 20% of 3rd output clones represented a single clone. This clone selectively bound tumor stroma in the breast cancer specimen and did not bind the malignant cell population. This clone, expressed as a soluble scFv, showed no significant binding to normal tissues, 13 other breast cancers or 4 colon cancer samples. This method is applicable for selection of ligands to virtually any portion of a histological specimen amenable to LCM. This may speed the process of generating ligands to any subset of cells or noncellular feature present on histological specimens.
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 5342.
Abstract 5354: HPV-16 E7 oncoprotein induces centriole multiplication through deregulation of PLK4, a master regulator of centriole biogenesis
Authors: Korzeniewski Nina , Duensing Anette , Duensing Stefan 
Published: February 2011

Abstract
Human papillomavirus (HPV)-associated neoplasms exhibit abnormal centrosome and centriole numbers that can cause mitotic defects, chromosome missegregation and aneuploidy. Centrosomes are the major microtubule-organizing centers in most mammalian cells and orchestrate the formation of mitotic spindle poles. The centrosome consists of a pair of centrioles that normally duplicate precisely once prior to mitosis. The HPV-16 E7 oncoprotein has been found to rapidly stimulate centriole overduplication within a single cell division cycle, thereby increasing the risk for cell division errors. We discovered that this activity of the HPV-16 E7 oncoprotein involves the concurrent formation of multiple daughter centrioles at single maternal centrioles (centriole multiplication). We found that deregulated cyclin E/cyclin dependent kinase 2 (CDK2) activity, as occurs following HPV-16 E7 oncoprotein expression, leads to the aberrant recruitment of polo-like kinase 4 (PLK4) to maternal centrioles, which is subsequently degraded by the SCF ubiqutin ligase complex. These and several other results underscore that the level of PLK4 at maternal centrioles is rate-limiting for centriole multiplication. Hence, we asked whether the HPV-16 E7 oncoprotein can alter PLK4 expression and/or localization. We found aberrant PLK4 protein expression at maternal centrioles in primary human keratinocytes engineered to stably express HPV-16 E7. Real-time quantitative RT-PCR revealed an increase in PLK4 transcription in keratinocytes stably expressing HPV-16 E7. The ability of HPV-16 E7 to upregulate PLK4 mRNA was found to depend on its ability to degrade the retinoblastoma (pRb) protein, suggesting a role of E2F-mediated gene transcription in deregulation of PLK4. Collectively, these results highlight the critical role of PLK4 as a regulator of centriole biogenesis and identify PLK4 as a novel target for small molecules to prevent centriole abnormalities, mitotic infidelity and malignant progression in HPV-associated neoplasms.
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 5354.
Abstract 535A: The tyrosine kinase Src co-operates with the ERM family member ezrin to promote Met activation and ECM degradation in a breast epithelial cell model
Authors: Hoskin Victoria , Organ Shawna , Furmaniak-Kazmierczak Emilia , Pilon Jenna , Meens Jalna , Cote Graham , Elliott Bruce 
Published: February 2011

Abstract
Over-expression and aberrant activation of the Met proto-oncogene frequently occurs in invasive breast cancer, and is linked with poor patient prognosis. We and others have shown that the tyrosine kinase Src mediates cell-adhesion dependent activation of Met in the absence of ligand (JCB 107:1168-81, 2009). We have also shown that Src acts co-operatively with the membrane cytoskeletal crosslinker ezrin to disrupt cell-cell contacts, and to increase cell spreading and scattering, all characteristics of epithelial-to-mesenchymal transition (EMT) (JCB 92:16-28, 2004). We therefore examined the role of Src and ezrin in Met activation and invasion of breast epithelial cells. As a model, we used the HC11 breast epithelial cell line expressing various combinations of activated Src and ezrin mutants, as well as a dominant negative ezrin mutant. In contrast to activated Src, which promotes the phosphorylation and hence activation of Met and cell spreading, activated ezrin alone induces the formation of numerous filopodia-like structures, but not Met phosphorylation or cell spreading. Co-activation of Src and ezrin produces a combination of both cell spreading and filopodia-like structures, and strongly increases Met phosphorylation over levels resulting from activated Src alone. Interestingly, Src/ezrin co-operativity dramatically increases tyrosine-phosphorylation of cortactin and MMP2 expression, resulting in the formation of invadopodia and extracellular matrix degradation, a hallmark feature of invading cancer cells. However expression of a dominant negative ezrin domain (aa1-309) abolishes Src and ezrin-induced morphological phenotypes, as well as Src-dependent Met phosphorylation and invadopodia formation, suggesting an important requirement for ezrin in these processes. These findings implicate the Src/ezrin axis in regulating adhesion-dependent Met activation and invadopodia formation, and may provide important clues toward treatment strategies for invasive breast tumors which exploit this signaling pathway (Supported by CBCRA and CIHR).
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 535A.
Abstract 5360: Leptin-induced SIRT1 expression in human colon cancer cells: a potential link between obesity and cancer
Authors: Song Na-Young , Surh Young-Joon 
Published: February 2011

Abstract
Recently, several epidemiological studies have shown that obesity is one of the prime factors in the etiology of some malignancies. The molecular mechanism underlying obesity-induced carcinogenesis, however, is not fully clarified yet. Leptin, a representative adipokine secreted from the white adipose tissue, is considered as a potential linker between obesity and cancer. Although leptin has been identified as an anorexic adipokine, obese subjects exhibit unexpectedly higher circulating levels of leptin than non-obese individuals. Increased serum levels of leptin may activate the pro-inflammatory signals and stimulate the tumor growth. In the present study, we have found that treatment with leptin (100 ng/ml) promotes migration and invasion of human colon cancer (HCT-116) cells, suggesting leptin as a molecular link between obesity and cancer. Interestingly, leptin induced expression as well as activity of SIRT1, a NAD+-dependent class III histone deacetylase, recognized as an important metabolic regulator. It has been reported that SIRT1 exerts an anti-aging effect. Paradoxically, SIRT1 gene is highly expressed in certain types of tumors, and is speculated to function as an oncogene. We found that leptin-induced HCT-116 cell migration and invasion were blocked by treatment with sirtinol (25 μM), an inhibitor of SIRT1. NF-E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor responsible for regulating expression of a battery of stress-responsive genes. Considering that obesity is a state of chronic oxidative stress, Nrf2 might be involved in leptin-induced SIRT1 up-regulation. In line with this notion, several consensus antioxidant response elements (AREs) specified for Nrf2 binding are found within a promoter region of SIRT1. Treatment of HCT-116 cells with leptin provoked nuclear translocation and ARE binding of Nrf2. Moreover, siRNA knockdown of Nrf2 abrogated leptin-induced SIRT1 expression, lending further support to the notion that Nrf2 regulates SIRT1 expression in leptin-treated HCT-116 cells. We also found that treatment with leptin led to accumulation of reactive oxygene species (ROS) in HCT-116 cells. Pre-treatment with N-acetyl cysteine attenuated leptin-induced SIRT1 expression, indicating a possible involvement of ROS. In conclusion, leptin, a key adipokine in obesity, may mediate colon tumor progression via Nrf2-dependent SIRT1 expression.
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 5360.
Abstract 5366: NAD(P)H-Quinone oxidoreductase (NQO1): Potential role in the prevention of estrogen-induced breast cancer
Authors: Singh Bhupendra , Bhat Hari K. 
Published: February 2011

Abstract
The importance of estrogens in the etiology of breast cancer is widely recognized. However, the exact mechanisms underlying the initiation and progression of estrogen-related cancers are not clear. Literature evidence and our studies strongly support the role of estrogen metabolism-mediated oxidative stress in estrogen-induced breast carcinogenesis. The objective of the current study was to characterize the role of NQO1 in the prevention of estrogen-induced mammary tumorigenesis by antioxidants vitamin C or butylated hydroxyanisole (BHA). NQO1 converts 17β-estradiol (E2)-quinones back to E2-catechols, thus making E2-quinones unavailable for oxidant damage. Female ACI rats were treated with E2 (3 mg); vitamin C (1% in drinking water); E2 + vitamin C; BHA (0.7% in diet); and E2 + BHA for up to 8 months. The female ACI rat is an established animal model to study the mechanisms of E2-induced breast cancer. The protein isolated from breast tissue and breast tumor tissue of rats treated with E2 and antioxidants was analyzed for NQO1 expression. NQO1 was suppressed in E2-exposed mammary tissue after treatment of rats with E2 for 8 months and in mammary tumors. This suppression was overcome by co-treatment of rats with E2 and vitamin C or BHA. Co-treatment of rats with E2 and vitamin C resulted in a 4-fold induction of NQO1 compared to control mammary tissue. Similarly, co-treatment of rats with E2 and BHA induced NQO1 4.4-fold compared to control mammary tissue. There was no change in NQO1 expression during early time points of E2 exposure (7 and 15 days). The up-regulation of NQO1 by vitamin C or BHA was evident after 4 months of treatment. There was no effect of BHA or vitamin C treatment on NQO1 expression on other non-target organs like liver, lung and heart except kidney. These studies suggest a protective role of NQO1 in E2-induced breast carcinogenesis. NQO1 may thus have a great potential in the development of therapeutic strategies for the prevention of estrogen-induced neoplasia.
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 5366.
Abstract 5370: Potentiation of the novel topoisomerase I inhibitor indenoisoquinoline NSC743400 by Chk1/2 inhibitors in p53-deficient cells
Authors: Aris Sheena M. , Pommier Yves 
Published: February 2011

Abstract
Clincally available camptothecin derivatives, though highly effective against a broad range tumors, are limited by their chemical instability, solubility, ABCG2-mediated efflux and reversibility of Top1-DNA complexes. Indenoisoquinolines were identified as topoisomerase I (Top1) inhibitors by the COMPARE analysis of the NCI drug screen database. Although structurally similar to camptothecin, idenoisoquinolines are chemically stable, able to overcome ABCG2 efflux while forming more persistent Top1-DNA complexes and maintaining potent antitumor activity. The potential for indenoisoquinoline derivatives as possible clinical agents is further aided by the synergistic effect observed between camptothecin and Chk1/2 inhibitors. Chk1/2 kinases regulate cell cycle, DNA damage response via ATM, ATR and DNA-PK, which are activated by genomic instability. Previous studies have shown Chk1/2 inhibitors, such as UCN-01, can potentiate camptothecin-mediated cytotoxicity in p53 mutant cells by eliminating the DNA replication checkpoint.
Further synthesis has led to the water-soluble indenoisoquinoline derivative, NSC743400 for clinical development. Current checkpoint kinase inhibitors, like PV1019 or AZD7762, offer a higher level of specificity than their predecessors that can be exploited by combination with indenoisoquinolines. Checkpoint inhibition showed synergistic antiproliferative activity with NSC743400 in human colon carcinoma HT-29 cells. Furthermore, AZD7762 was able to abrogate the late S-phase arrest induced by NSC743400 as early as 3h post treatment. Inhibition of checkpoint kinases also abrogated the DNA replication fork progression response to NSC743400. The effect of these inhibitors on the autophosphorylation of both Chk1 and Chk2 post NSC743400 was examined by Western blot. These results further substantiate the idea that checkpoint inhibition is a viable strategy in enhancing the antiproliferative effect of novel non-camptothecinn inhibitors such as the indenoisoquinolines.
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 5370.
Abstract 5371: Synergistic antitumor effect of HDAC inhibitor PXD101 in combination with irinotecan in colon cancer
Authors: Na Young-Soon , Jung Kyung-A , Kim Seung-Mi , Ryu Min-Hee , Hong Yong Sang , Kim Jin Cheon , Lee Jung Shin , Kim Tae Won 
Published: February 2011

Abstract
The histone deacetylase inhibitors (HDACi), such as PXD101 or SAHA, inhibit the proliferation and stimulate the apoptosis in tumors. The enhanced effect of HDACi combined with chemotherapy or radiotherapy has been reported in several cancers. In this study, we investigated the antitumor effect of HDACi PXD101 combined with irinotecan in colon cancer.
PXD101 and SN38, active form of irinotecan, had a dose-dependent anti-proliferative activity in HCT116 and HT29 colon cancer cells. PXD101 combined with SN38 had a synergistic effect in colon cancer cell lines, as shown by combination index. The combination of PXD101 with SN38 had an effect on XIAP and p21 protein expressions with time- and dose-dependent manner, more prominently in HCT116 than HT29 cells. These effects were further enhanced by the addition of PXD101 than irinotecan alone in both cell lines. In xenograft mice, PXD101 in combination with irinotecan dramatically inhibited tumor growth without additive toxicity. In addition, antiumor effect was more prominent in HCT116 than HT29 xenografts. Apoptotic effects of tumor in xenografts treated with these combinations were better than irinotecan alone. Combination of PXD101 and irinotecan resulted in 63 % of relative SUV mean in [18F]FLT-PET in mice with established HCT116 xenograft. Early response to these agents can be detected with [18F]FLT-PET. These data suggest that PXD101 increases the cytotoxic activity of iriontecan in colon cancer and these drug combinations should be explored in the treatment of colon cancer.
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 5371.
Abstract 5377: Disruption of akt/hif1 signaling can enhance the therapeutic efficacy of ischemic hypoxia and chemotherapy
Authors: Lau Chi-Keung , Yang Zhen Fan , Ho Wing Yuen , Ng Michael , Poon Tung Ping , Fan Sheung Tat 
Published: February 2011

Abstract
PURPOSE: This study investigates the possible molecular basis leading to failure in a treatment that is composed of hypoxia and chemotherapy in a rat orthotopic hepatoma model. EXPERIMENTAL DESIGNS: Cell viability after cisplatin treatments under normoxia and hypoxia would be measured by 3,[4,5-dimethylthiazol-2-yl] −2,5-diphenyl-tetrazolium bromide (MTT) assay and cytofluorometric annexin-V apoptotic assay would be used to compare the apoptotic cells induced by cisplatin under normoxia and hypoxia. Western blotting would be employed to determine the akt/hif1 signaling. In vivo hypoxic condition was induced by hepatic artery ligation, whereas chemotherapeutic effect was achieved by intraportal injection of cisplatin. Hif1 inhibitor was administered to blockade Hif-1α expression both in vitro and in vivo. RESULTS: Cell viability was higher under hypoxic than normoxic conditions shown by MTT assay and decreased apoptotic cells could be observed by apoptotic assay under hypoxia. Hif-1α and akt were regulated each other under hypoxic conditions to confer cisplatin resistance in vitro. In an rat orthotopic hepatoma model, combining blockade of Hif-1α activity with ischemic hypoxia significantly enhanced the efficacy of chemotherapy, leading to suppression of tumor growth and prolongation of animal survival. CONCLUSION: Combined Hif1 inhibitor with hypoxia and chemotherapy can be a new and promising therapeutic approach to the treatment of HCC.
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 5377.