bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 347: Gene expression signature of the gross morphology and the specific role of EpCAM in hepatocellular carcinoma
Authors: Tanaka Shinji , Murakata Ayano , Mogushi Kaoru , Yasen Mahmut , Ban Daisuke , Noguchi Norio , Irie Takumi , Kudo Atsushi , Nakamura Noriaki , Inazawa Johji , Tanaka Hiroshi , Arii Shigeki 
Published: June 2012

Abstract
Tumor morphologies have been identified to associate with their malignant properties such as the invasive, metastatic and/or even recurrent potentials after the cancer treatment. Hepatocellular carcinoma (HCC) is known to demonstrate a variety of morphological appearances. Eggel's nodular type of HCC is morphologically subclassified into single nodular type (SN), single nodular type with extranodular growth (SNEG), and confluent multinodular type (CM), but their biomolecular differences remain unclear. In this study, the clinicopathologic characteristics as well as genome-wide gene expressions were analyzed in relation to the gross morphology of curatively resected HCC. Among 275 patients with nodular type HCC (124 SN-type, 91 SNEG-type and 60 CM-type), significantly poor prognosis was recognized in CM-type in overall survival (p=0.0020) as well as recurrence-free survival (p=0.0066) after the curative resection. The genome-wide expression patterns were evaluated by 3D principal component analysis using Kruskal-Wallis test, and p-value distribution histograms using Mann-Whitney U test. Both of the analyses on the gene expression signature revealed the significant deference in CM-type HCC compared to either SN or SNEG-type HCC. In particular, a stem cell marker EpCAM was dominantly expressed in CM-type HCC. Immunohistochemical studies confirmed the specific expression of EpCAM in HCC cancer cells of CM-type. In multivariate analysis, the gross morphology of CM type was significantly associated with EpCAM expression (p=0.0133), AFP-L3 level (p=0.0311) and the portal vein invasion (p=0.0138). Furthermore, EpCAM was predictive for poor prognosis in overall and recurrence-free survivals of patients with CM-type HCC (p=0.0082 and p=0.0043, respectively). Our studies suggested the distinct signature of gene expression closely related to the morphological progression in HCC. Especially, EpCAM might play a critical role in the aggressiveness of CM-type HCC.
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 347. doi:10.1158/1538-7445.AM2011-347
Abstract 3476: Blockade of endothelial Notch diminishes tumor growth and perfusion
Authors: Patenaude Alexandre , Chang Linda , Diaz Erika , Fuller Megan , Wong Fred , Karsan Aly 
Published: June 2012

Abstract
Canonical Notch signaling comprises a family of receptors and ligands that modulate cell fate and differentiation. Upon ligand binding, Notch receptors undergo a series of cleavages that culminate in the translocation of the intracellular domain to the nucleus, resulting in transcriptional activation through the derepression and activation at CSL-bound promoters. Notch activity is essential for embryonic vascular development and was recently also shown to be important for adult neovascularization. Notably, blocking Notch signaling by inhibition of the ligand Dll4 increased endothelial proliferation and sprouting, but resulted in non-perfused vasculature and tumor growth inhibition. Moreover, Dll4 inhibition was shown to diminish vascular mural cells, such as pericytes, in tumors. Whether these effects of Dll4 blockade on tumor vasculature resulted specifically from Notch inhibition in endothelial cells remains to be fully elucidated. We investigated this question using a tetracycline-inducible binary transgenic system, in which Notch is blocked by the expression of a dominant-negative form of mastermind-like 1 (dnMAML-GFP) under the control of the VE-cadherin promoter. Lewis lung carcinoma (LLC) cells overexpressing VEGFA (LLC-VEGFA) were implanted subcutaneously in the dorsa of double transgenic (Tg) or control mice. Tumors in the double Tg mice were significantly smaller than in control single Tg mice. Moreover, blood vessel perfusion from LLC-VEGFA tumors was significantly reduced in the double Tg mice compared to the control Tg mice. However, neither the abundance nor the branching architecture of LLC-VEGFA tumor blood vessels appeared to be different in the double Tg mice. Pericyte abundance, maturation and distribution relative to blood vessels did not change in the double Tg mice. Flow cytometry of tumor-derived cells and fluorescence microscopy analysis of tumor cryosections confirmed that dnMAML-GFP is expressed specifically in endothelial cells. Our data suggest that specific blockade of Notch in endothelial cells, induced by dnMAML-GFP, affects tumor growth through a mechanism different from previously-reported Dll4 inhibition studies.
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 3476. doi:10.1158/1538-7445.AM2011-3476
Abstract 350: High-throughput drug screens identify novel synthetic lethal interactions with MLH1-deficient cancers
Authors: Hewish Madeleine , Lord Chris J. , Martin Sarah A. , Cunningham David , Ashworth Alan 
Published: June 2012

Abstract
Mismatch Repair (MMR) deficiency occurs in some inherited and somatic malignancies as a consequence of mutation or epigenetic silencing. Since MMR-deficient tumours exhibit tolerance to many commonly used chemotherapeutic agents, there is an unmet clinical need to develop novel treatment strategies for this group of cancers.
We utilized an in vitro isogenic colorectal model, the MLH1-deficient HCT116, and its isogenic comparator HCT116+Chr3, to perform high throughput screening of chemical libraries to identify novel drugs which were relatively cytotoxic to MLH1-deficient tumour cells compared with their MLH1-proficient comparators. The assay readout was cellular viability. ‘Hit’ drugs were then validated across a range of drug concentrations to determine the likelihood of ‘off target’ effects and potential clinical applicability, and further validated in clonogenic assays. Amongst the validated hits were cytosine arabinoside (ara-C), ethinyl oestradiol and desferoxamine. Ara-C was selected for further investigation and validated in two other in vitro models of MLH1 deficiency. Other nucleoside analogs were also investigated for MLH1-deficient selectivity and a lesser degree of selectivity was observed with gemcitabine. Compatible with the defective cell cycle checkpoints of MLH1-deficient cells, we have subsequently demonstrated that the excess cytotoxicity is associated with an increase in apoptosis that coincides with release from initial G1/early S phase arrest, suggesting that MLH1-deficient cells undergo mitotic catastrophe.
In summary, we have used high throughput screening to identify possible new strategies for the treatment of MLH1-deficient cancers. Further mechanistic studies are ongoing. Combinations of drugs known to be MLH1-deficient selective are also being tested with a view to increasing the therapeutic window of a possible MLH1-deficient therapeutic strategy.
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 350. doi:10.1158/1538-7445.AM2011-350
Abstract 3503: Targeting chemo-resistant colon cancer cells by the combination of dasatinib and curcumin: A novel therapeutic strategy
Authors: Nautiyal Jyoti , Yu Yingjie , Kanwar Shailender S. , Patel Bhaumik B. , Majumdar Adhip P. 
Published: June 2012

Abstract
Metastatic colorectal cancer remains a serious health concern with poor patient survival. 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX), the standard therapy for colorectal cancer, has met with limited success. Recurrence of the tumor after chemotherapy could partly be explained by the enrichment of the chemo-resistant sub-population of cancer stem cells (CSCs) that possess the ability for self-renewal and differentiation into different lineages in the tumor. Therefore development of therapeutic strategy that target CSCs is highly desirable in reducing the risk of relapse and metastasis. The current investigation was undertaken to examine the effectiveness of the combination therapy of dasatinib (a Src inhibitor) and curcumin (a dietary ingredient) in inhibiting the growth and other properties of carcinogenesis of chemo-resistant colon cancer cells that are enriched in CSCs. Human colon cancer cells HCT-116 (p53 wild type; K-ras mutant) and HT-29 (p53 mutant; K-ras wild type) were used to generate FOLFOX resistant {referred to as chemoresistant (CR)} cells. The CR cells showed higher expression of CSCs markers, cell invasion potential and ability to form colonospheres, compared to the corresponding parental cells. The combination therapy of dasatinib and curcumin demonstrated synergistic interactions in CR-HCT-116 and CR-HT-29 cells. This caused inhibition of cellular growth, invasion and colonosphere formation and reduction in CSC population as evidenced by decreased expression of CSC specific markers: CD133, CD44, CD166 and ALDH. In conclusion, we propose that the combination therapy of dasatinib and curcumin may be an effective therapeutic strategy for re-emergence of chemo-resistant colon cancer by targeting CSC sub-population.
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 3503. doi:10.1158/1538-7445.AM2011-3503
Abstract 3516: Combinations of chemotherapy with bevacizumab in a xenograft model of human ovarian carcinoma
Authors: Oliva Paolo , Decio Alessandra , Castiglioni Vittoria , Bassi Andrea , Belotti Dorina , Bani Maria Rosa , Giavazzi Raffaella 
Published: June 2012

Abstract
Ovarian cancer is the leading cause of death from gynecologic malignancy in women of the Western countries. The standard first-line therapy for this type of tumor is the combination of paclitaxel (PTX) and carboplatin. Vascular endothelial growth factor (VEGF) performs as an angiogenic and permeability factor in ovarian cancer, and its over-expression has been associated with poor prognosis. Inhibition of malignant ascites and tumor growth has been shown by blocking the VEGF/VEGFR pathway. Early clinical studies with bevacizumab, the monoclonal antibody directed against VEGF, have demonstrated efficacy in ovarian carcinoma patients as single and combined treatment.
The aim of this study was to evaluate the effect of chemotherapy in combination with bevacizumab given at different regimens in an in vivo model of human ovarian carcinoma xenograft. Nude mice were transplanted intraperitoneally with 1A9-luc ovarian carcinoma cells, over-expressing luciferase, that allows to monitor the tumor growth and dissemination in the peritoneal cavity of the mice by bioluminescence imaging analysis.
Mice were treated with PTX (20 mg/kg) or cisplatin (DDP, 3 mg/kg) as single therapy or in combination; bevacizumab (150 µg/mouse) was given concurrently for 3 weeks and either continued after the suspension of chemotherapy (maintenance regimen) or stopped.
Untreated mice developed heavy tumor burden in the peritoneal cavity with a median survival time (MST) of approximately 24 days. PTX or DDP given alone only marginally affected the survival of the mice. The addition of bevacizumab to PTX or DDP significantly improved the survival of the mice with an increased life span (ILS) of 117% and 75% respectively; this was ameliorated by the continuation of bevacizumab treatment after chemotherapy (ILS = 158% and ILS = 100% respectively).
The combined administration of PTX and DDP plus bevacizumab further improved the survival of the mice (ILS&gt;190%); most importantly, maintaining the treatment with bevacizumab (up to 90 days) after the suspension of chemotherapy resulted in tumor free mice. Monitoring the tumor burden by bioluminescence imaging analysis confirmed the different tumor response among the treatment groups.
These findings show a benefit from the combination of PTX/DDP plus bevacizumab in ovarian carcinoma, and are in favor of the maintenance regimen with bevacizumab.
Supported by AIRC and Fondazione Cariplo
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 3516. doi:10.1158/1538-7445.AM2011-3516
Abstract 3519: Histone deacetylase inhibitors upregulates thymidine phosphorylase gene and protein expression and synergize with capecitabine in breast cancer cells
Authors: Gennaro Elena Di , Cintio Alessandra Di , Piro Geny , Chianese Maria I. , Bruzzese Francesca , Budillon Alfredo 
Published: June 2012

Abstract
Capecitabine is a pro-drug which was designed to take advantage of the increased levels of thymidine phosphorylase (TP), a key enzyme for its conversion to 5-florouracil (5-FU), observed in tumours as opposed to normal tissues, potentially allowing for selective toxicity. Capecitabine is a valuable substitute for bolus or infusion 5-FU either as monotherapy or in combination with other cytotoxic drugs in the treatment of several tumor types including breast cancer. We have recently demonstrated for the first time, that the histone deacetylase-inhibitor (HDAC-I) vorinostat induces synergistic antitumour effects in combination with capecitabine by up-regulating, in vitro and in vivo, in colorectal cancer cells but not in ex vivo treated peripheral blood lymphocytes, the mRNA and protein expression of TP. We have also demonstrated that TP knockdown by a specific siRNA significantly impairs the synergistic apoptotic cell death induced by vorinostat/capecitabine combination. In this study we demonstrated a time and dose-dependent induction of TP mRNA and protein expression by several HDAC-Is in different breast cancer cell lines such MCF-7, SKBR3, MDA-MB-231and MDA-MB-468 cells. Interestingly, this effect was shared by pan-HDAC-Is such as panobinostat (LBH589), trichostatin A (TSA) or vorinostat and by class I HDAC-Is such as valproic acid (VPA) and entinostat (MS275), but not by the specific inhibitor of HDAC-6 tubacin, indicating that targeting class I HDACs is crucial for TP induction. Moreover, the mechanism of TP induction is dependent on a transcriptional effect since preliminary data showed that HDAC-Is did not interfere with TP protein stability. On these bases we investigated potential antitumor interaction between capecitabine and either vorinostat or panobinostat or VPA, demonstrating synergistic antiproliferative effects in all breast cancer cells independently of p53, ER or Her2 status. Overall, this study suggests that HDAC-Is, by upregulating TP expression, may improve the therapeutic index of capecitabine representing an innovative antitumour strategy for the treatment of breast cancer that warrants further clinical evaluation.
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 3519. doi:10.1158/1538-7445.AM2011-3519
Abstract 3529: Evaluation of PRI vitamin D analogues, alone or with enhancers, as antileukemia agents
Authors: Zhang Jing , Baurska Hanna , Chen-Deutsch Xiangwen , Gocek Elzbieta , Harrison Jonathan S. , Kielbinski Marek , Danilenko Michael , Kutner Andrzej , Marcinkowska Ewa , Studzinski George P. 
Published: June 2012

Abstract
The physiological form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D) has well established anti-cancer activity, but its potential use in the clinic is limited by the danger of life-threatening hypercalcemia. Efforts to overcome this difficulty include structural modifications of 1,25D, as well as enhancement of its activity by other compounds. In this study we have combined these two approaches by comparison of the efficacy of the induction of differentiation in AML using analogs synthesized in the Warsaw Pharmaceutical Research Institute(PRI), alone or with its enhancers carnosic acid (CA), a plant antioxidant, and SB202190 (SB), an inhibitor of p38MAPK α, β. The PRI analogs have previously been shown to have low calcemic activity in animals, and while the analogs PRI-1906 (24-ene-1,25-dihydroxy vitamin D2) and PRI-2191([24R]-1,24-dihydroxyvitamin D3) had greater activity on established AML cell lines than their congeners, their relative potency on AML blasts was not entirely clear. We therefore studied an additional cohort of 20 patients with AML, and when sufficient cell numbers were available the analogs were supplemented with CA and SB to form a “differentiation cocktail” for study ex vivo. In this series we found that there was variability in the differentiation responses between individual patients, but the majority (∼90 %) of the blast samples responded to 1,25D and to both analogs. The intensity of the response was greatly increased when the “differentiation cocktail” was used rather than the analog alone, and while there was a similarity between the potencies of PRI-1906 and PRI-2191, the most robust responses in this series were seen when PRI-1906, alone or with CA and SB, was used. The strength of responses correlated with the enhancement of VDR expression in treated cells studied by Western blots. We conclude that PRI analogs 1906 and 2191 supplemented with CA and SB merit further scrutiny as candidates for chemoprevention/ differentiation therapy of AML.
(Supported by USAPH NIH grant RO1 CA 44722-20 from NCI to GPS, the ISF grant 778/07 to MD, by Wroclaw Research Center EIT+ Operational Programme Innovative Economy, 1.1.2; POIG 01.01.02-02-003/08-00 to EM, and by the Foundation for Polish Science to EG).
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 3529. doi:10.1158/1538-7445.AM2011-3529
Abstract 3537: Synergistic effect of a Hedgehog pathway inhibitor in combination with erlotinib on multiple carcinoma cell lines
Authors: Sheng Qing , Li Hui , Do Hanh , Liu Natalie , Xu Zhidong , Jablons David , He Biao 
Published: June 2012

Abstract
The aberrant activation of Hedgehog(Hh)/Gli signaling has been implicated in a broad spectrum of malignant tumors. Targeted inhibition at the cell membrane of Hh pathway, for example with Smoothened(Smo) and Hh inhibitors, has shown promising preclinical and clinical anti-cancer activity. However, a growing body of evidence has revealed additional mechanisms in the activation of the Gli pathway that are independent of Hh/Smo regulation. These mechanisms are stimulated by the cross-talk between downstream components of the Hh/Smo and other oncogenic signaling pathways, such as the Epidermal Growth Factor Receptor (EGFR) pathway. Based on this, we hypothesized that the simultaneous inhibition of the EGFR pathway and Gli pathway would result in synergistic anti-tumor effects. To test this hypothesis, we used erlotinib, an EGFR tyrosine kinase inhibitor (TKI), in combination an Hh pathway inhibitor on various lung and mesothelioma cancer cell lines. It has been demonstrated that erlotinib and other TKIs are active in lung cancers with EGFR gene mutations, while not as effective in those with wild type EGFR. However in our studies, the application of the Hh pathway inhibitor sensitized EGFR wild type cells to erlotinib treatment with more than a 10-fold decrease of IC50 in multiple lung cell lines. In addition, the dual treatment resulted in promising synergism in both mesothelioma and lung cancer cell lines with a combination index of less than 0.7. To study the mechanism of crosstalk between the two pathways, we have examined the activities of EGFR, Hh and Wnt pathways in single and dual treatments. Based on our results, we believe that dual inhibition of Hh/Gli and EGFR pathways may be a promising targeted therapy for lung cancers and mesothelioma.
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 3537. doi:10.1158/1538-7445.AM2011-3537
Abstract 3544: Jak/Stat signaling: A potential target for pancreatic cancer management
Authors: Jingjing Gong , Batth Izhar S. , Kumar Addanki P. 
Published: June 2012

Abstract
NexrutineR (Nx) isolated from the bark of Phellodendron amurense is being sold as an anti-inflammatory herbal supplement over the counter in the US. Recent studies from our laboratory demonstrated its potential as an anti-prostatic agent by targeting multiple signaling pathways including Akt/CREB/NFkB/Cyclin D1/Cox-2 both in vitro and in vivo. Given the importance of some of these signaling pathways in multiple cancers, we explored its role in pancreatic cancer (PanCA) using variety of cell lines. Human pancreatic cancer cells that differ in the status of K-Ras (BxPC-3 with wild type K-Ras and Capan-2 with mutant K-Ras), non- tumorigenic HPNE-Ras, MIAPC and ASPC-1 were tested for growth inhibition, apoptosis, necrosis, Cox-2 expression and activity following treatment with Nx. Our data indicate that Nx can significantly inhibit proliferation of these cell lines differentially through induction of apoptosis and necrosis without any significant effect on cell cycle profile. Investigation of molecular mechanism of action identified a role for Jak1 and transcription factors NFkB and Stat3. Western blotting data show that Nx can inhibit the protein levels of pStat3 and Jak1 effectively without influencing the protein levels of total Stat3. Similarly Nx treatment decreased the DNA binding activities of both NFkB and Stat3. Chromatin immunoprecipitation assays revealed the binding of Stat3 to Cox-2 promoter. In addition combining Nx with Gemcitabine (standard of care treatment for PanCA) demonstrated strong synergistic growth inhibitory activity through modulation of Stat3. Overall, the present study unveils a novel interplay between Jak1/Stat3 and NFkB signaling in pancreatic cancer cells. These data further suggest that the targeted disruption of Jak1/Stat3 and NFkB may represent a valid therapeutic approach in this cancer. Supported by NCCAM (APK).
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 3544. doi:10.1158/1538-7445.AM2011-3544