bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3263: Synthesis of substituted N-(4-(6-methyl-1H-benzo[d]imidazol-2-yl)-5,6-dihydropyridin-1(2H)-yl) benzamide/benzenesulfonamide as anticancer agents
Authors: Farah Said M. , Gangapuram Madhavi , Mateeva Nelly , Mochona Bereket , Ardley Tiffany W. , Redda Kinfe K. 
Published: June 2012

Abstract
There is a strong association between chronic inflammatory conditions in a particular organ and the incidence of cancer specific to that organ. The longer the inflammation persists, the higher is the risk of associated carcinogenesis. Our interest is to synthesis new, potent and safer anticancer agents. The functionalized tetrahydropyridine (THP) ring systems are widely found in biologically active natural products and pharmaceuticals. The pharmacological activities of the THP derivatives depended greatly on the position and nature of the substitutions on the THP ring structure. 2-Substituted benzimidazole derivatives have been found to possess anti-inflammatory, antihistaminic, antimicrobial, anticancer, and cycloxygenase inhibiting activities. It is believed that synthesizing new compounds that contain both the pharmacophores of THP and benzimidazole could have the potential of becoming effective anticancer agents.
6-Methyl-2-(pyridin-4-yl)-1H-benzo[d]imidazole was obtained by the reaction of isonicotinc acid, 4-methyl benzene-1,2-diamine and polyphosphoric acid, which were stirred in an oil bath at 180oC for 2h. Mesitylene sulfonyl chloride was added with stirring to a solution of ethylacetohydroxymate and triethylamine in dimethylformamide at 0o C. Hydrolysis of this compound with the mixture of p-dioxane and 70% perchloric acid for 45 min gave a white solid of MSH. The MSH reacted with 6-methyl-2-(pyridin-4-yl)-1H-benzo[d]imidazole to give 1-amino-4-(6-methyl-1H-benzo[d]- imidazol-2-yl) pyridinium mesitylenesulfonate, which further reacted with different substituted benzoyl chlorides/benzenesulfonyl chlorides in 10% NaOH solution to gave stable benzoyl/benzenesulfonyl imino ylides. These ylides were reduced using sodium borohydride in absolute ethanol and gave the target compounds, substituted N-(4-(6-methyl-1H-benzo[d]imidazol-2-yl)-5,6-dihydropyridin-1(2H)-yl)benzamide/benzenesulfonamides. The cytotoxic effects of these substituted THP derivatives were determined using the MCF-7 estrogen receptor positive breast cancer cells, MDA-MB-231 estrogen receptor negative breast cancer cells, and Ishikawa cells, using the CellTiter-Glo (CTG) luminescent cell viability assay. Two target molecules exhibited strong cytotoxicity activities with significant IC50 values on MCF-7, Ishikawa and MDA-MB-231 cell lines.
This research was supported by the NIH/RCMI Grant G12RR03020 and Pharmaceutical Research Center NIH/NCRR Grant 1 C06 RR12512-01.
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 3263. doi:10.1158/1538-7445.AM2011-3263
Abstract 328: An integrated analysis of three distinct IBC/non-IBC Affymetrix gene expression data sets to study the transcriptional heterogeneity both between IBC and non-IBC and within IBC
Authors: Van Laere Steven J. , Ueno Naoto , Finetti Pascal , Vermeulen Peter B. , Lucci Anthony , Birnbaum Daniel , Robertson Fredika , Iwamoto Takayuki , Van Dam Peter , Woodward Wendy , Viens Patrice , Dirix Luc Y. , Reuben James Reuben , Bertucci François 
Published: June 2012

Abstract
Introduction. Several studies have applied gene expression profiling to inflammatory breast cancer (IBC). Most of these studies were underpowered, mainly because IBC is a rare disease and hence, IBC sample sizes are small. Here, we present an integrated analysis of three distinct gene expression data sets of IBC and non-IBC samples – thus with enhanced power – to further uncover the IBC-specific molecular biology.
Materials & Methods. Three Affymetrix gene expression data sets of 137 IBC and 252 non-IBC samples were integrated. Data were normalized, and genes with high signal-to-noise ratios in at least 1% of the arrays were filtered in. The samples were classified according to their molecular subtypes. IBC-specific heterogeneity was investigated using hierarchical clustering, coupled with silhouette score analysis. Supervised analysis, comparing IBC with non-IBC, was performed in non-stage-matched, stage-matched, and molecular subtype-matched approaches with global testing. IBC-specific activated pathways, miRNA-families, and transcription factors were identified with a target gene analysis approach.
Results. Four robust IBC sample clusters were identified, clearly associated with the molecular subtypes, with a predominance of the combined Basal-like, ErbB2+, and Luminal B subtypes (∼70% vs. ∼40% in non-IBC; P&lt;0.0001). When we compared IBC to non-IBC, stage-matched and non-stage-matched differences were identified (global test, P&lt;0.0001). After comparing IBC with non-IBC samples within each of the molecular subtypes, differences persisted only within the luminal A and normal-like subtypes (global test, P&lt;0.0001 and P=0.046, respectively). Target gene analysis identified two molecular pathways (TGFβ and INFα), 16 transcription factors (e.g. NKX2.2, FOXM1), and 10 miRNA families that were differentially activated in IBC and non-IBC (FDR&lt;0.01) but not in the four identified IBC sample clusters.
Conclusions. This meta-analysis demonstrates that IBC is indeed transcriptionally heterogeneous and that differences between IBC and non-IBC are predominated by the differences in the distribution of the molecular subtypes between IBC and non-IBC. Taking this into account, we were able to more accurately spot IBC-specific changes in pathway, miRNA, and transcription factor activation.
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 328. doi:10.1158/1538-7445.AM2011-328
Abstract 3291: Macrophages and granulocytes promote the malignant glioma phenotype
Authors: de Groot John F. , Liang Jane , Piao Yuji 
Published: June 2012

Abstract
Solid tumors, including glioblastoma, contain large populations of both malignant and non-malignant cells. The tumor microenvironment contains a multitude of different cell types and recent evidence supports the role of CD45+ bone marrow cells such as vascular modulating macrophages. Tumor associated macrophages accumulate in hypoxic or necrotic regions of human tumors where they release VEGF. Recent studies have demonstrated that the number of M2-skewed macrophages (CD163+/CD204+) in human tumors correlates with glioma grade, cell proliferation and microvascular density. Myeloid cells including macrophages and granulocytes are thought to promote the malignant phenotype of many solid tumor types but little is known about their influence on glioma biology.
To evaluate the impact of macrophages and granulocytes on the malignant phenotype, we used co-culture experiments to determine the influence of these cells on glioma cytokine and angiogenic factor release, glioma cell invasion and proliferation, and resistance to chemotherapy. Mouse macrophages or granulocytes (ATCC) were cultured alone or together with U87 or glioma stem cells using a Boyden chamber to maintain cell separation. Conditioned media and RNA were evaluated for expression of both mouse and human chemokine expression using ELISA and quantitative PCR. Co-culture resulted in a significant increase in macrophage VEGF-A, CXCL1, HGF, VEGF-C and PlGF expression and granulocyte IGF1, FGF, CCL11, VEGF-C and VEGF-D compared to baseline suggesting that myeloid cell-glioma crosstalk may promote VEGF-A-independent angiogenesis in glioma tumors. Co-culture promoted glioma cell expression of PDGF, CCL11, CXCL9, and INF-β. We next evaluated the impact of myeloid cells on glioma invasion. At baseline, U87 demonstrates minimal transwell migration in vitro and does not invade normal brain in vivo. When co-cultured, macrophages and granulocytes significantly increased U87 in vitro transwell migration compared to control. Finally, serum free media incubated for 48 hours with mouse macrophages or granulocytes was used as growth medium for U87 cells. Using a SRB cell proliferation assay, conditioned media from granulocytes but not macrophages increased glioma proliferation compared to controls. Conditioned media from both macrophages and neutrophils reduced the sensitivity of glioma cells to temozolomide in vitro.
These results suggest that both macrophages and granulocytes may play an important role in promoting glioma angiogenesis, invasion and resistance to chemotherapy. However, granulocytes were more effective in promoting glioma proliferation. Targeting myeloid cells may be an effective approach to inhibiting the glioma malignant phenotype.
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 3291. doi:10.1158/1538-7445.AM2011-3291
Abstract 3295: Inhibiting vascular morphogenesis in tumors: EGFL7 as a novel therapeutic target
Authors: Yeung Stacey , Smyczek Tanya , Cheng Jason , Lima Anthony , Molina Rafael , Hamilton Patricia , Long Jason , Berry Leanne , Nannini Michelle , Barck Kai , Bou-Reslan Hani , Cao Tim , Ho Calvin , Carano Richard , Kasman Ian , Plowman Greg , Singh Mallika , Ye Weilan , Johnson Leisa 
Published: June 2012

Abstract
EGFL7 is a vascular restricted extracellular matrix protein that is up-regulated during angiogenesis (Campagnolo et al., 2005; Fitch et al., 2004; Parker et al., 2004; Soncin et al., 2003). EGFL7 supports endothelial cell adhesion (Parker et al., 2004; Schmidt et al., 2007) and protects endothelial cells from stress-induced apoptosis (Xu et al., 2008). Inhibition of Egfl7 expression in zebrafish embryos abolished vascular lumen formation and reduced sprouting angiogenesis (Parker et al., 2004).
We developed a panel of anti-EGFL7 monoclonal antibodies that block the adhesive and pro-survival activities of EGFL7. Anti-EGFL7 in combination with anti-VEGF resulted in significant tumor regression in multiple murine xenograft models, whereas anti-VEGF alone only slowed tumor growth in the same models. Anti-EGFL7 monoclonal antibodies also demonstrated prolonged survival and anti-tumor angiogenesis effects in stringent murine genetic tumor models when used as a single agent, and enhancement of anti-VEGF therapy in the combination setting. An ongoing Phase I study is being conducted to evaluate clinical safety, PK, PD and efficacy of anti-EGFL7.
References:
Campagnolo, L., Leahy, A., Chitnis, S., et al. EGFL7 is a chemoattractant for endothelial cells and is up-regulated in angiogenesis and arterial injury. Am J Pathol (2005) 167, 275-284.
Fitch, M. J., Campagnolo, L., Kuhnert, F., et al. Egfl7, a novel epidermal growth factor-domain gene expressed in endothelial cells. Dev Dyn (2004) 230, 316-324.
Parker, L. H., Schmidt, M., Jin, S. W., et al. The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation. Nature (2004) 428, 754-758.
Schmidt, M., Paes, K., De Maziere, et al. EGFL7 regulates the collective migration of endothelial cells by restricting their spatial distribution. Development (2007) 134, 2913-2923.
Soncin, F., Mattot, V., Lionneton, F., et al. VE-statin, an endothelial repressor of smooth muscle cell migration. Embo J (2003) 22, 5700-5711.
Xu, D., Perez, R. E., Ekekezie, I., et al. Epidermal growth factor-like domain 7 protects endothelial cells from hyperoxiainduced cell death. Am J Physiol Lung Cell Mol Physiol (2008) 294, L17-L23.
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 3295. doi:10.1158/1538-7445.AM2011-3295
Abstract 330: Gene expression signature characterized by PI3Kinase activation and Stathmin overexpression validates to identify aggressive disease and a potential for PI3Kinase-inhibitors in endometrial carcinomas
Authors: Wik Elisabeth , Trovik Jone , Raeder Maria B. , Mannelqvist Monica , Mauland Karen K. , Oyan Anne M. , Kalland Karl H. , Akslen Lars A. , Salvesen Helga B. 
Published: June 2012

Abstract
Background: We have recently reported a gene expression signature defining an aggressive subgroup of endometrial cancer patients characterized by PI3Kinase activation and Stathmin overexpression, suggesting the potential for PI3Kinase inhibitors against this disease (Salvesen et al, PNAS 2009). In the present study we wanted to validate the value of these measures for PI3Kinase activation prospectively in an independent patient series.
Methods: A prospectively collected, independent patient series of 158 cases of endometrial carcinoma was assessed. Real-time quantitative PCR was performed for the 29 genes in the previously defined gene signature. Stathmin expression in formalin fixed tumor specimens was assessed by immunohistochemistry (IHC).
Results: A high signature score predicted shorter recurrence free (p=0.001) and disease-specific survival (p=0.002). A high score was also significantly associated with high age (p=0.04), high FIGO stage (p=0.03), non-endometrioid histology (p&lt;0.001), high grade (p&lt;0.001) and lymph node metastases (p=0.02). High signature score was also correlated with overexpression of Stathmin in tumor tissue (p≪0.002).
Conclusion: The finding validates that previously identified markers for PI3Kinase activation identify aggressive phenotype in endometrial cancer. This further supports a potential for PI3Kinase-inhibitors in the treatment of metastatic endometrial carcinoma. We suggest that clinical trials with drugs targeting the PI3Kinase pathway involve stratification related to biomarkers, including the expression levels for this gene signature and Stathmin.
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 330. doi:10.1158/1538-7445.AM2011-330
Abstract 3305: Trim3, the human homolog of Drosophila brat, regulates asymmetric division in glioblastoma stem cells
Authors: Chen Gang , Rong Y , Rahman F , Tucker-Burden C , Hadjipanayis C , Van Meir E G. , Brat D J. 
Published: June 2012

Abstract
Glioblastoma (GBM) is the most common and malignant primary brain tumor. The recently described stem cell component of malignant gliomas is biologically critical, yet mechanisms that underlie its regulation are not understood. Mutations in Drosophila Brain tumor (brat) result in a massively enlarged fly brain that consists of a neuroblast cell population with neoplastic growth properties that has lost the ability to divide asymmetrically. Brat has been shown to promote asymmetric cell division and direct neural differentiation at least partially through its translational suppression of Myc. Here we investigated the role of brat homologs for their regulation of glioma behavior, especially as related to asymmetric division of glioma stem cells. We found that the human brat homolog, Trim3, is highly expressed in normal brain and that a substantial subset of GBMs (25-30%) show loss of heterozygosity (LOH) of chromosome 11p15.5, the site of Trim3. Trim3 expression was markedly reduced in human GBM cell lines compared to human astrocytes and reduced in human GBMs specimens compared to normal brain, consistent with results from mining existing gene expression data sets (oncomine). Since Drosophila brat is critical to neural differentiation and regulates Myc, we explored whether human Trim3 might regulate glioma stem cell properties by its regulation of Myc. We found that the forced expression of Trim3 in human GBM cell lines led to reduced Myc protein expression. This inverse relationship between Trim3 and Myc also held true in GBM samples. We used a lentiviral system to stably express Trim3 in GBM cell lines and neurospheres and found that Trim3 expression reduced glioma proliferation and colony formation in vitro and also led to smaller and less frequent neuropheres. In vivo, Trim3 suppressed tumor growth in an orthotopic xenograft model and led to prolonged survival. Trim3 expression was associated with reduced expression of nestin and CD133 by GBM neurosphere cultures, suggesting that its loss may enrich the stem cell compartment. Moreover, Trim3 expression by neurosphere stem cells favored a pattern of asymmetric cell division in GBM. Thus, Trim3 appears to direct asymmetric cell division in glioma stem cells and its loss is associated with stem cell enrichment and greater biologic potential.
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 3305. doi:10.1158/1538-7445.AM2011-3305
Abstract 3308: Endothelin 3/endothelin receptor B signaling pathway blockade depletes radio-chemoresistant glioblastoma stem cells
Authors: Ye Fei , Yamada Kazunari , Liu Yue , Choe Jinny , Dembo Anna , Tso Jonathan L. , Cloughesy Timothy F. , Schaue Dörthe , McBride William , Liau Linda M. , Tso Cho-Lea 
Published: June 2012

Abstract
Background: Patients with glioblastoma multiforme (GBM) despite being treated with gross total resection and post-operative temozolomide (TMZ) plus radiation therapy (RT), will almost always develop tumor recurrence.
Hypothesis and objective: We hypothesize GBM stem cells (GSC) are responsible for post-treatment tumor recurrence and blockade of endothelin-3 (EDN3)/endothelin receptor B(EDNRB) signaling, a signaling pathway for neural crest development that hyperactivated in GSC, will enhance TMZ/RT treatment efficacy for GSC.
Materials and Methods: Patient tumor-derived GSC were seeded at clonal density and subjected to radiochemotherapy at dose and schedule comparable to patient treatment. Treatment efficacy and synergy of EDNRB antagonist (BQ788) plus TMZ/RT were evaluated by the clonogenic efficiency, cell proliferation, and cell apoptosis of GSCs.
Results: GSC are resistant to TMZ treatment alone (10μM), while treatment with BQ788 (75μM) alone can restrict cell migration, decrease clonogenic efficiency, and induce cell apoptosis. The RT displays the highest treatment efficacy on GSC when compared to TMZ or BQ788 alone and addition of TMZ to RT is slightly synergistic. Although only few small tumor spheres were detected when treated with RT or RT/TMZ, the survival clones regain proliferative activity and possess enhanced clonogenicity and anti-apoptotic ability when compared to untreated GSC. Treatment efficacy was greatly improved when GSC treated with BQ788 combined with RT/TMZ and no cells with self- renewal capacity were detected or recovered from the treatment.
Conclusion: Subsets of GSC clones are resistance to standard RT/TMZ treatment and possess enhanced tumor sphere-forming capacity. Incorporate EDN3/EDNRB antagonist to a standard radiochemotherapy provide a significant treatment synergy in depletion of functional GSC and thus highlights a novel therapeutic strategy for the prevention of GSC-mediated tumor occurrence and recurrence.
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 3308. doi:10.1158/1538-7445.AM2011-3308
Abstract 3311: IL6-Stat3 signaling promotes glioma stem cell (GSC) survival under hypoxia environment through inhibition of cell-death inducing gene Bnip3
Authors: Wang Hui , Wang Xiao-Fan , Rich Jeremy , Wang Qinhong , Hjelmeland Anita 
Published: June 2012

Abstract
Glioblastomas (GBMs) are the most common and lethal brain tumor in adults. In rapid-growing tumors like malignant glioma, hypoxia is an unavoidable condition even with aggressive angiogenesis. Recent studies implicate an important role for a restricted population of neoplastic cells (glioma stem cells, GSCs) in glioma maintenance and recurrence. However, how these glioma stem cells survive and escape from harsh conditions like hypoxia is barely known. Our previous study and others’ have shown that GSCs preferentially express the interleukin 6 (IL6) receptors and Stat3 signaling is preferentially activated in GSCs. We further found that perturbation of IL6 signaling in GSCs reduced Stat3 activation, and small molecule inhibitors of Stat3 potently induced GSC cell death partially through induction of a BCL2 family member Bnip3. Despite its controversial role in cell survival, massive expression of Bnip3 is a well-studied mediator of cell death in hypoxic tumor cells. Furthermore, we found that enhanced IL6-Stat3 signaling in GSCs could counter the induction of Bnip3 under hypoxia, which provided an extra survival advantage for these glioma stem cells under severe hypoxic condition. These data indicated that Stat3 is a downstream mediator of pro-survival IL6 signals in GSCs partially through suppressing Bnip3 expression, especially under hypoxia condition. Together, our data indicate that IL6-Stat3 signaling contributes to glioma malignancy through the promotion of GSC survival under harsh conditions like hypoxia, and that targeting IL6-Stat3 signaling pathway may offer benefit for glioma patients.
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 3311. doi:10.1158/1538-7445.AM2011-3311
Abstract 3322: Downregulation of XIAP by cord blood stem cells is associated with inhibition of heat shock protein 90 in glioblastoma
Authors: Dasari Venkata Ramesh , Velpula Kiran Kumar , Dinh Dzung H. , Tsung Andrew J. , Rao Jasti S. 
Published: June 2012

Abstract
Heat shock protein 90 (HSP90) is highly expressed under stressful conditions in eukaryotic cells showing chaperone activity including the suppression of protein aggregation and signaling pathways. HSP90 is upregulated in various human tumors, including glioblastoma, and targeting its function might provide new therapeutic opportunities. Previously, we have shown that human umbilical cord blood-derived mesenchymal stem cells (hUCBSC) downregulate XIAP in glioblastoma cells in vitro and in vivo. In the present study, we report that downregulation of XIAP by hUCBSC is associated with inhibition of HSP90. Under in vivo conditions, hUCBSC induce apoptosis by downregulation of XIAP in which XIAP migrates from the cytosol to the nucleus in mice brain xenografts. Immunoprecipitation experiments proved that SMAC is associated with Cytochrome C and XIAP in the mitochondria, indicating mitochondrial apoptosis. Simultaneously, cytosolic HSP90 is downregulated and co-localized with TNFR2 in hUCBSC-treated tumors, proving that TRAIL-mediated apoptosis is taking place in hUCBSC-treated tumor xenografts. Also, expression of mitochondrial HSP90 (TRAP-1) is downregulated in glioma cells. The downregulation of XIAP by hUCBSC is shown to be under the transcriptional control of SP1 under both in vitro and in vivo conditions. These results have been confirmed by using shRNA for XIAP. Taken together, these results prove that hUCBSC are efficient in the inhibition of HSP90, and hUCBSC have the potential to be therapeutic tools for the treatment of glioblastoma.
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 3322. doi:10.1158/1538-7445.AM2011-3322