bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3465: shRNA against uPA and uPAR enhances secretion of sVEGFr1 in tumor endothelial and glioblastoma cells independent of GMCSF
Authors: Raghu Hari , Gondi Christopher S. , Nalla Arun Kumar , Rao Jasti S. 
Published: June 2012

Abstract
The uPA/uPAR system is known to play a critical role in angiogenesis of glioblastomas. Previously, using protein array antibody analysis, we demonstrated that shRNA against uPA and uPAR (pU2) inhibits angiogenesis in vitro and in vivo by regulating a number of pro-angiogenic, angiostatic and anti-angiogenic molecules. GMCSF, a pleiotropic cytokine that stimulates proliferation, differentiation, and survival of various hematopoietic cells, was significantly inhibited in U87MG and 4910 cells co-cultured with endothelial cells and transfected with pU2. In this study, we evaluated the effect of shRNA against uPA and uPAR on GMCSF, sVEGFr1, GMCSF receptors and GMCSF-induced signaling and its significance on angiogenesis in glioblastoma and endothelial cells. ELISA revealed that simultaneous knockdown of uPA and uPAR in U87MG, 4910 and HMEC cells decreased secretion of GMCSF but enhanced the secretion of sVEGFr1, a known scavenger of VEGF-A. The results of the western blot analysis were consistent with our ELISA results. In endothelial cells treated with shRNA against GMCSF, recombinant uPA (ruPA) resulted in activation of GMCSFR-α and GMCSFR-β at very early time points. Moreover, endothelial tube formation was inhibited with the addition of rsVEGFr1, and antibody to rsVEGFr1 blocked GMCSF-induced tube formation in endothelial cells. The addition of ruPA to endothelial and glioblastoma cells activated phosphorylation of JAK2 and STAT3. p27, an effector of the GMCSF signaling pathway, was downregulated in puPA-, puPAR- and pU2-transfected U87MG and 4910 cells. To determine the significance of these events in vivo, nude mice were checked for levels of GMCSF and sVEGFr1 before and after tumor formation and also after treatment with puPA, puPAR and pU2. Results showed increased levels of sVEGFr1 but decreased levels of GMCSF in shRNA treated mice in comparison to controls. Taken together, these results suggest that knockdown of uPA/uPAR in tandem induces sVEGFr1, which plays a vital role in inhibition of angiogenesis, and its secretion is independent of GMCSF in endothelial cells.
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 3465. doi:10.1158/1538-7445.AM2011-3465
Abstract 348: Analysis of somatic hypermutations in IGHV genes from Hairy Cell Leukemia Immunoglobulin Heavy Chain rearrangements
Authors: Arons Evgeny , Suntum Tara , Roth Laura , Sapolsky Jeffrey , Kreitman Robert J. 
Published: June 2012

Abstract
The B-cell receptors of malignant B-cells each contain a monoclonal immunoglobulin sequence which may be relevant for both prognosis and cell of origin. The character of somatic hypermutations (SHM) has been studied to predict whether antigen contacted the B-cell prior to its malignant transformation, or at least whether the SHMs observed are ‘canonical’, or consistent with those expected from mutation machinery used for antigen-driven SHM. Hairy cell leukemia B-cell receptors have previously been evaluated for gene usage and homology to germline sequence, but detection of canonical SHMs was not previously possible because of the limited number of HCL rearrangements. To compare HCL with CLL and normal B-cells, somatic hypermutation (SHM) features in hairy cell leukemia (HCL) were examined in a series of 130 immunoglobulin heavy chain gene (IgH) rearrangements, including 102 from 100 classic (HCLc) and 28 from 26 variant (HCLv) patients. The frequency of unmutated rearrangements in HCLc was much lower than that in HCLv (18% vs 54%, p=0.0003) or historically in CLL (18% vs 46%, p=9×10-9), but HCLv and CLL were similar (p=0.45). As previously reported for CLL, evidence of canonical SHM was observed in HCLc rearrangements including 1) a higher ratio of replacement to silent mutations (R/S ratio) in the complementarity determining regions (CDRs) than framework regions (FRs) (2.83 vs 1.40, p &lt; 0.0001), 2) higher than random transition to transversion ratio (1.48 vs 0.5, p=7 × 10-39), and 3) higher than random percentage of mutations located in RGYW hot spots (13.88% vs 3.31%, p=1.5×10-44). HCLv met these 3 criteria of canonical SHM to a lesser extent (p=0.067, p=8×10-6 and p=0.0001, respectively). In comparing HCLv with HCLc directly, HCLv showed 1) a trend for lower R/S ratios in the CDRs (p=0.07), 2) lower transition to transversion ratio (p=0.045), and 3) lower percent of mutations in RGYW hot spots (p=0.03). In comparing HCLv and HCLc with respect to specific immunoglobulin variable heavy chain (IGHV) families, it was noted that 1) R/S ratio trended lower for HCLv IGHV4 CDRs compared to HCLc IGHV4 CDRs (p=0.064) and 2) transition to transversion ratio was lower for HCLv IGHV3 compared to HCLc IGHV3 (p=0.0013). Thus HCLc rearrangements exhibited canonical SHM similarly to CLL and normal B-cells, and significantly more than HCLv rearrangements, suggesting that malignant cells from HCLc patients may have recognized antigen prior malignant transformation, and that in some HCLv patients the malignant cells may originate by a different pathway.
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 348. doi:10.1158/1538-7445.AM2011-348
Abstract 3485: Insulin-like growth factor binding protein-4 (IGFBP-4) differentially inhibits growth factor induced angiogenesis in vivo
Authors: Contois Liangru W. , Caron Jennifer M. , Tweedie Eric , Liebes Leonard , Friesel Robert , Vary Calvin , Brooks Peter C. 
Published: June 2012

Abstract
Angiogenesis contributes to the development and progression of malignant tumors. An expanding body of evidence also suggests that the response of both vascular and tumor cells to growth factor stimulation depends in part on cellular communication with the extracellular matrix (ECM), and studies have documented important roles for the integrin family of ECM receptors in modulating growth factor signaling. Therefore, uncovering molecular mechanisms by which integrin-mediated cellular communication with the ECM modulate the specificity of growth factor signaling during pathological angiogenesis may provide unique insight into malignant tumor progression.
Here we provide evidence that disruption of αvβ3-dependent interaction with the ECM enhance expression of Insulin-like growth factor binding protein-4 (IGFBP-4), a well-known regulator of IGF-1 signaling. Interestingly, IGFBP-4 significantly (P&lt;0.05) inhibited IGF-1 and bFGF-induced angiogenesis by greater than 50%. In contrast, IGFBP-4 alone failed to inhibit VEGF-induced angiogenesis in chick CAM. Levels of phosphorylated p38 MAP kinase were elevated in chick CAM tissues treated with VEGF as compared to those in tissues stimulated with either IGF-1 or bFGF. Surprisingly, while the p38 MAP kinase inhibitor SB 202190 alone had little effect on VEGF-induced angiogenesis, a combination of IGFBP-4 and the p38 MAP kinase inhibitor significantly (P&lt;0.05) inhibited VEGF-induced angiogenesis. These novel findings are consistent with a role for elevated levels of activated p38 MAP kinase in modulating the anti-angiogenic activity of IGFBP-4 in vivo. Taken together, our experimental findings provide additional molecular insight into how integrin-mediated interactions with the local ECM microenvironment may modulate the responses of cells to distinct growth factor signaling pathways during angiogenesis.
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 3485. doi:10.1158/1538-7445.AM2011-3485
Abstract 3486: CXCR1 and CXCR2 silencing alters endothelial cell proliferation, migration and capillary tube formation
Authors: Singh Seema , Varney Michelle L. , Singh Rakesh K. 
Published: June 2012

Abstract
CXCR1 and CXCR2 are receptors for CXCL-8 and are differentially expressed on endothelial cells, however, their functional significance in angiogenesis remains unclear. In this study, we determined the functional role of these receptors in modulating endothelial cells phenotype by knocking-down the expression of CXCR1 and/or CXCR2 in human microvascular endothelial cells (HMEC-1) using short-hairpin RNA (shRNA). Cell proliferation, migration, invasion and capillary tube formation were carried out in in vitro. Our data demonstrate that knock-down of CXCR1 and/or CXCR2 expression, inhibited endothelial cell proliferation, survival, migration, invasion and capillary tube formation in vitro. Additionally, we examined the mechanism of CXCL-8-dependent CXCR1 and/or CXCR2 mediated phenotypic changes by evaluating ERK phosphorlyation and cytoskeletal rearrangements. We observed inhibition of ERK phosphorylation and cytoskeltal rearrangement in HMEC-1-shCXCR1, HMEC-1-shCXCR2 and HMEC-1-shCXCR1/2 cells. The number of apoptotic cells acquiesced with decreased survival-associated gene expression. Together, these data demonstrate that CXCR1 and CXCR2 expression play a critical role in regulating multiple biological activities in human microvascular endothelial cells.
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 3486. doi:10.1158/1538-7445.AM2011-3486
Abstract 3491: Chromosome 14q loss leads to haploinssuficiency of HIF-1a and poor outcomes in metastatic clear cell renal cell carcinoma
Authors: Monzon Federico A. , Alvarez Karla , Peterson Leif , Tannir Nizar , Jonasch Eric 
Published: June 2012

Abstract
Purpose – One of the current key dilemmas in the management of metastatic renal cell carcinoma (mRCC) is the manifestation of innate or acquired resistance to anti-angiogenic therapy. Currently there are no biomarkers of therapeutic efficacy for antiangiogenic agents in clear cell renal cell carcinoma (ccRCC). Loss of chromosomal arm 14q has been previously associated with poor outcomes in surgically treated patients. We evaluated the association between 14q loss and therapeutic resistance in metastatic ccRCC (mRCC) and explored the role of candidate effector genes on this chromosome.
Experimental Design – DNA from archival FFPE tumor specimens from 56 mRCC patients treated with sorafenib or bevacizumab was analyzed with Affymetrix 250K Nsp SNP microarrays. We identified the presence of genomic imbalances focusing on the presence of 14q loss. We then evaluated candidate genes in chromosome 14 by qPCR and immunohistochemistry (IHC) in the bevacizumab treated cohort.
Results – 14q loss showed a significant association with worse response (SDPD vs. CRPR) in bevacizumab cohort (Fisher's exact test, p=0.0473), and with shorter progression free survival (PFS) in the sorafenib cohort (p=0.0318). HIF1A mRNA expression was significantly reduced in specimens with loss of 14q and was associated with PFS in the bevacizumab treated cohort (p=0.045). HIF-1alpha protein expression was also reduced in samples with 14q loss.
Conclusions – Our studies demonstrate an association between a specific chromosomal alteration (14q loss) and clinical outcome in patients with advanced renal cell carcinoma treated with antiangiogenic agents. Loss of 14q was also associated to changes in the expression of HIF1A. Low HIF1A expression was strongly correlated with shorter PFS. We hypothesize that loss of 14q could lead to an imbalance in HIF-1α/HIF-2α activity, leading to increased HIF-2α, which has been shown to improve tumor cell viability by upregulating various pro-survival pathways.
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 3491. doi:10.1158/1538-7445.AM2011-3491
Abstract 3517: Epigenetic interactive regulation and synergistic action of Trichostatin A, 5-aza-2′-deoxycytidine and Cisplatin in ovarian cancer
Authors: Meng Fanliang , Sun Guigin , Zhong Mei , Yu Yanhong , Brewer Molly A. 
Published: June 2012

Abstract
Objective: To investigate the relationship between histone modification, DNA methylation and DNA damage repair response that occur in platinum resistant ovarian cancer cell lines treated with epigenetic modifiers in combination with low dose chemotherapy to develop new approaches for chemotherapy resistant ovarian cancer.
Materials and Methods: We selected two common epigenetic modifiers Trichostatin A (TSA), a histone deacetylase inhibitor and 5-aza-2′-deoxycytidine (decitabine), a demethylating agent which were evaluated alone and in combination with low dose Cisplatin for their tumorigencity in SCID mice and their spheroid formation in serum-free medium with two ovarian cancer cell lines SKOV3 and Hey. We also measured the effect of these drugs on tumor suppression pathways, AKT pathway, and expression of cadherins as well as histone modification.
Results: All combinations of TSA, decitabine and Cisplatin inhibited both tumorigenicity and spheroid formation in both cell lines with Hey exhibiting more resistance to treatment. E-cadherin expression was suppressed in SKOV3 cells while N-caderin expression was suppressed in Hey cells with both TSA and Cisplatin and decitabine and Cisplatin. In the Hey cell line, p53 expression was increased by sequential treatment with low dose decitabine and low dose cisplatin and by low dose TSA and low dose cisplatin. The profiling of histone code revealed distinctly different chromatin regulation between Hey cells and SKOV3 cells. The expression patterns and characteristics of cell adhesion, mutiple-drug transporter, apoptosis are distinctly different in these two ovarian cancer cell lines, which may be due to the different origins and stages of these cell lines.
Conclusions: The combinations of decitabine, TSA and Cisplatin suppressed the formation and growth of xenograft and tumor spheroid, altered the molecular mechanism of cell adhesion, chemosensitivity, and chromatin modification which may provide a new and promising treatment strategy for chemoresistant ovarian 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 3517. doi:10.1158/1538-7445.AM2011-3517
Abstract 3520: The use of vasodilators to enhance efficacy of hypoxia or acid activated prodrugs in pancreatic cancers
Authors: Cornnell Heather H. , Baker Amanda F. , Torres Tedman A. , Hashim Arig Ibrahim , Rejniak Katarzyna A. , Gatenby Robert A. , Gillies Robert J. 
Published: June 2012

Abstract
The vasculature of tumors is torturous and immature and in many cases lacks tone (the ability to self-regulate pressure). The administration of vasodilating agents induces a drop in systemic blood pressure which is not matched in the tumor, resulting in decreased intratumoral perfusion due to the “steal phenomenon”. This research uses this phenomenon to induce decreased tumor perfusion which results in increased tumor acidity and hypoxia. We hypothesize that this change in the tumor microenvironment can be used in combination with hypoxia- and acid-activated prodrugs (HAPs and AAPs) to enhance their efficacy, by increasing both the depth and distribution of hypoxia or acidosis within the tumor. Specifically, we have investigated the administration of hydralazine in several pancreatic xenograft tumors and used a needle microelectrode to measure decreases in pH as a result of decreased perfusion. We have also employed a computational math model to investigate the timing of the delivery of both hydralazine and HAPs to optimize the cell death.
Preliminary computational results suggest that multiple rounds of vasodilators may be given with a single round of HAPs, depending on several factors including duration of vasodilation effect and half-life of the HAP. The pH investigation showed a substantial pH drop in one tumor type (MiaPaca2), but no change in two others (HS766t and SU8686), suggesting that the ‘steal’ phenomenon is not universal. Preliminary data suggest that combination therapy in the ‘steal’-sensitive models will increase efficacy. We are continuing research with the combination therapy, employing the timing strategies suggested by the computational models. We are also investigating different imaging modalities to monitor the effects of the steal phenomenon, including Ultrasound (for perfusion) and MRI (for bulk tumor changes and monitoring pH).
In conclusion, the preliminary data supports the hypothesis that vasodilatation agents may be used to induce increases in acidosis and hypoxia within the microenvironment of some (but not all) tumors. These effects can be taken advantage of through combination with HAPs or AAPs to enhance antitumor effects. Further, computational math models can be employed to help determine the best timing for the combination therapies.
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 3520. doi:10.1158/1538-7445.AM2011-3520
Abstract 3522: Pre-treatment with FSH enhances the ability of EP-100 to target and destroy human pancreatic cancer cells
Authors: Solipuram Rajasree , Aggarwal Sita , Leuschner Carola , Alila Hector , Hansel William 
Published: June 2012

Abstract
The expression of luteinizing hormone releasing hormone (LHRH) receptors by pancreatic cancer cells has been clearly established. We observed that pancreatic cancer cell lines contain different numbers of LHRH receptors (BxPC3&gt;MIAPaCa-2&gt;PANC-1) using relative quantitation of RNA by real time PCR. In an in vitro study, we found that treatment of PANC-1 cells in culture with small amounts (10 or 30 ng/ml) of follicle stimulating hormone (FSH) caused a 3-fold increase in LHRH receptor gene expression. Therefore, we hypothesized that pre-treatment of nude mice bearing PANC-1 tumor xenografts with FSH will increase the number of LHRH receptors which will enhance the ability of the EP-100 (LHRH conjugated lytic peptide) to target and destroy PANC-1 pancreatic cancer cells. Our main objective was to determine in vitro and in vivo if FSH enhances the efficacy of EP-100 in targeting and destroying PANC-1 cells. PANC-1 cells (5000/well) were pretreated with FSH (10 and 30 ng/mL) for 24 h followed by EP-100 (4 and 6 µM) for 24 h in a medium containing 0.2% Dextran charcoal treated serum. MTT cell viability assay results showed that pre-treatment of PANC-1 cells with FSH significantly (P&lt;0.001) enhanced the cytotoxicity of EP-100. PANC-1 tumor xenograft bearing Athymic Balb/C nude mice (n=11) were treated with EP-100 (0.2 and 0.02 mg/kg), iv, once a week for three weeks with or without FSH pre-treatment, sc, (3 mg/kg for three days prior to administering the conjugate). The treatment groups included were baseline (sacrificed at the beginning of treatment), vehicle, FSH alone, EP-100 (0.02 mg/kg) alone, EP-100 (0.02mg/kg) with FSH, EP-100 (0.2 mg/kg) alone, EP-100 (0.2 mg/kg) with FSH. FSH pre-treatment significantly enhanced the ability of EP-100 (0.02 mg/kg – P&lt;0.05 and 0.2 mg/kg – P&lt;0.001 compared to baseline) to regress the growth of PANC-1 tumor xenografts in vivo. Histopathological evaluation revealed an increase in tumor necrosis in FSH pre-treated mice.
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 3522. doi:10.1158/1538-7445.AM2011-3522
Abstract 3524: Structure-based molecular docking of DNA polymerase β as a novel target for chemotherapeutic intervention of colorectal cancer
Authors: Jaiswal Aruna S. , Banerjee Sanjeev , Aneja Ritu , Sarkar Fazlul H. , Ostrov David A. , Narayan Satya 
Published: June 2012

Abstract
Colorectal cancer is the third most common cancer and the second most common cause of cancer related deaths worldwide. In the year 2010, an estimated 102,900 new colorectal cases will be diagnosed and 51,370 deaths will occur in the United States only. Chemoprevention presents a major strategy for the medical management of colorectal cancer risk. Most drugs used for colorectal cancer therapy induce DNA alkylation damage, which are primarily repaired by the base excision repair (BER) pathway. Thus, blockade of BER pathway is an attractive option to inhibit the spread of colorectal cancer. Here we used structure-based molecular docking of DNA polymerase β (Pol-β) and identified a potent anti-Pol-β compound NSC-124854. Our aim was to examine whether NSC-124854 could enhance the therapeutic efficacy of DNA-alkylating agent, Temozolomide (TMZ), by blocking BER. First, we determined the specificity of NSC-124854 for Pol-β by using in vitro activities of APE1, Fen1, DNA ligase I, and Pol-β-directed single nucleotide (SN)- and long-patch (LP)-BER. Second, we determined the effect of NSC-124854 on the cytotoxicity of TMZ to mismatch repair (MMR)-deficient and MMR-proficient colon cancer cells by using in vitro clonogenic assays. Third, we used female homozygous SCID mice as a pre-clinical xenograft model to determine the effect of NSC-124854 on the in vivo tumor growth inhibition of MMR-deficient and MMR-proficient colonic tumors in mice. Our data showed that NSC-124854 elicit specificity to Pol-β and blocked Pol-β-directed SN- and LP-BER activities in vitro reconstituted system. Furthermore, NSC-124854 effectively induced the sensitivity of TMZ to MMR-deficient and MMR-proficient colon cancer cells both in vitro cell culture system and in vivo mouse model. Our findings suggest a potential novel strategy for the development of highly specific, and thus safer structure-based inhibitor(s) for the prevention of colonic tumor progression. This work has been supported by NCI/NIH grants (R01 CA-097031 and CA-100247) to SN.
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 3524. doi:10.1158/1538-7445.AM2011-3524