bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4738: Utilizing genotype imputation for the augmentation of sequence data
Authors: Fridley Brooke L. , Jenkins Greg , Deyo-Svendsen Matthew , Hebbring Scott , Freimuth Robert 
Published: February 2011

Abstract
The advancement in genotyping technology and large SNP arrays has led to an increase in the number of genome-wide association studies (GWAS) for various complex traits. These GWAS have resulted in the implication of over 1500 SNPs for association with disease traits. However, the SNPs identified from these GWAS are not necessarily the functional variants. Therefore, the next phase in GWAS will involve the validation, augmentation and refining of these putative regions or loci.
One possible “next phase” approach would be to catalog all variants found in the study subjects within the loci of interest using sequencing technology, followed by the association analysis. However, sequencing a locus in a large number of subjects is still relatively expensive. By sequencing only a portion of the samples for the follow-up of signals from GWAS, followed by imputation in the remaining samples, one can significantly reduced the cost to localize the punitive variant involved in the etiology of complex phenotypes. A potentially attractive alternative option would be to impute based only on the 1000 Genomes Project; however, this has the drawbacks of using a reference population that does not necessarily match with disease status and LD pattern.
Therefore, we conducted a study to investigate the ability to carry-out genotype imputation using a reference panel consisting of sequencing data for a fraction of the study participants. The various approaches were implemented using data from the candidate gene sequencing study conducted at the Mayo Clinic and the 1000 Genomes Project. Our results show that imputation of untyped markers based on sequencing a portion of the study participants is a reasonable, cost-saving, approach for disease mapping and the refinement of putative regions detected with GWAS. We recommend a few guidelines in designing sequencing studies to take advantage of the recent advances in genotype imputation: (1) Select the largest and most diverse reference panel for sequencing, with respect to both haplotypes and phenotypes. One can also use the 1000 Genomes Project in addition to the sequencing of a portion of the study participants; (2) Genotype as many “anchor” markers as possible, in that, the number of markers genotyped on all subjects impacts accuracy. Therefore, additional genotyping of a few common SNP markers not already genotyped on all subjects using a cost effective platform may be needed if the GWAS SNP array does not provide adequate coverage in the locus to be sequenced.
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 4738.
Abstract 4749: Genetic signature of malignant glioma is associated with responsiveness to autologous tumor lysate-pulsed dendritic cell vaccination + TLR agonists
Authors: Prins Robert M. , Soto Horacio , Konkankit Vera , Yong William H. , Nelson Stanley F. , Liau Linda M. 
Published: February 2011

Abstract
Purpose: We previously reported that the toll-like receptor (TLR)-7 agonist, imiquimod, could enhance dendritic cell activation and migration, as well as stimulate T cell-mediated anti-tumor immune responses in a murine glioma model. To translate these findings, a Phase I clinical trial was initiated to evaluate this strategy for its feasibility, safety, and induction of immune responses in patients with malignant glioma. Herein, we report the results of this phase I, dose escalation clinical trial using autologous tumor lysate-pulsed dendritic cell (DC) vaccination, supplemented with the toll-like receptor agonists, imiquimod or poly ICLC, for patients with malignant glioma.
Patients and Methods: Twenty-two glioblastoma patients (15 newly diagnosed, 7 recurrent) were enrolled into a multi-cohort dose-escalation study and treated with 1, 5, or 10 million autologous DC pulsed with tumor lysate. Three biweekly intradermal vaccinations were initially administered. Subsequently, patients received booster vaccinations together with imiquimod or poly ICLC every three months until tumor progression or lysate was depleted. Patients were monitored for adverse events, survival, and immune responses. For patients with available pre-treatment tumor and/or PBMC, microarray-based hierarchical clustering, lymphocyte immunohistochemistry, FACS and cytokine bead arrays were performed for monitoring purposes.
Results: DC vaccinations were not associated with any evidence of dose-limiting toxicity or serious adverse effects. The median survival was 35 months for newly diagnosed patients and 11 months for recurrent patients, but still increasing as several patients are still alive at this point. Typical glioblastoma gene expression signatures, previously characterized by our group, were found. Contrary to our previous reports, however, patients with proliferative (Pro) or mesenchymal (Mes) signatures exhibited prolonged survival, while patients with pro-neural (PN) signatures did not. Pre-treatment Pro, Mes or Pro/Mes tumor sections had increased CD3 and CD8 positive cells within the tumor compared with PN tumor sections.
Conclusions: Pro, Mes or Pro/Mes gene expression signatures may identify patients with pre-existing immunity and who may benefit from immune-based vaccination studies. However, prospective studies will need to be performed to establish the validity of these findings.
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 4749.
Abstract 4769: Relevance of the TRIF pathway for in vivo gp96-mediated CD8+ T cell cross presentation
Authors: Luna Ernesto , Fukata Masayuki , Strbo Natasa , Abreu Maria T. , Podack Eckhard R. 
Published: February 2011

Abstract
Heat shock protein gp96 is an intracellular chaperone for proteins and peptides generated during protein synthesis and degradation. Different candidate receptors including CD91, TLR2 and TLR4 have been shown as important binders in the gp96 mediated cross-priming process. Both TLR2 and TLR4 use the common MyD88 signaling pathway suggesting it is an important mediator of gp96-mediated cross-priming. Our group has produced a secreted form of hsp-gp96, a fusion protein gp96-Ig. Ggp96-Ig-transfected tumor cells secrete gp96-Ig in vivo and cross prime CD8 CTL that are specific for genuine tumors antigens (Ag) and for the surrogate Ag OVA. In this work, we studied the role of both MyD88 and TRIF signaling pathways in gp96-mediated cross presentation. Briefly, one million of ovalbumin specific T cell receptor (TCR) transgenic CD8+ cells (OT-I)-gfp, were transferred intravenously into MyD88 deficient (MyD88−/−) mice, TRIF deficient (TRIF Lps2/Lps2) mice and C57/BL6 wild type (B6-WT) mice as control. Two days later the mice were immunized intraperitoneally with two million of 3T3-gp96-mIgG1-OVA cells or 3T3-OVA cells respectively. Five days later, we obtained peritoneal cells (PECs) and splenocytes in order to analyze OT-I-gfp expansion, IFNγ production, CD107a degranulation and cytokine (IL-6, TNFα, IL-10) production by ELISA. Gp96 induced CD8 CTL (OT-I) expansion is significantly increased in MyD88−/− mice compared to WT mice and significantly decreased in TRIF deficient mice. However, the frequency of IFNγ expression in CTL is diminished in MyD88−/− while is normal in TRIF deficient mice. IL-6 and TNFα production by antigen presenting cells isolated from the peritoneal cavity, was reduced in MyD88−/− mice compared with WT and TRIF deficient mice. The data indicate that both, MyD88 and TRIF mediated signals are required for full CD8 CTL expansion and cytotoxic differentiation.
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 4769.
Abstract 4809: Targeting integrin function in melanoma cells using vinculin activators results in enhances chemosensitivity
Authors: Nelson Elke S. , Folkmann Andrew , DeMali Kris 
Published: February 2011

Abstract
Current therapies aimed at manipulating cell adhesion work by modulating interactions between integrins (the major adhesion receptors on the cell surface) and components of the extracellular matrix. However, a complete gain or loss of integrin function can lead to mechanism-based toxicities. An attractive alternative approach is to manipulate integrin-associated proteins. Vinculin, an actin binding protein that is recruited to the cytoplasmic tail of integrin β1, is a good candidate protein for such an approach, as it regulates the strength and lifetime of such complexes. Here we have investigated the effect that a vinculin activating peptide (VAP) has on integrin-mediated adhesion. In HeLa cells and mouse embryonic fibroblasts, VAP increased integrin-mediated signaling, as well as adhesion to fibronectin and collagen, in an integrin- and vinculin-dependent manner. These regulatory effects of VAP were dependent on the peptide's ability to bind to an amphipathic α-helix in the vinculin head; substitution of an isoleucine for alanine at position 50 within this region of vinculin abolished VAP's ability to enhance adhesion. In melanoma cells, VAP likewise increased integrin-mediated cell adhesion, and increased the cells’ sensitivity to cancer chemotherapeutics, suggesting that it might serve as an effective therapeutic agent. Overall, our findings demonstrate that integrin function can be manipulated by targeting the regulation of proteins that associate with the cytoplasmic domains of the integrins, and suggest that small molecules capable of such regulation may be employed as effective adjuvants to chemotherapy for melanoma. These findings lay the foundation for the development of a new class of therapeutics that act by regulating integrin-associated proteins.
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 4809.
Abstract 5038: AZD8055 is an effective inhibitor of mTOR kinase signaling and breast cancer growth while relieving feedback inhibition of HER-kinase signaling
Authors: Rodrik-Outmezguine Vanessa S. , Cao Nen , Chandarlapaty Sarat , She Qing-Bai , Ye Qing , Smith Paul , Guichard Sylvie , Rosen Neal 
Published: February 2011

Abstract
The PI3K signaling pathway is often dysregulated in human cancer. mTOR kinase is a component of this pathway that mediates activation of cap-dependent translation, other AGC-kinases and feedback inhibition of upstream components of the pathway. The natural product rapamycin binds to and inhibits the mTOR-containing TORC1, but not the TORC2 complex. Rapamycin-like TORC1 inhibitors have modest clinical activity in renal cell and other cancers, but only marginal activity in glioblastoma, prostate and breast cancers in which PI3K/AKT signaling is often activated. The limited antitumor activity of rapamycin may be due to inefficient inhibition of TORC1, induction of TORC1-dependent feedback, or lack of inhibition of TORC2. Potent mTOR kinase inhibitors could obviate these issues by inhibiting both TORC1 and TORC2 and by preventing induction of phosphorylation of AKT at Serine 473.
We have now compared the effects of the specific mTOR kinase inhibitor AZD8055 and rapamycin in breast cancer models with amplified HER2 or mutant p110alpha PI3K. As expected, AZD8055 and rapamycin both inhibit S6K and S6 phosphorylation, but only the former inhibits AKT phosphorylation at Serine 473, which is, instead, induced by rapamycin. Moreover, AZD8055 is a more potent inhibitor of 4EBP-1 phosphorylation, CAP-dependent translation, and D-cyclin expression. Thus, the mTOR kinase inhibitor inhibits mTOR functions more effectively than rapamycin. Whereas both drugs cause tumor cells to undergo autophagy and G1 arrest, only AZD8055 induces significant apoptotic cell death.
The more effective inhibition of 4EBP1 phosphorylation, cap-dependent translation and enhancement of apoptosis compared to that caused by rapamycin may be due to more complete inhibition of TORC1 function or to abolition of feedback activation of AKT by AZD8055. As previously established with rapamycin, we now show that AZD8055 causes relief of feedback inhibition of HER kinase signaling in these tumors, resulting in marked induction of both ERK and PI3K signaling. These results suggest that mTOR kinase inhibition with drugs such as AZD8055 can more effectively inhibit TOR activity than rapamycin. They therefore have the potential for increased antitumor activity, but relief of TOR kinase-dependent negative feedback could create a rationale for combination therapy.
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 5038.
Abstract 5045: The Hh inhibitor IPI-926 inhibits relapse of a non-small cell lung cancer xenograft model following treatment with an EGF-R targeted tyrosine kinase inhibitor
Authors: Mandley Everton , White Kerry , Faia Kerrie , Travaglione Veronica , Read Margaret , McGovern Karen , MacDougall John R. 
Published: February 2011

Abstract
The Hedgehog (Hh) pathway plays a key role in multiple types of cancer, either by mutational activation of the pathway in tumor cells or by ligand-dependent signaling to the tumor cells or paracrine signaling between tumor cells and the tumor microenvironment. We have previously shown in a primary model of SCLC that the Hh pathway inhibitor IPI-926 prevents tumor relapse after regression of the tumor with chemotherapy (Travaglione et al., AACR 2009). To investigate whether tumor regression with a targeted agent could elicit a similar response as that seen with chemotherapy, two NSCLC lines (H1650 and HCC827), with activating mutations in the EGFR were evaluated. NSCLC cell lines bearing mutant EGFR are exquisitely sensitive to EGFR kinase inhibitors. Upon treatment with gefitinib in vitro, HCC827 increased the expression of Indian and Sonic hedgehog ligands 10-fold, as measured by qRT-PCR. When grown in mice as subcutaneous xenografts, H1650 tumors regressed following treatment with the EGFR inhibitor gefitinib (40 mg/kg every day) for 7 days. The gefitinib-treated mice were then administered either vehicle or IPI-926 at 40 mg/kg every other day for three weeks, and in this setting IPI-926 treatment led to a 65% decrease (p=0.0104) in tumor volume compared to vehicle-treated mice. Conversely, tumors that had not been regressed with the EGFR TKI showed no response to the Hh pathway inhibitor, similar to our previous results in SCLC with chemotherapy. Studies are ongoing to define the mechanism of action of IPI-926 in this setting. When grown in mice as subcutaneous xenografts, these tumor cells produce Shh ligand in conjunction with stromal Gli-1 expression in the murine stroma. Stromal Gli-1 expression is inhibited by treatment with IPI-926, indicating that Hh ligand produced by NSCLC tumor cells signals to stroma in a paracrine manner. Together with our previous results in SCLC, these data suggest that therapeutic inhibition of the Hh signaling pathway might be an important strategy to extend progression free survival in patients who initially respond to therapy but later relapse, and that this paradigm is applicable to multiple cancer types and treatment modalities.
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 5045.
Abstract 5181: Forced hemidesmosome assembly blocks pancreatic cancer cell invasiveness
Authors: Laval Séverine , Laklai Hanane , FanJul Marjorie , Pucelle Mélanie , Susini Christiane , Pyronnet Stéphane , Bousquet Corinne 
Published: February 2011

Abstract
Hemidesmosomes (HDs) play a critical role in epithelia integrity by anchoring epithelial cells to the basement membrane (BM). These structures, present at the basal cell surface, link the intracellular intermediate filament network with the extracellular laminins of the BM. Interestingly, HDs are frequently lost in cancer cells, thereby facilitating epithelial tumor cell detachment from the BM.
Surprisingly, we here provide evidence that a strong immunoreactivity for the integrin α6β4 and BP180, two specific hemidesmosomal proteins, is observed in human pancreatic ductal adenocarcinoma cells, where their function served paradoxically to stimulate migration and invasion. Using human pancreatic cancer cells in culture, we described molecular events explaining why these proteins are hijacked from their primary function and, importantly, how to force back the reassembly of HDs, thereby decreasing cancer cell migration and invasion.
This is achieved by introducing in these cells the somatostatin receptor sst2, whose expression is lost in 90% of pancreatic cancers, and which we have shown to have oncosuppressive functions including inhibition of tumor progression and metastasis. Cell treatment with somatostatin forced HDs reassembly by stimulating two separate critical events, as demonstrated in pancreatic cancer cells and in migrating keratinocytes: 1- the dephosphorylation of the α6β4 integrin which drives its relocalization from lamellipodia, where it is delocalised upon its phosphorylation by growth factors in migrating cells, to HDs; 2- the inhibition of the cleavage of BP180 into its pro-migratory BP120 form, which is here shown to account for the strong BP180 immunoreactivity observed in human pancreatic tumor samples as compared to normal pancreas where the full-length BP180 form is mostly expressed. BP180 cleavage into BP120 is here shown to rely at least on the activity of the MMP-9 metalloprotease whose activity is inhibited by sst2. Strikingly, knocking-down BP180 expression (siRNA) impairs somatostatin-induced HDs assembly in sst2-expressing cells. Interestingly, BP180 siRNA partially revert sst2 inhibitory role on in vitro and in vivo cell migration and invasion, as demonstrated using the chick chorioallatoic membrane model whereby tumor progression of pancreatic cancer cell xenografts is monitored. We have identified novel and original mechanisms for somatostatin-activated sst2 to revert cancer cell pro-migratory phenotype by facilitating HD assembly and cancer cell anchorage to the BM.
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 5181.
Abstract 558: Constitutive activation of p38 MAPK signaling in tumor cells induces osteolytic bone lesions via regulating bone marrow microenvironment
Authors: Yang Jing , Yi Qing 
Published: February 2011

Abstract
Bone residing tumor cells cause osteolysis, characterized with severe bone pain, multiple fractures and hypercalcemia in patients. While it has been proposed that tumor cells activate osteoclasts and/or inhibit osteoblasts, leading to bone resorption, the mechanism underlying tumor-induced osteoclastogenesis activation in bone marrow microenvironment, which causes osteolytic bone lesions, is yet to be elucidated. P38 mitogen-activated protein kinase (MAPK) is commonly constitutively activated in malignant osteolytic tumors. We hypothesize that constitutive activity of p38 MAPK in tumor cells might contribute to osteolytic bone lesions via regulating bone marrow microenvironment. For this purpose, we applied of small hairpin RNAs (shRNAs) to disrupt p38 MAPK activity in myeloma ARP-1 and bone metastatic breast cancer MDA-MB-231 cells. To evaluate the role of tumor p38 MAPK in bone lesions, tumor cells with p38 MAPK-shRNAs or control vectors were intravenously injected to SCID mice. Lytic lesions in tibial bones were measured by radiograph and μ-CT, and further confirmed by histological examination. The results showed that lytic bone lesions were found in mice bearing of tumor cells with control vectors. In contrast, no or less bone lesions were found in mice with shRNA-expressing tumor cells. Moreover, decrease of osteoclast amounts covered bone surface, as well as circulating levels of collagen type I (bone resorption marker) and TRAP5b (active osteoclast marker), but increase of osteoblast amounts, and osteocalcin (bone formation marker) and ALP (active osteoblast marker), were found in those mice injected with shRNA-tumor cells. Noticeably, tumor p38 MAPK enhanced osteoclast differentiation and activity, as well as inhibited osteoblast maturation and function in vitro. However, disruption of p38 MAPK activity in tumor cells did not affect tumor growth and tumor cell homing to bone. We further identified that tumor p38 MAPK-derived monocyte chemotactic protein-1 (MCP-1) and dickkopf-1 (DKK-1) induced bone lesions via activation of RANK/RANKL-mediated NFκB, p38 MAPK and ERK1/2 signaling pathways. In conclusion, our results elucidate a novel mechanism that tumor p38 MAPK activity regulates bone marrow microenvironment and contributes to tumor-induced osteolytic bone lesions. Thus, inhibition of p38 MAPK signaling in tumor cells may have an important implication to treat bone lesions in patients with osteolytic tumors.
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 558.