bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-268: Loss of HPV16 E2 protein expression and transcriptional modulation of cellular and viral genes correlate with progression to cervical carcinoma
Authors: Thierry Francoise 
Published: August 2012

Abstract
Integration of the viral DNA in the cellular genome has been suggested to be critical in carcinogenic progression of HPV-associated cervical neoplasia. This event can be accompanied by disruption of the open reading frame (ORF) encoding the E2 repressor, thus leading to transcriptional up-regulation of the E6 and E7 viral oncogenes. At this stage, it is unclear whether disruption of the E2 ORF is mandatory for carcinogenic progression. We measured E2 RNA and protein expression in clinical samples of various grades of HPV16-associated cervical neoplasia and compared it with the status of the viral genome. RNA extracted from paraffin embedded tissues was hybridized to specific probes and quantified by the NanoString technology. Protein expression was appreciated by immunohistochemistry and the status of viral DNA was determined by in situ hybridization, all performed on serial sections of the same samples. E2 protein was found highly expressed in CIN2 lesions where the HPV DNA was highly replicating, while it was decreased in more advanced grade lesions where replication is decreased or lost (CIN3 and SCC). Our data demonstrate that integration of the viral DNA in the cellular genome is always accompanied by drastic reduction of expression of the E2 protein, even when the E2 ORF is not disrupted by integration. The viral genes appear differentially expressed during progression as transcription of the HPV16 E6/E7 oncogenes, only when compared to E2-E4, is significantly higher in high grade lesions than in CIN2. In addition, transcription of 400 cellular genes of the cell cycle and immune-response were also studied in 20 clinical samples that show modulation during progression. We will discuss the establishment of a transcriptional signature for progression in cervical cancer and the role of local immune response in the fate of cervical lesions associated with HPV16.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-268. doi:1538-7445.AM2012-LB-268
Abstract LB-281: Hodgkin Lymphoma requires stabilized NIK and constitutive RelB expression for survival
Authors: Ranuncolo Stella M. , Xiao Wenming , Wright George , Abu-Asab Mones , Pittaluga Stefania , Jaffe Elaine S. , Lewis Brian 
Published: August 2012

Abstract
The REL family of transcription factors plays major roles in diverse cell processes and tumor etiology. Despite considerable evidence supporting the role of the REL members in the immune system and lymphomagenesis, it is not clear whether each REL controls unique targets in distinct subsets of B cell-derived lymphomas or whether each is redundant. We delivered specific shRNAs to knock down each REL member in representative non-Hodgkin (NHL) and Hodgkin lymphoma (HL) cell lines. All NHL and HL cell lines were dependent on RelA and c-Rel for survival but only HL cells were sensitive to RelB depletion. ChIP-seq analysis uncovered an extensive nonoverlapping REL networks and that RelB directly controlled cell cycle regulators and apoptosis inhibitors including BCL2 and BCLx. However, the RelB shRNA in HL cells does not kill these cells by apoptosis. Electron microscopy revealed intact nuclei with considerable numbers of cytosolic vacuoles, indicative of autophagy. Secondly, ATG7, a key player in the autophagosomes development, is induced. We found that HL cell lines and primary tumors stably expressed NIK and that HL cell lines are missing either TRAF2 or TRAF3 protein (negative regulators of NIK). Unexpectedly, RelB shRNA resulted in the re-expression of TRAF2 and degradation of NIK protein. Lastly, both NIK shRNA and a small molecule inhibitor of NIK had the same phenotype as the relB shRNA. These data shed light on unexplored aspects of HL biology. We found that HL is the only GC B-cell derived malignancy that relies on RelB for viability, and thus differentiates Hodgkin lymphoma from non-Hodgkin lymphomas. These data argue that each REL member has specific and unique functions and gene targets, as we predicted from the lack of similarities in their transactivation domains. Furthermore, the RelB dependency in HL suggests that NIK is an attractive therapeutic target and the possibility of targeting NIK enzymatic activity in HL patients with diminishing side effects.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-281. doi:1538-7445.AM2012-LB-281
Abstract LB-283: Aurora B binds p53 during both interphase and mitosis, phosphorylates it and promotes its degradation
Authors: Fuentes-Mattei Enrique , Gully Christopher , Velazquez-Torres Guermarie , Shin Ji-Hyun , Chen Jiun-Sheng , Choi Hyun Ho , Chou Ping-Chieh , Adams Henry P. , Phan Liem , Yang Tsung-Ying , Yeung Sai-Ching J. , Lee Mong-Hong 
Published: August 2012

Abstract
Aurora B (AurB) is a mitotic checkpoint kinase that plays a pivotal role in the cell cycle, ensuring correct chromosome segregation and normal progression through mitosis. Tumor suppressor p53 is a genome guardian and an important negative regulator of the cell cycle. Although overexpression of AurB and loss or degradation of p53 have been described in many types of human cancers, it is not known whether AurB and p53 are coordinately regulated during the cell cycle. Recently has been shown that NIR, which is a transcriptional co-repressor of histone acetyltransferase activity, interact with and suppress p53 via interaction with AurB. Our results show that AurB directly interacts with p53 in a NIR-independent matter. To prove direct molecular interaction between AurB and p53 in whole cells, we employed the method of bimolecular fluorescent complementation (BiFC). AurB-p53 interaction occurs at the nucleus in interphase and at the centromeres in prometaphase of mitosis. We observed that AurB-p53 interaction co-localized with Survivin and CENP-A, suggesting that AurB and p53 interact at the centromeres. Our results also show that Aurora B phosphorylates p53 to accelerate p53's degradation through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis. Inhibition of Aurora B in cancer cells with wild-type p53 increased p53 protein level and expression of p53 target genes to inhibit tumor growth. Together, these results give a new insight of a novel mechanism of p53 inactivation during the cell cycle and imply that oncogenic hyperactivation or overexpression of AurB may compromise p53's tumor suppressor function.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-283. doi:1538-7445.AM2012-LB-283
Abstract LB-294: Transforming growth factor beta 3 (TGF-ß3) contributes to epithelial-mesenchymal transitions (EMT) in human prostate cancer
Authors: Zhang Qiang , Lin Xiao , Helfand Brian , Chen Lin , Kozlowski James , Yang Ximing J , Zhu Lihua J , Lee Chung 
Published: August 2012

Abstract
Introduction and Objective: TGF-ß3 is considered as an important endogenous mediator of normal developmental and cellular repair, but its role in cancer is not well characterized. We recently reported that over-production of TGF-ß1 by tumor cells is involved in the epithelial-mesenchymal transition (EMT) in cancer cells. Based upon our prior findings, we hypothesized that, in addition to TGF-ß1, TGF-ß3 may also be involved in the EMT and contribute to prostate cancer (PCa) progression. In the present study, we explored the relationship between TGF-ß3 and TGF-ß1 induced EMT pathway in PCa. Methods: We studied 287 prostatectomy specimens obtained from the Northwestern University Prostate SPORE tissue bank. 165 specimens had low Gleason score (≤6, LGS), 55 had intermediate Gleason score (7, IGS), and 67 had high Gleason score (8-10, HGS). The median follow-up was 60 months (range 22-82). Levels of TGF-ß 1, TGF-ß 3, NF-kB and vimentin were analyzed using a high-throughput tissue microarray analysis and immunohistochemistry staining. Clinical correlation was performed based on patient follow-up information from the Prostate SPORE clinical-linked database which includes pre- and post-operative serum PSA levels. Results: High levels of TGF-ß3 expression were identified in 33.8%, 2.8% and 1.1% of HGS, IGS and LGS tumors, respectively, while high levels of vimentin expression occurred in 23.9%, 3.6% and 1.8% of HGS, IGS and LGS tumors, respectively. Expression of vimentin was significantly associated with high levels of TGF- ß3 (P=3.22E-06). Furthermore, TGF- ß3 overexpression was significantly associated with more aggressive tumors with high Gleason score (P=9.76E-09). Furthermore, there was a positive and significant correlation between expression of TGF- ß 3 and TGF-ß1 (P=2.29E-07), and between the expression levels of TGF- ß3 and NF-kB (P=7.52E-12), which were previously reported to be important mediators of the EMT in PCa. Conclusion: Our results firstly demonstrate that TGF-ß3 has a close correlation with TGF-ß 1 mediated overexpression of vimentin in PCa, which highly suggests that TGF-ß3 may play a critical role in the TGF- ß1 induced NF-kB mediated EMT signaling pathway. This pathway was reported to play a dramatic effect on the progression of human PCa and disease recurrence after prostatectomy. Consideration of TGF- ß3 tissue immunohistochemistry should be considered as a novel potential biomarker for EMT of PCa in clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-294. doi:1538-7445.AM2012-LB-294
Abstract LB-297: The EMT inhibitor AB-16B5 interacts with specific isoforms of secreted clusterin
Authors: Tremblay Gilles B. , Viau Elisabeth , Filion Mario 
Published: August 2012

Abstract
Secreted clusterin (sCLU) exhibits elevated expression in several cancer indications. sCLU plays a pro-survival role in tumors and, more recently, it was found to be a potent stimulator of the epithelial-to-mesenchymal transition (EMT). These findings led to the development of a monoclonal antibody, AB-16B5, that interacts with a specific EMT-inducing domain in sCLU resulting in abrogation of migration and invasion of many types of cancer cells. We previously showed that blocking tumor-associated sCLU with AB-16B5 reduced the expression of mesenchymal markers and restored the expression of epithelial markers in human tumor xenografts, observations that were in line with inhibition of EMT in vivo. Consequently, this resulted in reduced metastatic invasion and increased response to cytotoxic agents in animal models of human cancer. We now report new results that shed light on the biochemical differences between sCLU that is secreted by tumor cells or normal cells. Using two-dimensional gel electrophoresis, we found that there was a difference in the number and composition of sCLU isoforms present in the plasma of cancer patients compared with those expressed in healthy individuals. In particular, the post-translational modifications were more complex on sCLU secreted from tumor cells compared with those present in sCLU from healthy individuals. Moreover, AB-16B5 was found to specifically interact with several of the isoforms expressed from tumor cells but exhibited a reduced ability to interact with sCLU from plasma from healthy individuals. We also examined the interaction between AB-16B5 and tumor-associated sCLU in vivo. In these studies, injection of AB-16B5 conjugated to a fluorophore in mice harboring sub-cutaneously implanted human pancreatic tumor xenografts resulted in a rapid enrichment of fluorescence signal in the tumors. Interestingly, administration of high concentrations of human recombinant sCLU immediately prior to injection of the AB-16B5 fluorophore-conjugate still resulted in enrichment of fluorescence signal in the tumors, albeit at slightly lower intensity than was observed in the absence of recombinant sCLU. Our findings indicate that AB-16B5 can efficiently interact with tumor-associated sCLU despite the presence of excess concentrations of sCLU in the circulation. Taken together, our results suggest that AB-16B5 has increased affinity for sCLU isoforms that are specifically expressed from tumor cells that have undergone an EMT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-297. doi:1538-7445.AM2012-LB-297
Abstract LB-426: Potent inhibitors of RAS pathways that bind directly to Ras proteins
Authors: Johannessen Liv , Remsberg Jarrett R. , Ivanova Alla , Gaponenko Vadim , Khavrutskii Lyuba , Tarasov Sergey G. , Dean Michael , Kates Joseph , Tarasova Nadya I. 
Published: August 2012

Abstract
RAS genes are the most frequently mutated oncogenes in human cancer. Although they are believed to be among the most important drug targets in oncology, no synthetic molecules that directly target any member of the family and inhibit its function with appreciable in vivo or even in vitro activity have been identified. We have utilized a previously developed approach of peptide structural stabilization by membrane anchoring for the development of potent inhibitors of Ras proteins. We have tested lipopeptide analogs of different parts of Ras proteins and their interaction partners and have found lipopeptide analogs of hypervariable regions and of the C-terminal alpha helix (helix 6) of Ras proteins to be the most effective in interfering with Ras function and inhibiting Ras-dependent, but not Ras-independent growth of cancer cells. Direct binding of inhibitors to recombinant K-Ras (1-166) was detected by Microscale Thermophoresis (MST), and circular dichroism spectroscopy. NMR titration data revealed a localized interaction of helix 6 analogs with the Switch I region of K-Ras with the most significant chemical shift perturbations found in residues Q25, N26, S32, T35, and E37. Compounds inhibit the formation of active RasGTP and prevent Ras signaling to downstream effectors. Structural optimization of helix 6 analogs resulted in a metabolically stable, 12 amino acid residues long peptide made of all-D amino acids that inhibited the growth Ras-dependent cancer cell lines with GI50 below 1 nM. MST studies have shown that a fluorescently-labeled version of the compound binds to recombinant GDP-loaded K-Ras (1-166) with KD= 86 ±8 nM. Derivatives of K-Ras4B hypervariable region exert their activity by a significantly different mechanism: they cause degradation of Ras protein. Partially optimized compound of the series inhibit growth of cancer cells with GI 50 in submicromolar range and bind to recombinant K-Ras (1-166) with KD=1250±140nM (as determined in MST assay). CD spectroscopy data suggest that binding of compounds of both classes to K-Ras is accompanied by significant changes in protein secondary structure. In mice, inhibitors potently inhibited growth of H358 human lung tumor xenograft and Lewis lung carcinoma when injected subcutaneously every second day. The compounds are promising drug candidates for the treatment of many tumor types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-426. doi:1538-7445.AM2012-LB-426
Abstract LB-450: Necrosis predicts benefit from hypoxia-modifying therapy in urothelial cell carcinoma of the bladder
Authors: Irlam-Jones Joely J. , Williamson Amanda , Taylor Janet , Denley Helen , Agrawal Shailesh , Choudhury Ananya , Ryder David , Rojas Ana M. , Hoskins Peter J. , Miller Crispin J. , Ord Jonathan J. , Harris Adrian L. , West Catharine M.L. 
Published: August 2012

Abstract
To investigate the ability of tumor necrosis to predict benefit following radiotherapy with and without hypoxia-modifying treatment in high grade urothelial cell carcinoma of the urinary bladder. Background: There is no predictive marker of hypoxia-modifying therapy in cancer patients in routine clinical use. Methods: We identified 231 patients who participated in the BCON phase III randomised trial comparing radical radiotherapy (RT) with and without carbogen and nicotinamide (CON) in patients with urothelial cell carcinoma of the bladder who were suitable for this retrospective study. Tumor necrosis was scored on whole tissue sections as absent or present. Results: Tumor necrosis was identified in 121 of the 231 patients (52%). 5-year overall survival estimates were 41% for the RT arm and 48% for the CON arm (log rank p=0.14). When stratified using tumor necrosis, the 5-year overall survival estimates were 48% (RT) and 39% (CON) (log rank p =0.32) in patients with no evident tumor necrosis, and 34% (RT) and 56% (CON) (log rank p=0.004) in patients with tumor necrosis. Multivariate analyses showed that the presence of tumor necrosis was a significant predictor of benefit from CON with the risk of dying 57% lower compared to RT alone (HR 0.43, 95% CI 0.25-0.73, p=0.002). This trend was not observed when there is no evident tumour necrosis (HR 1.64, 95% CI 0.95-2.85, p=0.08). Test for heterogeneity in treatment effect by necrosis strata (p=0.007 unadjusted, p=0.001 adjusted). Conclusions: Tumor necrosis significantly predicts benefit from radiotherapy with hypoxia-modifying treatment. Independent validation in a prospective trial is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-450. doi:1538-7445.AM2012-LB-450
Abstract LB-465: The miRNA cluster 424/503 is an integral part of the TGFb-mediated cytostatic response in human mammary epithelial cells
Authors: Navas David Llobet 
Published: August 2012

Abstract
TGF-beta plays a major role during development and normal tissue homeostasis. Indeed and focusing in mammary tissue biology TGF-beta has been unmasked as a key component during epithelium cell proliferation, lactancy and involution. However, and despite most of the TGF-beta actions are well known for decades, its dichotomic effects depending on cell type, context and disease states and the mechanisms that lie underneath are still not fully understood. In this study we uncover a novel player in the mechanism through which TGF-beta induces cell cycle arrest in mammary epithelial cells. Using microRNA array expression profile we found a strong correlation between the expression of miRs 424 and 503 and TGF-beta treatment in MCF10A cells. Interestingly, this microRNAs are located clustered in the long arm of the X chromosome, regulated by a region located upstream containing a canonical SMAD3/4 binding site and expressed as a policistronic pri-miRNA. Ectopic upregulation of miR-424/503 induces cell cycle arrest at G1 phase mimicking TGF-beta actions. Our mechanistic studies have unveiled that this miRNA cluster exerts its function by modulating the expression of CDC25A through binding to its 3′UTR. Altogether our results point to miRs 424/503 as a new player in the cytostatic program mediated by TGF-beta in mammary epithelial cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-465. doi:1538-7445.AM2012-LB-465
Abstract LB-470: Tumor suppressor role of microRNA-18b in melanoma
Authors: Dar Altaf A. , Majid Shahana , de Semir David , Bezrookove Vladimir , Nosrati Mehdi , Kashani-Sabet Mohammed 
Published: August 2012

Abstract
MicroRNAs play important roles in gene regulation, and their expression is frequently dysregulated in various tumors. Here, we report that expression of miR-18b is significantly suppressed in melanoma specimens when compared with nevi. miR-18b is silenced in melanoma cell lines due to hypermethylation and is re-expressed by 5-AZA-deoxycytidine (5-AZA) in melanoma cell lines. miR-18b overexpression suppressed cell survival, colony formation, invasiveness and migratory ability and induced apoptosis in melanoma cell lines. Stable overexpression of miR-18b suppressed melanoma cell proliferation, colony formation, and tumor cell growth in-vivo. miR-18b reverses epithelial-to-mesenchymal transition in melanoma cell lines and its expression was induced by the chemotherapeutic drug cisplatin. These results demonstrate a novel role for miR-18b as a tumor suppressor in melanoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-470. doi:1538-7445.AM2012-LB-470
Abstract LB-475: 3′UTR polymorphisms affect expression and activity of IGF1R, a therapeutic target in pediatric neuroblastoma
Authors: Sotillo-Piñeiro Elena , Xu Liu , Nguyen Le , Laver Travis , Attiyeh Edward , Cole Kristina , Diskin Sharon , Maris John , Thomas-Tikhonenko Andrei 
Published: August 2012

Abstract
For patients with high-risk neuroblastoma (NB) survival remains below 40%, and survivors suffer from life-long treatment-related disabilities. This necessitates the development of oncogene-specific targeted therapies. We and others observed that small-molecule inhibitors of IGF1R exhibit anti-proliferative effects against NB cells in vitro and in vivo. Yet given the apparent lack of somatic mutations in the IGF1R gene, it remains to be determined what subset of NB patients would benefit from this approach. We hypothesized that IGF1R expression could be affected by alterations in the 3′UTR that prevent binding by microRNAs. Indeed, as evidenced by cancer gene sequencing data on 188 primary high-risk NBs, IGF1R was the gene by far most frequently affected by 3′UTR alterations. We initially focused on the genetic variant rs3833015, a small 2-nt deletion found in ∼50% of NB patients and overlapping with the putative miR-140 binding site. The positive effects of this 3′UTR variant on IGF1R expression were established using luciferase sensor assays, immunoblotting on commonly available NB cell lines, and transcriptome profiling of 28 primary neuroblastomas using Gene Set Enrichment Analysis. Additional 3′UTR variants that affect IGF1R expression and map in the proximity of miR-binding sites were identified using Expression Quantitative Trait Loci (eQTL) analysis. Our experimental data lead us to postulate that rs3833015 and other IGF1R 3′UTR variants help sustain IGF1 signaling, resulting in the “addiction” to this survival pathway and increased sensitivity to small-molecule IGF1R inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-475. doi:1538-7445.AM2012-LB-475