bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2045: Identifying key molecular events at the onset of melanoma using a neural crest stem cell marker
Authors: Kaufman Charles K. , Mosimann Christian , White Richard M. , Matos Dominic , Zon Leonard I. 
Published: May 2015

Abstract
An ongoing challenge in cancer biology is understanding the earliest, initiating events that switch a premalignant cell into a fully competent cancer cell. Driven by this challenge, we focused on the zebrafish gene crestin that marks the embryonic neural crest from the onset of somitogenesis through 72 hours post fertilization when it normally turns off. Surprisingly, our lab previously showed that crestin mRNA is reexpressed in melanoma tumors in adult zebrafish, reading out a neural crest progenitor state. We have developed a fluorescent reporter using the crestin promoter/enhancer that recapitulates the embryonic expression pattern of crestin, and when bred into our BRAFV600E/p53 mutant melanoma zebrafish model, marks grossly visible melanoma tumors. Remarkably, we found that crestin:EGFP becomes active when lesions are only a few cells in number, potentially in the first cell of the melanoma. Using a crestin:CreERt2 inducible recombinase together with a lox-dependent fluorescent lineage tracer line ubi:switch, multiple neural crest descendant lineages including melanocytes can be traced. Further by expressing the melanocyte lineage master transcription factor mitf under the control of the crestin promoter, we can rescue melanocyte formation in mitf null embryos, and in the Na/BRAFV600E/p53 melanoma-prone mutant background, some adult fish develop darkly pigmented patches and melanoma tumors. Finally, we isolated small patches of crestin:EGFP positive cells and show that these precursor lesions are enriched for expression of the neural crest progenitor transcription factor sox10. These data support a model in which BRAFV600E/p53 mutated melanocytes stochastically reactivate an early melanocyte or neural crest progenitor program as read out by crestin reactivation at the initiation of melanoma formation. Using our novel reporter, we are able to analyze in vivo the earliest steps of cancer formation as well as the neural crest lineage program.
Citation Format: Charles K. Kaufman, Christian Mosimann, Richard M. White, Dominic Matos, Leonard I. Zon. Identifying key molecular events at the onset of melanoma using a neural crest stem cell marker. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2045. doi:10.1158/1538-7445.AM2014-2045
Abstract 2476: A novel NUT translocation partner binds to BRD4 and is necessary for the blockade of differentiation in NUT midline carcinoma
Authors: Walsh Erica , Kuhnle Simone , Rahman Shaila , Lemieux Madeleine , Howley Peter , French Christopher 
Published: May 2015

Abstract
NUT midline carcinoma (NMC) is an aggressive type of squamous cell carcinoma that typically harbors BRD4/3-NUT fusion oncogenes which encode chimeric proteins that block differentiation and maintain tumor growth. However, in 30% of cases NUT is fused to yet to be identified non-BRD gene(s). Using RNA sequencing, we identified a novel gene fused to NUT in a NMC cell line (1221), fusing a novel 5′ coding sequence to the NUT gene. Like Brd4/3, this gene encodes a protein that is also involved in epigenetic regulation, and we find that siRNA knockdown of this protein leads to differentiation of the 1221 cells as well as of three BRD4-NUT-positive NMC cell lines. We have established that the novel NUT fusion protein encoded by this translocated gene binds to BRD4. We have mapped the regions of Brd4 and of the novel fusion protein involved in complex formation and are exploring whether association of the novel protein with Brd4 is required for the blockade of differentiation in NMC. Differentiation of TC-797 cells induced by knockdown of BRD4-NUT is abrogated by enforced expression of the novel NUT-fusion gene. Together, these findings identify a novel BRD4-NUT-interacting protein whose expression is required for the maintenance of the undifferentiated state in NMC, and when fused to NUT, is oncogenic and can recapitulate the function of BRD4-NUT to block differentiation.
Citation Format: Erica Walsh, Simone Kuhnle, Shaila Rahman, Madeleine Lemieux, Peter Howley, Christopher French. A novel NUT translocation partner binds to BRD4 and is necessary for the blockade of differentiation in NUT midline carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2476. doi:10.1158/1538-7445.AM2014-2476
Abstract 2481: Complex deregulation of p73 transcripts in breast tissues: overexpression in benign breast fibroadenomas, and down-regulation in breast cancers
Authors: Tourpin Sophie , Alsafadi Samar , Mathieu Marie-Christine , Delaloge Suzette , Andre Fabrice , Ahomadegbe Jean C. 
Published: May 2015

Abstract
p73, a p53-related gene, encodes two classes of isoforms with opposing functions: (1) a full-length transactivation-competent p73 protein (TAp73) with tumor suppressor activity; and (2) a group of NH2-terminally truncated, transactivation-deficient p73 proteins, ΔEx2p73, ΔEx2-3p73, ΔNp73 and ΔN'p73 (collectively named DNp73) which exert oncogenic activity by inactivating p53 and TAp73. In contrast to p53, p73 is essentially never mutated in cancer. Some studies have focused on the analysis of p73 alterations in breast cancer, but the results are often contradictory. However, it should be noted that there is no study on the comparative analysis of the p73 levels in matched normal breast tissues-breast cancer from the same patients, probably because of the difficulty of obtaining such matched tissues. To study whether p73 is associated with breast carcinogenesis, deregulations of TAp73 and DNp73 were assessed in 103 breast tissues including breast cancer (BC) exhibiting no inflammatory symptoms, inflammatory BC (IBC), normal breast epithelium adjacent to BC (N) and benign breast fibroadenomas (FA). IBC is a rare but aggressive form of BC with a very poor prognosis. Tumor characteristics and the risk of death and relapse were examined in each patient. Surprisingly, we found that antiapoptotic ΔNp73 transcripts and protein levels were down-regulated in BC, compared to that found in normal adjacent tissue, suggesting that this isoform could be associated with other processes during breast carcinogenesis such as differentiation. In contrast with this finding, ΔNp73 was unchanged in FA. Δex2p73 levels were upregulated in BC and FA (p=0.06 and 0.04 respectively), but the level was higher in FA. TAp73 and Δex2-3p73 were unchanged in FA and BC. Intriguingly, TAp73 and Δex2-3p73 transcripts were higher in ER-negative BC, compared to ER-positive BC (p=0.07 and 0.04 respectively). Taken together, our results show that, surprisingly, both suppressor and oncogenic isoforms of p73 were more deregulated in FA than in BC. Consequently, the reports demonstrating upregulation of p73 isoforms in BC should be considered with caution.
Note: This abstract was not presented at the meeting.
Citation Format: Sophie Tourpin, Samar Alsafadi, Marie-Christine Mathieu, Suzette Delaloge, Fabrice Andre, Jean C. Ahomadegbe. Complex deregulation of p73 transcripts in breast tissues: overexpression in benign breast fibroadenomas, and down-regulation in breast cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2481. doi:10.1158/1538-7445.AM2014-2481
Abstract 2494: A pilot proteomic analysis to identify biomarker proteins in human pancreatic cancer using reverse phase protein array
Authors: Huang Yu-jing , Zhang Nianxiang , Frazier Marsha , Wei Chongjuan 
Published: May 2015

Abstract
Background: Pancreatic cancer is the fourth leading cause of cancer death in the U.S, and with an overall 5-year survival rate less than 4%. The high mortality rate of patients with pancreatic cancer is primarily due to the difficulty of early diagnosis and a lack of effective therapies. There is an urgent need to discover novel molecular targets for early diagnosis and new therapeutic approaches to improve the clinical outcome of this deadly disease. Reverse-phase protein assay (RPPA), a high throughput proteomic approach, provides us a platform to identify differentially expressed proteins and characterize posttranslational protein modifications involved in tumorigenesis.
Methods: In the present study here, we carried out proteomic analysis of pancreatic cancer specimens with matched adjacent, normal-appearing tissue samples from 15 pancreatic cancer patients to evaluate the differentially expressed biomarker proteins. The antibody panel used for RPPA included 132 key proteins involved in various cancer-related pathways. The paired t test was used to determine the significant differences between matched pairs, and the false discovery rate-adjusted p values (q values) were calculated to take into account the effect of multiple comparisons.
Result: Out of the panel of 132 proteins included in RPPA, we found 19 of them had statistically significant differences in expression between matched pairs (q &lt;0.05). Among these 19 proteins, AKT, -catenin, GAB2, and PAI-1 were identified as differentially overexpressed in the pancreatic tumor (a fold change of T/N ≥ 1.5). In addition, overexpression of AKT, -catenin, and GAB2 in pancreatic cancer tissue identified in RPPA has been confirmed by western blot analysis. Further analysis identified several significantly associated canonical pathways and overrepresented network functions using the Ingenuity Pathway Analysis (IPA) tool.
Conclusion: In conclusion, among the three proteins identified in RPPA and validated by western blot, overexpression of GAB2 has not been reported previously in pancreatic cancer. Considering the essential role of GAB2 in two major signaling pathways in cancer (the PI3-AKT and the ERK signaling pathways), identification of GAB2 in pancreatic cancer may provide additional insight into this cancer's pathogenesis.
Citation Format: Yu-jing Huang, Nianxiang Zhang, Marsha Frazier, Chongjuan Wei. A pilot proteomic analysis to identify biomarker proteins in human pancreatic cancer using reverse phase protein array. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2494. doi:10.1158/1538-7445.AM2014-2494
Abstract 2522: Development of GADD45β (growth arrest DNA damage-inducible gene 45 beta) agonists for the treatment of hepatocellular carcinoma (HCC)
Authors: Hsu Chiun , Ou Da-Liang , Chen Kuen-Feng , Lin Zhong-Zhe , Cheng Ann-Lii , Shiau Chung-Wai 
Published: May 2015

Abstract
Induction of GADD45β expression, which is associated with cellular stress response and apoptosis regulation, in HCC cells was found to correlate with sensitivity of sorafenib, the standard molecular targeted therapy for advanced HCC. In this study, we use this GADD45β induction as a screening platform to identify novel agents for HCC treatment from sorafenib derivatives that lack RAF kinase inhibition activity. GADD45β expression in Huh-7 cells was measured by quantitative RT-PCR. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was examined by flow cytometry. Signal transduction pathways in cells were assessed by western blotting. In vivo anti-tumor efficacy was tested in mouse xenograft models using Huh7 and Huh7R cells, the latter had acquired resistance to sorafenib. Pharmacokinetic studies were done in Sprague-Dawley rat model. The compound SC-20, which had a N-(4-(quinolin-4-yloxy)phenyl)benzamide scaffold, showed greater GADD45β induction than other derivatives. The nitro group on the quinolone ring of SC-20 was considered important in GADD45β induction. SC-20 induced more prominent apoptosis and inhibition of proliferation in Huh7 cells than sorafenib, independent of MEK/ERK signaling activity in Huh7 cells. SC-20 showed more prominent GADD45β induction and better antitumor activity than sorafenib in both Huh-7 and Huh7R xenograft models and good safety. Pharmacokinetic studies indicated that SC-20 had long plasma half-life (22.5 ± 0.51 hours), low water solubility, high (&gt; 99%) plasma protein binding, and inhibited CYP2C9 and 2C19. GADD45β agonists warrant further development for HCC treatment. (supported by NSC 101-2325-B-002 -039, NSC 101-2321-B-002 -014, NSC 102-2325-B-002 -038)
Citation Format: Chiun Hsu, Da-Liang Ou, Kuen-Feng Chen, Zhong-Zhe Lin, Ann-Lii Cheng, Chung-Wai Shiau. Development of GADD45β (growth arrest DNA damage-inducible gene 45 beta) agonists for the treatment of hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2522. doi:10.1158/1538-7445.AM2014-2522
Abstract 2524: Promising early-stage novel androgen receptor antagonists in head-head comparisons with Enzalutamide and Bicalutamide
Authors: Shaw Arthur Y. , Gokhale Vijay , Hulme Christopher , Stratton Steven P. 
Published: May 2015

Abstract
Prostate cancer is the most common male cancer and the second leading cause of cancer-related deaths in developed countries. The androgen receptor (AR) is a key molecular target in the etiology and progression of the disease where the early stages of prostate cancer tumor growth are androgen dependent and respond well to androgen ablation and androgen receptor antagonists. However, castration-resistant prostate cancer (CRPC) typically develops in 1-2 years after androgen deprivation therapy and AR antagonist administration. Despite promising results from the recently approved second-generation AR antagonist Enzalutamide (MDV3100), CRPC remains a largely unmet medical need with less than a 15% 5-year survival rate.
This poster introduces the discovery of a novel series of significantly structurally distinct small-molecule androgen antagonists from current therapeutics with promising biological profiles in (1) an FP binding assay, (2) a GeneBlazerTM functional assay and (3) a study of anti-proliferative activity against LNCaP cell growth. One of several promising compounds from a current collection of ∼100 analogs is exemplified by AR002.
CompoundFP AR binding assay (IC50)GeneBlazerTM β-lactamase reporter assay (IC50)LNCAP cell growth inhibition (GI50)AR002328.7 nM557 nM2.3 μMEnzalutamide920 nM1150 nM11.65 μMBicalutamide145 nM1370 nM30.68 μM
In summary, a novel class of AR antagonists has been identified, encouragingly demonstrating potent activity against AR and inhibition of cell growth in the prostate specific line LNCaP.
Citation Format: Arthur Y. Shaw, Vijay Gokhale, Christopher Hulme, Steven P. Stratton. Promising early-stage novel androgen receptor antagonists in head-head comparisons with Enzalutamide and Bicalutamide. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2524. doi:10.1158/1538-7445.AM2014-2524
Abstract 2527: Aspirin and aspirin analogs on esophageal cancer
Authors: Kilari Rajagopal Sharada , Perry Christopher J. , Devitt Andrew , Safrany Stephen T. , Nicholl Iain D. 
Published: May 2015

Abstract
Background
Esophageal cancer is the eighth most common cancer seen worldwide and is the sixth most common cause of death from cancer. The UK alone has over 8,000 new cases of esophageal cancer every year. Epidemiological studies have shown that low-dose daily intake of aspirin can decrease the incidence of esophageal cancer. However, its use as an anti-cancer drug has been restrained because of its side effects exerted through inhibition of cyclooxygenase (COX) enzymes. In our study, we have investigated the effects of a number of novel aspirin analogs on esophageal cancer cell lines.
Methods
The effects of aspirin and its analogs on the viability of esophageal cancer cell lines were tested using the MTT assay. ApoSense and flow cytometric analysis were performed to examine whether aspirin analog-mediated tumor cell death is due to apoptosis or necrosis. Colorimetric assays measuring peroxidase component of cyclooxygenases were employed to screen aspirin analogs for COX inhibition.
Results
Our data suggests that the anti-proliferative property of certain aspirin analogs is greater than that of aspirin itself. Benzoylsalicylates and fumaroyl diaspirin were more effective than aspirin against the oe21 squamous cell carcinoma cells and oe33 esophageal adenocarcinoma cells. Flo-1 esophageal adenocarcinoma cells showed resistance to aspirin and most of the aspirin analogs other than the benzoylsalicylates. Both diaspirin and benzoylsalicylates inhibited metabolic activity in all these esophageal cells. However, apoptosis was induced in only a small proportion. We have also shown that these aspirin analogs do not appear to inhibit COX enzymes.
Conclusion
We have synthesized and characterized a number of novel aspirin analogs that are more effective against esophageal cancer cell lines than aspirin. These compounds do not exert their anti-proliferative effect through induction of apoptosis. Moreover, these analogs inability to inhibit COX enzymes suggests that they may cause fewer or no side effects compared to aspirin.
Citation Format: Rajagopal Sharada Kilari, Christopher J. Perry, Andrew Devitt, Stephen T. Safrany, Iain D. Nicholl. Aspirin and aspirin analogs on esophageal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2527. doi:10.1158/1538-7445.AM2014-2527
Abstract 2529: Optimization of small molecules targeting BMI1 protein expression. Part 1. Amino-thiazoles: the first-in-class highly potent inhibitors of BMI1 protein
Authors: Sydorenko Nadiya , Baiazitov Ramil , Choi Soongyu , Lee Chang-Sun , Cao Liangxian , Davis Thomas W. , Almstead Neil G. , Moon Young-Choon 
Published: May 2015

Abstract
BMI1 (B-cell specific Moloney Murine Leukemia Virus Insertion 1) is a gene predominantly expressed in stem cells. A deficiency of BMI1 protein leads to a reduction in the adult stem cell population. Decreasing of BMI1 protein levels by siRNA causes apoptosis and/or senescence in tumor cells in vitro and increases susceptibility to cytotoxic agents. In tumors, the level of BMI1 protein is often elevated. Consequently, the expression level of BMI1 is highly prognostic in many types of cancers. Since BMI1 is non-enzymatic, targeting this protein by traditional drug discovery approaches has not met with success. PTC Therapeutics has developed a novel screening technology referred to as GEMSTM (Gene Expression Modulation by Small molecules) to identify small molecules that modulate the levels of a protein of interest by targeting post-transcriptional regulatory processes. Using this screening technology, we have identified a number of compounds that can selectively reduce levels of BMI1 protein. Schematically, the lead scaffold could be represented by four key components: a bicyclic right core, a heterocyclic middle ring (thiazole), a linking group and a left aryl region. Structure-activity relationships associated with this series have been investigated through medicinal chemistry efforts. Incorporation of a small electron-donating para- substituent at the left part of the molecule is highly effective in decreasing levels of BMI1, indicating the strong influence of both steric and electronic effects on activity. An amino (linking group) moiety was found to be essential for activity. Variation at the right-hand moiety appears to be more tolerated, allowing improvements in both pharmacokinetic and activity profiles. These SAR findings have revealed important pharmacophoric and structural features required for the desired biological activity with this series, and provide a foundation for further lead optimization efforts.
Citation Format: Nadiya Sydorenko, Ramil Baiazitov, Soongyu Choi, Chang-Sun Lee, Liangxian Cao, Thomas W. Davis, Neil G. Almstead, Young-Choon Moon. Optimization of small molecules targeting BMI1 protein expression. Part 1. Amino-thiazoles: the first-in-class highly potent inhibitors of BMI1 protein. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2529. doi:10.1158/1538-7445.AM2014-2529
Abstract 2545: Histamine dihydrochloride and interleukin-2 for relapse prevention in AML: Initial results of the Re:MISSION phase IV trial
Authors: Martner Anna , Rydström Anna , Riise Rebecca , Aurelius Johan , Brune Mats , Hellstrand Kristoffer , Thorén Fredrik Bergh 
Published: May 2015

Abstract
BACKGROUND AND METHODS. Immunotherapy with histamine dihydrochloride and low-dose interleukin-2 (HDC/IL-2) has been approved within the EU for relapse prevention in the post-consolidation phase of acute myeloid leukemia (AML) (Blood 108:88). We have performed a phase IV trial (Re:MISSION) to assess the immunomodulatory properties of this regimen and to correlate potential biomarkers of immunity with outcome. Eighty-nine patients (age 19-80) with AML in first complete remission received HDC (0.5 mg sc bid) and human recombinant IL-2 (1MIU sc bid) in ten repeated three-week cycles for 18 months or until relapse. Mononuclear cells were analyzed for NK and T cell phenotypes by flow cytometry at onset and during cycles 1 and 3.
INDUCTION OF NK CELLS AND NCR EXPRESSION DURING THERAPY. Treatment with HDC/IL-2 resulted in a 3-fold expansion of both CD56bright (CD56/CD16-) and CD16+ (CD56+/CD16+) NK cells during cycle 1 (CD56+, P= 10-6, n=47; paired samples t-test). During cycle 1, the median expression intensity of the natural cytotoxicity receptors (NCRs) NKp46 and NKp30 on CD16+ NK cells increased by 50% and 30%, respectively (P=6 x10-8 for NKp46; P=2 x10-7 for NKp30, n=56). For CD56bright cells, the results were discordant for the NCRs with pronounced induction of NKp30 (P=4 x10-13) during cycle 1 but no induction of NKp46 (P=0.51, n=56).
ROLE OF NCR EXPRESSION FOR MAINTENANCE OF REMISSION. An interim analysis of immune markers vs. relapse-free survival (RFS) revealed a strong impact of NK cell NKp46 expression. Patients with NKp46 expression above the median after one 21-day cycle of HDC/IL-2 thus showed significantly higher RFS than those with lower expression (CD16+, P=0.003, HR=3.0, CI 1.4-6.4; CD56bright, P=0.002, HR=3.3, CI: 1.5-7.0; logrank test). High NK cell expression of NKp46 after a treatment cycle also identified a population of elderly patients (&gt;60 years old) with favorable outcome (CD16+, P=0.002, HR=4.1, CI: 1.6-10.2; logrank test). We observed a pronounced expansion of CD4+/CD25+/Foxp3+ regulatory T cells during cycles that did not impact on relapse risk. CONCLUSION. These results highlight the role of NK cells and NCR expression for relapse-free survival in AML.
Citation Format: Anna Martner, Anna Rydström, Rebecca Riise, Johan Aurelius, Mats Brune, Kristoffer Hellstrand, Fredrik Bergh Thorén. Histamine dihydrochloride and interleukin-2 for relapse prevention in AML: Initial results of the Re:MISSION phase IV trial. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2545. doi:10.1158/1538-7445.AM2014-2545