bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 75: CpG methylation signature to predict outcome in preoperatively treated rectal cancer.
Authors: Gaedcke Jochen , Claus Rainer , Leha Andreas , Grade Marian , Beißbart Tim , Ghadimi Michael , Weichenhahn Dieter , Plass Christoph 
Published: August 2014

Abstract
Introduction: Introducing a preoperative therapy in locally advanced rectal cancer significantly decreased the local recurrence rate whereas outcome was not improved. To identify patient subgroups that could benefit from an adjusted therapy a prediction prior to the preoperative therapy is necessary.
Material and methods: Whole genome promoter methylation analyses were applied to a pilot group of patients (n=11) to identify targets that separate a good and a bad prognosis group based on their methylation level. Using a mass spectrometry based approach (MassArray) candidate CpG probes were assessed in set of 63 patients (training set). Relevant probes were then validated independently in an additional patient set (n=93). Data were then compared to the previously identified biomarkers (CpG island methylatior phenotype (CIPM)) and clinical data.
Results: Relevant DNA regions from whole genome screen were filtered and the number was reduced down to 20 DNA regions located within 17 different genes (244 different CpGs). In the training set thirteen regions could be confirmed and a clear separation into a good and a bad prognosis group was possible (p=0.0394). Validation in an independent cohort revealed a highly significant result (p=0.000341). Comparing the results the methylation panel outperformed CIMP or clinical data.
Conclusion: Using the retrieved methylation panel of 13 different DNA regions allows a highly significant assignment to a good and a bad prognosis group. These data can now be used to identify patients that are well treated by standard therapy and others that benefit from alternative treatment modalities.
Citation Format: Jochen Gaedcke, Rainer Claus, Andreas Leha, Marian Grade, Tim Beißbart, Michael Ghadimi, Dieter Weichenhahn, Christoph Plass. CpG methylation signature to predict outcome in preoperatively treated rectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 75. doi:10.1158/1538-7445.AM2013-75
Abstract 753: Reciprocal regulation of HOXB13 and androgen receptor in prostate cancer.
Authors: Chen Shuangling , Johng Dorhyun , Isaacs William B. 
Published: August 2014

Abstract
The androgen receptor (AR), a member of the nuclear receptor superfamily of ligand-regulated transcription factors, plays a pivotal role in the initiation and progression of prostate cancer. HOXB13, a prostate-specific homeodomain-containing transcription factor, interacts with AR to regulate the cellular response to androgens (Norris et al. Mol Cell 2009). Our group recently identified a rare but recurrent germline mutation (G84E) in HOXB13 as a prostate cancer susceptibility allele by sequencing the 17q21-22 region of the genomic DNA from families with hereditary prostate cancer. (Ewing et al. NEJM 2012). Our research goal is to study how HOXB13 regulates AR function and how this mechanism might be affected by mutant HOXB13. The overexpression of wild type HOXB13 in LNCaP cells led to an increased expression of AR at the mRNA and protein levels; this induction of AR was attenuated with HOXB13 G84E over-expression. Upon the reduction of endogenous HOXB13 by siRNA in LNCaP cells, the amount of AR decreased at the mRNA and protein levels, indicating that HOXB13 promotes the expression of AR. Conversely, when AR was knocked down with siRNA, the level of HOXB13 transcripts and proteins increased, indicating that AR suppresses HOXB13 expression. Furthermore, co-immunoprecipitation experiments demonstrate that FOXA1, the pioneer factor implicated to control prostate-specific transcription of HOXB13 (McMullin et al. 2009), interacts with AR and HOXB13. These analyses implicate at least a three factor mechanism whereby the levels of critical components of prostate-specific androgen signaling network might recruit and/or titrate one another, and suggest this network may be perturbed by mutations in HOXB13. Since LNCaP cells contain a mutated copy of HOXB13 (L144P), these analyses need to be performed in additional prostate cancer cells before general conclusions can be reached.
Citation Format: Shuangling Chen, Dorhyun Johng, William B. Isaacs. Reciprocal regulation of HOXB13 and androgen receptor in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 753. doi:10.1158/1538-7445.AM2013-753
Abstract 763: Hyperthermia promotes c-myc turnover and reduces ODC expression in colorectal cancer cells.
Authors: Wales Christina T.K. , Jacobs Aaron T. 
Published: August 2014

Abstract
Hyperthermia therapy is an FDA-approved procedure that is used to improve the clinical response to radiation and chemotherapy in a variety of solid malignancies. This method involves raising the temperature of tumor-bearing tissues to 41-43°C, which is commonly achieved by using microwave or radiofrequency (RF)-emitting devices. Despite a multitude of treatment centers that are now providing this type of therapy, the cellular and molecular processes are not fully understood. Here, we report that that the oncogenic transcription factor, c-myc has a potentially important role in the anti-cancer mechanism of hyperthermia. By treating colorectal cancer cells (RKO cell line) with heat (incubation at 42°C), we observe a rapid decrease in c-myc levels that is not seen with other transcription factors. We have also observed a similar effect in other cell types, including lung (A549) and neuroblastoma (SH-SY5Y). It is already known that the turnover of c-myc protein is enhanced by phosphorylation at Thr58. Our Western blot data reveal that hyperthermia causes a significant increase in Thr58 phosphorylation, which is accompanied by a reduction in total c-myc levels. c-Myc is frequently deregulated in human cancers, where it promotes the expression of genes that drive tumor cell proliferation. To assess the role of c-myc target genes in the response to hyperthermia, we looked at one such target gene, ornithine decarboxylase (ODC), which catalyzes the rate-limiting step in polyamine biosynthesis. We see that the hyperthermia-induced degradation of c-myc is accompanied by a drastic reduction in ODC mRNA and protein levels. Using actinomycin D, we observe that heat has no effect on ODC mRNA stability, suggesting that the decrease in ODC is due to a reduction in gene transcription. In support of this, we find that silencing c-myc expression with siRNA inhibits ODC mRNA and protein levels by a similar amount as hyperthermia. We propose that the down-regulation of ODC caused by c-myc degradation may be an important part of the clinical response to hyperthermia, and future work will evaluate the effect of heat on cellular polyamine levels.
Citation Format: Christina T.K. Wales, Aaron T. Jacobs. Hyperthermia promotes c-myc turnover and reduces ODC expression in colorectal cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 763. doi:10.1158/1538-7445.AM2013-763
Abstract 766: Phenformin is a MYCN/MYC destabilizer that can specifically target neural crest derived tumors.
Authors: Ikegaki Naohiko , Lomahan Srah , Tang Xao X. 
Published: August 2014

Abstract
We have been interested in identifying MYCN/MYC destabilizers that can specifically target neural crest derived tumors (neuroblastoma, melanoma, and malignant pheochromocytoma). MYCN amplification and its over-expression are associated with the worst neuroblastoma disease outcome. Non-MYCN amplified neuroblastomas express high-levels of MYC, and prognosis of these neuroblastomas is very poor. Melanoma and malignant pheochromocytoma are also known for high MYC expression. Interestingly, these neural crest derived tumors characteristically express the norepinephrine transporter (NET). This feature can be used to specifically target the tumor cells with agonists of NET, such as Meta-Iodo-BenzylGuanidine (MIBG). In the previous AACR meeting, we presented our finding that non-radio-labeled MIBG can suppress growth of neuroblastoma cells in vitro, and this effect is in part related to its ability to destabilize MYC and MYCN. We have also shown that FCCP, a well-known mitochondrial respiration inhibitor, destabilized MYCN and MYC in neuroblastoma cells and caused growth suppression. Recently, it has been reported that Phenformin, a Type II diabetic drug, binds NET, suggesting that NET positive cells preferentially uptake Phenformin. It is also known that Phenformin inhibits the mitochondrial electron transfer system. In this study, we have investigated a possible effect of Phenformin on growth and MYC/MYCN stability in neuroblastoma cells in vitro. SKNBE(2)C and CHP134 neuroblastoma cell lines were treated with various doses (0-2.5mM) of Phenformin for two days. MTS assay was used to assess the effect of Phenformin on growth of the cells. There was a dose-dependent growth suppression of the NB cell lines tested. Phenformin was more effective against growth of SKNBE(2)C than CHP134 cells. The effect of Phenformin on MYC/MYCN expression in four neuroblastoma cell lines [SKNBE(2)C, CHP134, SKNAS, and SY5Y] was also examined by Western blot assay. SKNBE(2)C and CHP134 express MYCN, whereas SKNAS and SY5Y express MYC at high levels. Treatment of these cells with Phenformin at the dose of 1mM for 24 hours resulted in destabilization of MYCN/MYC, suggesting that the growth suppressive effect of Phenformin on neuroblastoma cells was in part due to reduction in MYC/MYCN expression. We are currently examining whether the above observations made in neuroblastoma are also applicable to other neural crest derived tumors. In addition, we are investigating how Phenformin-related mitochondrial dysfunction causes destabilization of MYC/MYCN in neuroblastoma cells.
Citation Format: Naohiko Ikegaki, Srah Lomahan, Xao X. Tang. Phenformin is a MYCN/MYC destabilizer that can specifically target neural crest derived tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 766. doi:10.1158/1538-7445.AM2013-766
Abstract 775: Mutant Wilms' tumor gene 1 devoid of zinc-fingers promotes proliferation of human hematopoietic progenitor cells in vitro.
Authors: Vidovic Karina 
Published: August 2014

Abstract
The transcription factor Wilms’ tumour gene 1 (WT1) is present in some primitive hematopoietic cells and is highly expressed in the majority of lymphoid and myeloid leukemias, suggesting a role for WT1 in leukemogenesis. Mutations within the WT1 gene are present in 10-15 % of patients with cytogenetically normal acute myeloid leukemias and may be an independent predictor of poor clinical outcome. The mutations are most often heterozygous frameshift mutations leading to premature termination of the reading frame and therefore deletion of the entire DNA-binding zinc-finger domain. We have investigated the cellular effects of mutant WT1 protein lacking all four zinc-fingers, WT1(delZ). We report that expression of WT1(delZ) prolongs the proliferation of human hematopoietic CD34+ progenitor cells in vitro. Moreover, WT1(delZ) transduced cells express erythroid markers, including hemoglobin and elevated STAT5 protein levels, in part independently of addition of erythropoietin. STAT5 was increased by a posttranscriptional mechanism. The erythroid phenotype was also observed at global gene expression level, where WT1(delZ) caused coordinated up-regulation of genes associated with erythroid maturation, as well as genes related to cell division, while monocytic and neutrophil genes were down modulated. Our results indicate that WT1(delZ) promotes cell proliferation and erythroid differentiation at the expense of monocytes and granulocytes.
Citation Format: Karina Vidovic. Mutant Wilms' tumor gene 1 devoid of zinc-fingers promotes proliferation of human hematopoietic progenitor cells in vitro. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 775. doi:10.1158/1538-7445.AM2013-775
Abstract 78: Fractionated whole brain irradiation modulates Homer1a expression in a brain region specific manner.
Authors: Moore Elizabeth , Kooshki Mitra , Miller Lance , Robbins Mike 
Published: August 2014

Abstract
About 500,000 new cancer patients will develop brain metastases in 2012. The primary treatment modality for ∼250,000 of these patients is partial or whole brain irradiation. While effective for controlling metastatic brain tumors, there are significant late effects (&gt; 6 months) following radiotherapy which include a progressive, irreversible cognitive impairment. Although the exact mechanism(s) behind this radiation-induced brain injury are unknown, preclinical studies suggest that radiation alters neuronal plasticity. Indeed irradiating the rodent brain decreases long term potentiation, alters N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptor expression and ablates neurogenesis. In this study, we used microarray analysis to show that Homer1a, a transcriptionally-regulated early response gene, was transiently upregulated in the hippocampus and downregulated in the cortex at 48 hours after fractionated (total dose of 40 Gy delivered as 2 Gy/fraction, 2X/week) whole brain irradiation (fWBI) in young adult male Fischer 344 X Brown Norway rats. Two months after fWBI Homer1a gene expression was downregulated in both the hippocampus and cortex. Homer1a binds the consensus sequence on the C-terminus of the group I metabotropic glutamate receptors (mGluR); thereby, disrupting the cross-linking of constitutively expressed forms of Homer1 and activating mGluR in the absence of glutamate. Radiation did not alter phosphorylation of mGluR1, total GluR2 or phosphorylation of GluR2/3 in the hippocampus or cortex at 2 months after fWBI. However, the radiation-induced changes in Homer1a expression appeared to produce a significant downregulation in mGluR1 in the hippocampus, and a significant upregulation in the cortex. Memory/learning paradigms suggest that trafficking of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptors containing mGluR1 from intracellular compartments to the plasma membrane is an “early” event during neural plasticity; thus decreased mGluR1 may result in alterations in hippocampal neural plasticity following fWBI. These data suggest a novel mechanism for the development of radiation-induced cognitive impairment. (Supported by CA122318)
Citation Format: Elizabeth Moore, Mitra Kooshki, Lance Miller, Mike Robbins. Fractionated whole brain irradiation modulates Homer1a expression in a brain region specific manner. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 78. doi:10.1158/1538-7445.AM2013-78
Abstract 788: Effects of ATF3 on the gain-of-function of mutant p53.
Authors: Wei Saisai , Malmut Sarah , Wang Hongbo , Yan Chunhong 
Published: August 2014

Abstract
Activating Transcription Factor 3 (ATF3) is a member of the ATF/CREB family of transcription factors and can be rapidly induced by DNA damage and other cellular stresses. We previously found that ATF3 activates p53 by binding to the C-terminus of the tumor suppressor and blocking its ubiquitination, and consequently inhibits cellular transformation. Since TP53 is mutated in half of human cancers and mutant p53 proteins (mutp53) acquire oncogenic activities including promoting drug resistance and driving cancer cell invasion and metastasis, we were interested to explore effects of ATF3 on the mutp53 gain-of-functions (GOF). One major mechanism by which mutp53 promotes tumorigenesis is through binding another p53 family member p63 and inhibiting its tumor suppressor functions. We found that ATF3, but not a mutated ATF3 protein (▵102-139) devoid of its p53-binding region, bind the p53R175H mutant and disrupted the interactions between mutp53 and p63. As a consequence, while mutp53 inhibited the p63 transcriptional activity, ATF3 but not the ▵102-139 protein counteracted mutp53 and resumed p63 activity. Consistent with these results, ATF3 expression inhibited mutp53-promoted cell migration and invasion. In addition to effects on the mutp53-p63 interaction, we also found that ATF3 repressed mutp53-induced NFκB activity, thereby sensitizing mutp53-expressing cells to treatments with etoposide and cisplatin. We conclude that ATF3 suppresses the GOF of mutant p53 and thus may also contribute to tumor suppression in p53-mutated cancer cells.
Citation Format: Saisai Wei, Sarah Malmut, Hongbo Wang, Chunhong Yan. Effects of ATF3 on the gain-of-function of mutant p53. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 788. doi:10.1158/1538-7445.AM2013-788
Abstract 796: Utilizing TCRβ and whole exome sequencing to determine the clonality and mutational spectrum of p53-null thymic lymphomas.
Authors: Dudgeon Crissy , Chan Chang , Sun Yvonne , Levine Arnold J. 
Published: August 2014

Abstract
The tumor suppressor p53 is nonfunctional in over 50% of cancers. The ability for p53 to protect the cell from tumorigenesis is rooted in its ability to induce cell cycle arrest, apoptosis, and senescence following genotoxic stress. Furthermore, loss of p53 in mice gives rise to spontaneous thymic lymphomas and sarcomas. In this study, we used the p53-KO mouse as a model for progression of tumorigenesis. We first analyzed genomic DNA of p53-KO and WT normal thymus at various ages using TCRβ sequencing. This procedure allowed us to determine the clonality of the T cell repertoire. We then analyzed the clonality of p53-KO thymic lymphomas. Our results indicated that while the highest T cell clone was 0.08% for normal thymus, the highest T cell clone for the p53-KO tumor was 70%, indicating that the p53-KO thymic lymphomas were monoclonal. Building on this data, we analyzed the mutations occurring in the thymic lymphomas by mouse exome sequencing. We believe that combining TCRβ sequencing with mouse exome sequencing will allow for a better understanding of the clonality and genetic mutations required for cellular transformation.
Citation Format: Crissy Dudgeon, Chang Chan, Yvonne Sun, Arnold J. Levine. Utilizing TCRβ and whole exome sequencing to determine the clonality and mutational spectrum of p53-null thymic lymphomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 796. doi:10.1158/1538-7445.AM2013-796
Abstract 820: Genome-wide aberration analysis of rare cancer cell populations derived from formalin fixed paraffin embedded tissue.
Authors: Juskevicius Darius , Ruiz Christian , Dietsche Tanja , Rufle Alex , Barrett Michael T. , Bubendorf Lukas , Dirnhofer Stephan , Tzankov Alexander 
Published: August 2014

Abstract
Introduction. The majority of clinically described patient material worldwide is available as formalin fixed parafin embedded (FFPE) tissue blocks. Despite being a cheap and convenient way of archiving tissue suitable for review under the microscope, FFPE blocks are difficult to interrogate with modern molecular biology methods due to changes occurring during the process of fixation, embedding and aging. Genetic analysis of tumours with limited malignant cell count, like classical Hodgkin lymphoma (cHL) or T-cell/histiocyte-rich B cell lymphoma (TCHRBCL) is impeded by a bulk mass of non-malignant tumour infiltrating cells. Laser capture microdissection is currently a method of choise for rare tumor cell isolation, however it induce serious damage for gDNA, therefore additional techniques for enrichment are needed to enable meaningful genome-wide aberration analysis of tumors with low cancer cell content.
Methods. For extraction of nuclei from FFPE blocks of cHL and TCHRBCL cases enzymatic digestion and mechanical force were utilized. Pure populations of cancer cell nuclei were isolated by fluorescence-activated cell sorting (FACS) based on cancer type-specific nuclear markers Pax-5, Mum-1, Bcl-6, Ki-67. Array comparative genomic hybridization (aCGH) was utilized for genome-wide aberration analysis.
Results. We have optimized a set of methods to successfully isolate intact, high quality nuclei from FFPE tissue blocks. Nuclei retain their antigenicity and, therefore, are suitable for labelling with frourophore-conjugarted antibodies, which enables flow-sorting based not only on physical parameters and DNA content, but also on positivity for highly specific nuclear markers. Tumour nuclei populations from cHL and TCHRBCL of 70-90% in purity were isolated. DNA extracted from as little as 500 flow-sorted nuclei was sufficient to generate high-resolution and reproducible aCGH data.
Conclusions. Our proposed methodology allows the use of tissues in FFPE blocks more widely. Efficient isolation of malignant cells from the tumour mass was achieved. In the cases where starting material is scarce and very low number of target nuclei can be isolated, DNA extraction with improved recovery together with commercially available whole genome amplification methods enable genome-wide aberration analysis.
Citation Format: Darius Juskevicius, Christian Ruiz, Tanja Dietsche, Alex Rufle, Michael T. Barrett, Lukas Bubendorf, Stephan Dirnhofer, Alexander Tzankov. Genome-wide aberration analysis of rare cancer cell populations derived from formalin fixed paraffin embedded tissue. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 820. doi:10.1158/1538-7445.AM2013-820