bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2348: Low PU.1 expression not only attenuates neutrophil differentiation of AML cells but also increases resistance to cytotoxic therapies
Authors: Tschan Mario P. , Haimovici Aladin , Brigger Daniel , Schläfli Anna M. , Shan Deborah , Fey Martin F. 
Published: May 2015

Abstract
Inactivation of PU.1 results in a myeloid differentiation block and contributes to the pathogenesis of acute myeloid leukemia (AML). A long list of PU.1 transcriptional targets with a direct function in myeloid development exits and clearly supports its role in cellular hematopoietic differentiation processes. Furthermore, we and others showed that PU.1 positively affects cell survival, for example by directly activating the anti-apoptotic genes BCL2A1 and BCL-XL. Recently, we demonstrated that the novel PU.1 target Hexokinase 3 supports acute promyelocytic leukemia (APL) cell survival. Surprisingly, our current data indicate that knocking down PU.1 in NB4 APL significantly increased resistance in apoptosis responses to anthracyclins. These findings were confirmed in MOLM-3 AML cells. Both cell lines showed an induction of the anti-apoptotic gene CFLAR (c-FLIP). c-FLIP blocks the activation of procaspase-8 at the death-inducing signalling complex (DISC) and is involved in AML chemotherapy resistance. Using PU.1 and c-FLIP double knockdown APL cells, we could significantly restore the sensitivity to anthracyclin treatment. This indicates that the PU.1 knockdown-dependent increase of c-FLIP is responsible for the resistance towards anthracyclin treatment. Moreover, we identified the pro-apoptotic kinase DAPK2 as novel transcriptional target of PU.1 in APL cells. Interestingly, we found that inhibiting DAPK2 in APL cells significantly attenuater arsenic trioxide (ATO)-induced cell death. Together, we link PU.1 to apoptosis and resistance against antracyclins and ATO via regulating c-FLIP and DAPK2. Our data indicate that low PU.1 level found in AML patients not only contribute to a block in differentiation but also increase resistance to cytotoxic therapies in AML.
Citation Format: Mario P. Tschan, Aladin Haimovici, Daniel Brigger, Anna M. Schläfli, Deborah Shan, Martin F. Fey. Low PU.1 expression not only attenuates neutrophil differentiation of AML cells but also increases resistance to cytotoxic therapies. [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 2348. doi:10.1158/1538-7445.AM2014-2348
Abstract 2363: Large scale gene expression analysis identifies key oncogenic pathways across hematological malignancies
Authors: Liuksiala Thomas , Teittinen Kaisa , Granberg Kirsi , Heinäniemi Merja , Annala Matti , Ylipää Antti , Mäki Markku , Nykter Matti , Lohi Olli 
Published: May 2015

Abstract
Hematological malignancies, consisting of all the subtypes of leukemia and lymphoma together with multiple myeloma, constitute a diverse assembly of cancers manifesting primarily in the circulatory or immune systems. Common to all of them is their developmental origin in the hematopoietic cell lineage, which normally produces mature blood cells. For this reason, numerous transcriptomic aberrations, along with their underlying mutations, are shared by different subtypes of hematological malignancies.
To enable concurrent gene expression analysis across a comprehensive range of leukemias, lymphomas and multiple myeloma, we compiled a hematological dataset from gene expression microarray data publicly available in the Gene Expression Omnibus data repository. This manually curated collection includes over six thousand neoplastic and nearly nine hundred healthy samples of multiple lineages descending from the hematopoietic stem cell. The cancer samples were manually re-annotated in a congruent manner into categories with three hierarchical levels so as to allow analysis at various levels of specificity. For instance, an early B cell acute lymphocytic leukemia (ALL) sample is classified first as leukemia, secondly as ALL, and in the third, most specific level, as early B-ALL.
The power of the dataset lays not only in its extensiveness in terms of subtypes of hematological malignancies, but also in the sheer number of samples within these categories. This enables the discovery of expression signatures with high statistical significance, as well as identification of key oncogenic pathways and regulatory networks within different subtypes. To demonstrate these analyses, we used our database to search for any specific expression patterns of small nucleolar RNAs (snoRNAs) in acute leukemias. Among thousands of leukemia patients, we identified a specific signature of SNORD114 in acute promyelocytic leukemia, previously revealed in a very restricted cohort of patients.
Citation Format: Thomas Liuksiala, Kaisa Teittinen, Kirsi Granberg, Merja Heinäniemi, Matti Annala, Antti Ylipää, Markku Mäki, Matti Nykter, Olli Lohi. Large scale gene expression analysis identifies key oncogenic pathways across hematological malignancies. [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 2363. doi:10.1158/1538-7445.AM2014-2363
Abstract 2364: Pancreatic cancer stem-like cells display aggressive behavior mediated through the activation of FoxQ1
Authors: Bao Bin , Azmi Asfar , Ahmad Aamir , Ali Shadan , Li Yiwei , Sarkar Fazlul H. 
Published: May 2015

Abstract
Pancreatic cancer (PC) remains as one of the most aggressive and deadly malignant diseases with poorest clinical outcome, and it is the 4th leading cause of cancer-related death in the USA. Higher mortality of patients diagnosed with PC is in part attributed to treatment resistance and early metastatic disease. Sub-populations of cancer cells commonly known as cancer stem cells (CSCs) or cancer stem-like cells (CSLCs) have been identified from most tumors including PC, and the existence of these cells are being recognized to be clinically relevant. Emerging evidence suggests that CSLCs are responsible for many cellular functions including their propensity of increased cell growth/proliferation, migration/invasion, metastasis, and chemo-radio-therapy resistance, all of these attributes lead to poor clinical outcome. However, the pathogenesis and biological significance of CSLCs in PC has not been well characterized. In the present study, we found that triple-marker positive cells (CD44+/CD133+/EpCAM+ cells) cells isolated from human PC cell lines behave like CSCs. These CSLCs exhibit aggressive behavior such as increased cell growth, migration, clonogenicity, and self-renewal capacity. The mRNA expression profiling analysis showed that CSLCs (triple-marker positive cells) exhibit differential expression of more than 1600 mRNAs including Bmi1, BMP4, BST2, BTG1, FOLR1, FoxQ1, PRKAR1A, Sox2, TACSTD2 and Wnt3a, compared to the cells that are triple-marker negative (CD44-/CD133-/EpCAM- cells). The knock-down of FoxQ1 by its siRNA in CSLCs resulted in the inhibition of aggressive behavior, consistent with reduced expression of EpCAM and Snail. These data clearly suggest the role of differentially expressed genes in the regulation of CSLC characteristics, which further suggest that targeting some of these genes in order to eliminate CSLCs could be important for the development of novel therapies for achieving better treatment outcome of patients diagnosed with PC.
Citation Format: Bin Bao, Asfar Azmi, Aamir Ahmad, Shadan Ali, Yiwei Li, Fazlul H. Sarkar. Pancreatic cancer stem-like cells display aggressive behavior mediated through the activation of FoxQ1. [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 2364. doi:10.1158/1538-7445.AM2014-2364
Abstract 237: Gene expression profiling identifies Sulindac-resistant colon tumors
Authors: Hanley Matthew P. , Miyamoto Shingo , Rosenberg Daniel 
Published: May 2015

Abstract
Sulindac is a non-steroidal anti-inflammatory drug (NSAID) with established chemopreventive efficacy for colorectal cancer (CRC). Despite its tumor suppressive effects, occasional resistance to this drug has been observed in clinical trials. To establish underlying mechanisms that may contribute to sulindac resistance, we have identified differentially expressed gene sets in two groups of colon tumors - those that respond to sulindac treatment and those that do not. Strain A mice were injected (ip) with azoxymethane (AOM) once per week for six weeks, followed by sulindac (180 ppm) treatment for an additional 15 weeks. Throughout the sulindac treatment period, tumor response was monitored endoscopically using a 3-mm fiber optic camera; tumor size and multiplicity were measured in situ every 3 weeks, allowing a real-time evaluation of tumor response to sulindac. At sacrifice, colons were removed and tumors were stratified according to size; large tumors (≥3 mm) were considered to be sulindac-resistant, whereas tumors ≤2 mm were classified as sulindac-responsive. Endoscopic measurements showed that presumed resistant tumors had an average doubling time of 0.9 ± 0.16 weeks, while sulindac-responsive tumors had an average doubling time of 4.0 ± 2.0 weeks. Whole genome expression analysis was conducted using an Illumina Mouse WG-6 Expression Microarray. Using Gene Ontology analysis, genes associated with inflammation, survival and proliferation were found to be differentially expressed between the two groups. Of particular interest was an increased expression of IL-1β and CXCL2, which have previously been implicated as part of a paracrine drug-resistance network in breast and lung cancers. Additionally, the growth factor MDK, which is involved in drug-resistant neuroblastomas, was found to be up-regulated in the largest colon tumors. These findings provide new insights into potential signaling networks that may contribute to the inconsistent response to sulindac chemoprevention and provide potential new targets for cancer protection.
Citation Format: Matthew P. Hanley, Shingo Miyamoto, Daniel Rosenberg. Gene expression profiling identifies Sulindac-resistant colon tumors. [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 237. doi:10.1158/1538-7445.AM2014-237
Abstract 2371: Heterogeneity of resistance mechanisms in lung adenocarcinoma patients with acquired resistance to EGFR inhibitors
Authors: Mu Xinmeng Jasmine , Allen Eli Van , Wagle Nikhil , Chong Curtis , Butaney Mohit , Farlow Deborah , Getz Gad , Jänne Pasi A. , Garraway Levi A. 
Published: May 2015

Abstract
Drug resistance is a major obstacle in overcoming cancer. Understanding the origin, extent and heterogeneity of resistance mechanisms within a patient is crucial to guide treatment and developing drugs/combinations to circumvent resistance. To this end, we studied autopsy samples collected from four EGFR-mutant lung adenocarcinoma patients who developed resistance to EGFR inhibitors. We used whole-exome sequencing to characterize genomic profiles of multiple metastasis tumors within each patient. To address the challenge of non-uniform variant detection power at sequenced genetic loci across multiple samples, we developed a computational framework that tackles variant detection from pooled tumor followed by a genotyping module. After the identification of somatic alterations, we determined the extent of heterogeneity of resistance mechanisms between multiple tumor samples. Our results revealed that multiple metastasis samples in a single patient can potentially use one common resistance mechanism. For example, one patient harbored a resistant EGFR T790M mutation in all 11 metastasis samples with a correlated allele frequency to the original L858R mutation. However, in some other cases, we found heterogeneous resistance mechanisms coexisting in multiple metastasis samples with various allele frequencies. For instance, one patient harbored both the resistance EGFR T790M mutation and an activating PIK3CA E542K mutation that appear with a range of allelic frequencies in multiple metastatic samples. Furthermore, branched evolutionary patterns of tumors were constructed using a phylogenetic approach, which inform resistance in the context of tumor evolution. Our findings are consistent with the model that cells harboring a variety of resistance mechanisms coexist in each metastasis tumor, and those subclones with higher selective advantage outgrow the others.
Citation Format: Xinmeng Jasmine Mu, Eli Van Allen, Nikhil Wagle, Curtis Chong, Mohit Butaney, Deborah Farlow, Gad Getz, Pasi A. Jänne, Levi A. Garraway. Heterogeneity of resistance mechanisms in lung adenocarcinoma patients with acquired resistance to EGFR inhibitors. [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 2371. doi:10.1158/1538-7445.AM2014-2371
Abstract 2378: Harmonization of next generation sequencing data within consortia for gene discovery in familial breast cancer
Authors: Vijai Joseph , Hart Steven , Thomas Tinu , Wubbenhorst Bradley , Guidugli Lucia , Schrader Kasmintan , Maxwell Kara , Jacobs Lauren , Villano Danylo , Klein Robert , Lipkin Steven , Neuhausen Susan , Weitzel Jeffrey , Altshuler David , Couch Fergus , Offit Kenneth , Nathanson Katherine 
Published: May 2015

Abstract
Massively parallel next generation sequencing data (NGS) has proved to be useful in identification of rare Mendelian disorders. Efforts are on-going to use NGS for discovery of novel rare variants in common disease etiology. Distinguishing rare private mutations from causal variants remains a major challenge in complex disorders. With decreasing cost, investigators are generating NGS data for common cancers. However, power and other considerations suggest that a consortia approach of pooling data is more likely to succeed where individual efforts fail. Combining data within such consortia brings its own level of challenges. We enumerate these challenges and suggest recommendations based on our experience of combining and harmonizing NGS data on 358 breast cancer samples from four centers; (City of Hope n=8, Mayo Clinic n=221, MSKCC n=96 and University of Pennsylvania n=33). Major concerns were ability of individual datasets to discover known and novel variations, depth of coverage across the exome, and quality of variants. Using pre- and post-processed data, we demonstrate an increased power for detecting variants when using a joint-calling method, quality control (QC) and quality assurance pre- and post-merge, as well as the advantages of combined annotations and filtering procedures. To generate a filtered list of high confident calls, we subset the data on Depth per Allele (DP), Genotyping Quality (GQ), Allele balance, Phred likelihood score (PL) as well as using frequency filters on the alternate allele both within the data and comparing against convenience control summaries. We describe general principles and QC measures to be adopted when NGS data is used from diverse sources, specifically applicable to large consortia.
Note: This abstract was not presented at the meeting.
Citation Format: Joseph Vijai, Steven Hart, Tinu Thomas, Bradley Wubbenhorst, Lucia Guidugli, Kasmintan Schrader, Kara Maxwell, Lauren Jacobs, Danylo Villano, Robert Klein, Steven Lipkin, Susan Neuhausen, Jeffrey Weitzel, David Altshuler, Fergus Couch, Kenneth Offit, Katherine Nathanson. Harmonization of next generation sequencing data within consortia for gene discovery in familial breast 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 2378. doi:10.1158/1538-7445.AM2014-2378
Abstract 2406: Epigenetics of chromosomal breakage sites and translocations
Authors: Burman Bharat , Zhang Zhuzhu , Burgess Rebecca , Roukos Vassilis , Lieb Jason , Misteli Tom 
Published: May 2015

Abstract
Chromosomal translocations are genetic hallmarks of most cancer cells. Translocations require the formation of DNA double-strand breaks (DSBs) at two or more genomic loci, followed by the illegitimate joining of broken chromosomal ends through DNA repair. There is increasing evidence that translocations occur at non-random sites in the genome, suggesting that certain regions of the genome are more susceptible to DNA breakage than others. We hypothesize that altered chromatin structure predisposes genomic sites to DNA breakage and translocations. To identify chromatin features that facilitate translocations, we have mapped histone modifications and DNase I hypersensitive sites (DHSs) at translocation-prone regions in anaplastic large cell lymphoma (ALCL) precursor cells. We find enrichment of active histone marks and a decrease in repressive marks near frequent translocation breakpoints. In a complementary approach using genome-wide histone modification mapping we have identified altered chromatin features at common leukemia and lymphoma breakpoints in CD34+ hematopoietic stem cells. In order to directly test the role of chromatin features in DNA breakage susceptibility, we have developed a protein-DNA tethering system that allows us to create local chromatin domains at pre-defined sites in the genome containing inducible DSB sites in vivo. By measuring the amount of DSBs using ligation-mediated PCR, we find that histone modifying enzymes that create active chromatin marks generally increase breakage susceptibility; however, repressive marks do not necessarily decrease breakage susceptibility. This suggests the involvement of other factors in breakage susceptibility. Taken together, these experiments provide first insights into the role of chromatin structure in the formation of nonrandom chromosomal breaks and the mechanisms that lead to clinically relevant translocations.
Citation Format: Bharat Burman, Zhuzhu Zhang, Rebecca Burgess, Vassilis Roukos, Jason Lieb, Tom Misteli. Epigenetics of chromosomal breakage sites and translocations. [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 2406. doi:10.1158/1538-7445.AM2014-2406
Abstract 241: CHOP-deficiency promotes chronic inflammation-induced pancreatic fibrosis
Authors: Taki Katsunobu , Ohmuraya Masaki , Sakata Kazuya , Hashimoto Daisuke , Abe Shinya , Nitta Hidetoshi , Hayashi Hiromitsu , Chikamoto Akira , Beppu Toru , Baba Hideo 
Published: May 2015

Abstract
Background and Aims: Endoplasmic reticulum (ER) stress is involved in the pathogenesis of various diseases, including neurodegenerative disease, diabetes mellitus, atherosclerosis, heart disease, and pancreatic disease. CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), also known as growth arrest- and DNA damage-inducible gene 153 (GADD153) is a transcriptional regulator induced by ER stress and a key factor in the ER stress-mediated apoptosis pathway. Chronic inflammation in the pancreas causes progressive pancreatic fibrosis that eventually leads to pancreatic ductal adenocarcinoma. The aim of our study is to prove the role of the ER stress-CHOP pathway in chronic pancreatitis. Methods: We generated gene engineered chronic pancreatitis model (Spink3 SPINK1/-) mice, and crossed them with CHOP-deficient (Chop-/-) mice. We assessed the pancreatic fibrosis by hematoxylin eosin and Sirius red staining, and performed Western blotting to measure α-SMA, which is a maker of the activated pancreatic stellate cells, transforming growth factor β, amylase, and trypsinogen, which are makers of exocrine function, in wild-type (Chop+/+) and CHOP-deficient chronic pancreatitis model (Chop-/-; Spink3 SPINK1/-) mice at 2-weeks- and 4-weeks-old. Results: There were no significant differences between the pancreases of Chop+/+ and Chop-/- mice. The body weight of Chop-/-; Spink3 SPINK1/- mice was not so different from that of Spink3 SPINK1/- mice at 2-weeks-old, but the body weight of Chop-/-; Spink3 SPINK1/- mice was lighter than that of Spink3 SPINK1/- mice at 4-weeks-old (p=0.001). However, there was no significant difference between the survival of Spink3 SPINK1/- mice than that of Chop-/-; Spink3 SPINK1/- mice. We found the progression of pancreatic fibrosis and the activated pancreatic stellate cells in Chop-/-; Spink3 SPINK1/- mice compared with Spink3 SPINK1/- mice at 2-weeks-old. In addition, the expression levels of α-SMA and Desmin increased in Chop-/-; Spink3 SPINK1/- mice at 2-weeks-old. Conclusions: These results indicated that the ER stress-CHOP pathway may have an essential role in the suppression of pancreatic fibrosis through the inactivation of pancreatic stellate cells in chronic pancreatitis. Therefore, anti-inflammatory treatment against chronic pancreatitis through the ER stress-CHOP pathway may reduce the risk of pancreatic cancer.
Citation Format: Katsunobu Taki, Masaki Ohmuraya, Kazuya Sakata, Daisuke Hashimoto, Shinya Abe, Hidetoshi Nitta, Hiromitsu Hayashi, Akira Chikamoto, Toru Beppu, Hideo Baba. CHOP-deficiency promotes chronic inflammation-induced pancreatic fibrosis. [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 241. doi:10.1158/1538-7445.AM2014-241
Abstract 2410: Crucial role of the non-BRCT automodification domain of PARP1 in either DNA binding and PARP inhibitor-mediated cell toxicity
Authors: Nakamura Jun , Tian Xu 
Published: May 2015

Abstract
Poly(ADP-ribose)polymerase (PARP) inhibitor (PARPi)-mediated synthetic lethality is an attractive new paradigm for cancer therapy. While it has been recently proposed some of PARPi may cause DNA single strand break (SSB)-PARP1 or -PARP2 complexes, leading to cell toxicity, the mode of action of PARPi-mediated synthetic lethality is not well understood. We analyzed DNA damage response to PARPi using an isogenic set of DT40 cells. Both PARP-1 ko mutants and PARP-1 ko mutants expressing DNA bindin domain-defficient PARP1 showed markedly more resistance to olaparib than parental DT40 cells, indicating that PARP1 binding to DNA strand break through DNA binding domain is critical in olaparib-mediated cell toxicity. While non-BRCT automodomain domain deletion mutant showed a resistant phenotype, olaparib causes similar toxicity in BRCT domain deletion mutant and parental DT40 cells. Furthermore, PARP1 localized in chromatin binding fraction in BRCT1 deletion mutant, but not in non-BRCT automodomain domain deletion mutant. These results indicate that non-BRCT automodification domain plays crucial role for the formation of stable DNA SSB-PARP1 complex and olaparib-mediated synthetic lethality.
Citation Format: Jun Nakamura, Xu Tian. Crucial role of the non-BRCT automodification domain of PARP1 in either DNA binding and PARP inhibitor-mediated cell toxicity. [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 2410. doi:10.1158/1538-7445.AM2014-2410