bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1765: Recurrent fusion of NTRK1 in glioblastoma multiforme.
Authors: Kim Jinkuk , Cho Hee-Jin , Cho Gye-Hyun , Ko Young-Hyeh , Paik Soonmyung , Nam Do-Hyun 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor, yet with no targeted therapy with substantial survival benefit. Recent studies on many types of solid tumors showed that fusion genes often play driver roles and are promising targets for pharmaceutical intervention. To survey potential fusion genes in GBM, we analysed RNA-Seq data from 162 GBM patients available through The Cancer Genome Atlas (TCGA). From the analysis, we identified recurrent fusion of neurotrophic tyrosine kinase receptor type 1 (NTRK1, also called TrkA) to the genes highly expressed in neuronal tissues, neurofascin (NFASC) and brevican (BCAN). NTRK1 is a mediator of the pro-survival signaling of nerve growth factor (NGF) and is a known oncogene, found commonly altered in human cancer. While GBMs largely lack NTRK1 expression, the fusion-positive GBMs express fusion transcripts in high abundance that retain NTRK1 kinase domain in frame. Analyses of the matching Exome-Seq data indicated that NFASC-NTRK1 fusion occurred through DNA-level rearrangement, whereas BCAN-NTRK1 fusion presumably occurred at RNA-level. As analogous NTRK1-fusions with thyroid-expressed genes were previously shown to drive thyroid cancer, NTRK1-fusion in GBM might have a similar role. Consistent with this hypothesis, the GBMs that harbor the NTRK1-fusion showed elevated NGF/NTRK1 pathway activity. About 1% of GBM patients are estimated to have NTRK1-fusion; these patients might benefit from potential NTRK1 inhibition therapies.
Citation Format: Jinkuk Kim, Hee-Jin Cho, Gye-Hyun Cho, Young-Hyeh Ko, Soonmyung Paik, Do-Hyun Nam. Recurrent fusion of NTRK1 in glioblastoma multiforme. [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 1765. doi:10.1158/1538-7445.AM2013-1765
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1766: Investigating Chk1 biology with selective oral Chk1 inhibitor.
Authors: Wang Zhenxiong 
Published: August 2014

Abstract
Chk1 inhibitor as a chemo-potentiator in cancer therapy was proposed more than 10 years ago. Most of the first generation i.v. dosing chk1 inhibitors were terminated in clinical trials recently. The second generation oral chk1 inhibitors were just launched by several companies. However, many questions in Chk1 biology remain unclear, which is important to guide Pfizer to develop oral chk1 inhibitor in the future.
Chk1 biology team investigated preclinical scheduling, biomarker, combination strategy, TGI, primary indication and patient selection with chk1 tool compounds. Biomarker is critical in evaluating POM in clinical trial phase I. Significant target modulations and dose responses of biomarkers p-Chk1 345, r-H2AX, cleaved-PARP were observed in both in vitro and in vivo studies, suggesting their potential application in clinical setting. The scheduling study indicated its importance in chk1 project. Both administration of chk1 inhibitor soon after chemotherapy and sustained inhibition of chk1 robustly improved efficacy in Miapaca2 pancreatic cancer model. There was no clear patient selection strategy for Chk1 clinical trials in the past. To investigate the primary indication and patient selection, 6 indications were indentified according to clinical trial results and human tumor tissue genomics, more than 100 cancer cell lines were screened with either chk1 inhibitor alone or in combination with SOC. 75%(12/16) cell lines in mesothelioma and 44% (4/9) in endometrial carcinoma demonstrated significant synergy in the combination treatment. Next generation sequencing and SiRNA library screening in DNA damage repair genes (DDR) will be used to clarify the mechanisms.
In summary, we have identified treatment schedule and potential new indications for Chk1 inhibitor, which could significantly increase efficacy, lower toxicity, and improve probability of success in clinical trials.
Citation Format: Zhenxiong Wang. Investigating Chk1 biology with selective oral Chk1 inhibitor. [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 1766. doi:10.1158/1538-7445.AM2013-1766
Abstract 1768: The oncogene Mdmx promotes genomic instability independent of p53.
Authors: Melo Alexia N. , Bouska Alyssa , Arrate Maria P. , Eischen Christine M. 
Published: August 2014

Abstract
Mdmx is upregulated in many human cancers. As a member of the Mdm2 protein family, Mdmx functions similar to Mdm2 as a negative regulator of the tumor suppressor p53. With the ability to form heterodimers with Mdm2, p53 regulation by Mdmx predictably relies on Mdm2. However, while the p53- and Mdm2-dependent functions of Mdmx understandably contribute to cancer, Mdmx has also displayed p53- and Mdm2-independent functions in tumor development that are less well characterized. Therefore, we investigated novel avenues in which Mdmx contributes to tumorigenesis. We demonstrate increased expression of Mdmx results in an inhibition in double-strand DNA break repair and a delay in DNA damage signaling that was independent of p53 and surprisingly, independent of Mdm2. We identified a novel association between Mdmx and a key mediator of DNA repair, the Mre11-Rad50-Nbs1 complex. We also detected increased genomic instability and promotion of in vitro transformation as a result of Mdmx overexpression that was also independent of p53 and Mdm2. Our data show that Mdmx interacts with the Mre11-Rad50-Nbs1 complex and delays DNA break repair, which leads to genome instability and cellular transformation. This novel function of Mdmx provides insight into an alternative mechanism by which Mdmx contributes to tumor formation and possibly tumor progression independent of its interaction with Mdm2 or its negative regulation of p53. These data also highlight the potential for novel therapeutic intervention strategies that capitalize on this newly identified function of Mdmx.
Citation Format: Alexia N. Melo, Alyssa Bouska, Maria P. Arrate, Christine M. Eischen. The oncogene Mdmx promotes genomic instability independent of 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 1768. doi:10.1158/1538-7445.AM2013-1768
Abstract 1771: Extrachromosomal microDNAs in normal vertebrate tissues.
Authors: Dillon Laura , Kumar Pankaj , Shibata Yoshiyuki , Dutta Anindya 
Published: August 2014

Abstract
MicroDNAs are small (&lt;400 base pairs in length) single- or double-stranded extrachromosomal circular DNAs that are derived by excision from tens of thousands of sites within the mammalian genome (Science, 2012, 336:86). Thus far, microDNAs have been detected in several mouse tissues, mouse and human cell lines, and both normal and malignant cells. Here, we examine the microDNAs across eight tissue types (brain, heart, lung, liver, thymus, spleen, kidney, and skeletal muscle) from normal adult mice and in chicken cell lines. We observed microDNAs in all tissue types, originating from thousands of unique genomic loci. As was previously described, these microDNAs are small circles (100 to 400 base pairs), possess a high GC content and are enriched in genic regions. The quantity and loci-of-origin of the microDNAs are compared between tissue types to ascertain tissue-specific differences that may be correlated with amount of cell proliferation and expression of specific genes. Previously, we suggested that the release of microDNAs leaves behind microdeletions within the source genomic loci, resulting in somatically mosaic cells. Our results confirm this possibility by demonstrating that microDNAs are universally present across cell and tissue types in vertebrates. In addition, short (2-15 bp) direct repeats that usually flank the genomic loci yielding microDNAs lead us to hypothesize that homologous-recombination or microhomology-mediated-repair may be involved in microDNA generation. A survey of microDNAs in cell lines defective in many of these repair pathways is being carried out to verify this hypothesis.
Citation Format: Laura Dillon, Pankaj Kumar, Yoshiyuki Shibata, Anindya Dutta. Extrachromosomal microDNAs in normal vertebrate tissues. [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 1771. doi:10.1158/1538-7445.AM2013-1771
Abstract 1772: p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression.
Authors: Zheng Hong , Chen Jiandong 
Published: August 2014

Abstract
Constitutive heterochromatin is important for maintaining chromosome stability but also delays the repair of DNA double strand breaks (DSB). DSB repair in complex mammalian genomes involves a fast phase (2-6 hrs) where most of the breaks are rapidly repaired, and a slow phase (up to 24 hrs) where the remaining damages in heterochromatin are repaired. We found that p53 deficiency delays the slow phase DNA repair after ionizing irradiation. P53 deficiency prevents down regulation of histone H3K9 trimethylation at pericentric heterochromatin after DNA damage. Moreover, p53 directly induces expression of the H3 K9 demethylase JMJD2b through promoter binding. P53 activation also indirectly down regulates expression of the H3 K9 methytransferase SUV39H1. Depletion of JMJD2b or sustained expression of SUV39H1 delays the repair of heterochromatin DNA and reduces clonogenic survival after ionizing irradiation. The results suggest that by regulating JMJD2b and SUV39H1 expression, p53 not only controls transcription but also promotes heterochromatin relaxation to accelerate a rate-limiting step in the repair of complex genomes.
Citation Format: Hong Zheng, Jiandong Chen. p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression. [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 1772. doi:10.1158/1538-7445.AM2013-1772
Abstract 1773: Nucleotide-resolution genomic breakpoint analysis of TMPRSS2-ERG rearrangements in prostate cancer by target-capture next-generation sequencing.
Authors: Weier Christopher , Haffner Michael , Mosbruger Timothy , Esopi David , Hicks Jessica , Zheng Qizhi , Isaacs William B. , De Marzo Angelo M. , Nelson William G. , Yegnasubramanian Srinivasan 
Published: August 2014

Abstract
TMPRSS2-ERG translocations occur in approximately 50% of prostate cancers and therefore represent one of the most frequently observed structural rearrangements in all cancers. However, little is known about the genomic architecture of such rearrangements. We therefore designed and optimized a pipeline involving target-capture of TMPRSS2 and ERG genomic sequences coupled with paired-end next generation sequencing to resolve genomic rearrangement breakpoints in TMPRSS2 and ERG at nucleotide resolution in a large series of primary prostate cancer specimens (n = 83). This strategy showed &gt;90% sensitivity and specificity in identifying TMPRSS2-ERG rearrangements, and allowed identification of intra- and inter-chromosomal rearrangements involving TMPRSS2 and ERG with known and novel fusion partners. Our results indicate that rearrangement breakpoints show strong clustering in specific intronic regions of TMPRSS2 and ERG. The observed TMPRSS2-ERG rearrangements often exhibited complex chromosomal architecture associated with several intra- and inter-chromosomal rearrangements. Nucleotide resolution analysis of breakpoint junctions revealed that the majority of TMPRSS2 and ERG rearrangements (∼88%) occurred at or near regions of microhomology or involved insertions of one or more base pairs. This architecture implicates nonhomologous end joining (NHEJ) and microhomology mediated end joining (MMEJ) pathways in the generation of such rearrangements. These analyses have provided important insights into the molecular mechanisms involved in generating prostate cancer-specific recurrent rearrangements.
Citation Format: Christopher Weier, Michael Haffner, Timothy Mosbruger, David Esopi, Jessica Hicks, Qizhi Zheng, William B. Isaacs, Angelo M. De Marzo, William G. Nelson, Srinivasan Yegnasubramanian. Nucleotide-resolution genomic breakpoint analysis of TMPRSS2-ERG rearrangements in prostate cancer by target-capture next-generation sequencing. [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 1773. doi:10.1158/1538-7445.AM2013-1773
Abstract 1774: Emerging role of Smad7 in DNA damage response pathway as a positive regulator.
Authors: Park Sujin , Kang Jin Muk , Kim Staci Jakyong , Kim Hyojung , Kim Seong-Jin 
Published: August 2014

Abstract
The cellular response to DNA damage is essential in maintaining genomic stability. As DNA damage accumulates, the occurrence rate of cancer is significantly enhanced. Smad7 is known as an inhibitory Smad which negatively regulates TGF-β-induced signaling pathway. Smad7 is predominantly localized in the nucleus even without TGF-β stimulation. However, TGF-β-independent Smad7 function in the nucleus is still not clear. Here, we report Smad7 regulates DNA damage signaling in response to double-strand break induced by radiomimetic drug, neocarzinostatin (NCS). Smad7 overexpression accelerates DNA repair by enhancing phosphorylation of ATM and γH2AX, major DNA damage response signaling, after DNA damage. In Smad7−/− MEF cell, loss of Smad7 leads to failure of ATM phosphorylation and nuclear foci formation at the site of DNA damage upon NCS treatment. We show that Smad7 interacts with activated ATM/MRN complex and this interaction is significantly increased after DNA damage. Additionally, Smad7 co-localizes with pATM, MRN complex and γH2AX at the sites of DNA damage. Taken together, our data suggests that Smad7 plays a critical role in DNA damage response pathway through interaction with activated ATM. In this study, we reveal the de novo function of Smad7 in the nucleus.
Citation Format: Sujin Park, Jin Muk Kang, Staci Jakyong Kim, Hyojung Kim, Seong-Jin Kim. Emerging role of Smad7 in DNA damage response pathway as a positive regulator. [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 1774. doi:10.1158/1538-7445.AM2013-1774
Abstract 1777: Genome-wide identification of replication-associated breakpoints.
Authors: Tsai Yu-Chen , Shastri Nishita , Smith Kevin D. , Schug Jonathan , Casellas Rafael , Brown Eric J. 
Published: August 2014

Abstract
Previous studies have defined sequences that are difficult to replicate and, consequently, are more vulnerable to replication-associated breaks and recombination events. However, many of these sequences have been identified through indirect and biased approaches. To identify genomic sequences that contribute to replication-associated breakpoints, we have performed genome-wide screens to determine the location, sequence, and frequency of replication perturbations within the mammalian genome. To convert these transient pause sites in S phase into longer-lived intermediates, asynchronous ATR-inhibited cells were treated with a low dose of polymerase inhibitor (0.2 μM aphidicolin) to promote selective replication fork collapse at difficult-to-replicate sequences. Affected regions were then isolated by chromatin immunoprecipitation of RPA (RPA-ChIP) and by a recently developed novel DNA breakpoint isolation method. Following deep sequencing, these sites were mapped within 1-5 kb regions and sequences at the center of these peaks were binned to quantify the overall frequency of replication fork collapse at such sites. Surprisingly, sequences that have long been thought to be among the most difficult to replicate, such as CGG repeats, were overshadowed by distinct repetitive sequences that are relatively uncharacterized. These sites were greater than 50-fold enriched over background, and were more common as replication-troubled regions than other well characterized sequences (e.g. triplet repeats, fragile sites, etc). In total, over 100 independently confirmed sites were identified, with most sequences observed in multiple locations across the genome. Notably, common fragile sites, which have been speculated to harbor such replication slow zones, were not observed to be particularly enriched in RPA-ChIP samples, consistent with recent observations that these sites are fragile for reasons other than impeded DNA replication rates. These findings and others indicating a larger role of chromatin structure in common fragile site breakage will be discussed.
Citation Format: Yu-Chen Tsai, Nishita Shastri, Kevin D. Smith, Jonathan Schug, Rafael Casellas, Eric J. Brown. Genome-wide identification of replication-associated breakpoints. [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 1777. doi:10.1158/1538-7445.AM2013-1777
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1779: BRCA2 interacts with an essential replication factor, MCM10.
Authors: Alcivar Allen L. , Ma Jianglin , Xia Bing 
Published: August 2014

Abstract
The BRCA2 (Breast Cancer 2, early onset) gene is implicated in a variety of familial cancers. Loss of BRCA2 function results in severe defects in DNA double-strand break repair, DNA damage-induced checkpoint response and the stability of stalled DNA replication forks, all of which are important for genomic stability. About 50% of BRCA2 is associated with PALB2 (partner and localizer of BRCA2), which anchors BRCA2 onto chromatin and directs its recruitment to DNA damage sites. By tandem affinity purification of PALB2 we identified MCM10, an essential DNA replication factor, as a component of the PALB2/BRCA2 complex. MCM10 promotes initiation of DNA replication through binding to MCM2-7 helicase complex and recruiting the initial DNA polymerase, pol α, to replication origins.
Interestingly, we found that MCM10 binds to BRCA2 instead of PALB2 in the complex. Cells depleted of BRCA2 or MCM10 showed similar instability of stalled replication forks, indicating possible cooperation between the two proteins in fork stabilization following replication stress. Moreover, DNA damage-induced CHK1 activation is markedly reduced in both BRCA2- and MCM10-depleted cells even though RPA (replication protein A) is hyperphosphorylated. Our findings suggest that BRCA2 checkpoint function may be mediated through MCM10 and their interaction may be important for stalled replication fork stability. Domain mapping experiments showed that an evolutionarily conserved coiled-coil motif in the N-terminus of MCM10 which is required for BRCA2 binding and that BRCA2 has at least two MCM10-binding sites, both in its central region. BRCA2 and MCM10 mutants lacking these interaction domains will be used to further test the functional relevance of their interaction.
Citation Format: Allen L. Alcivar, Jianglin Ma, Bing Xia. BRCA2 interacts with an essential replication factor, MCM10. [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 1779. doi:10.1158/1538-7445.AM2013-1779
Abstract 1780: The MAD1 1673 GA polymorphism alters the function of the mitotic splindle assembly checkpoint and is asociated with a worse response to induction chemotherapy and sensitivity to treatment in patients with advanced epithelial ovarian cancer.
Authors: Santibañez Miguel , Gallardo Dolores , Morales Flavia , Lopez Alejandro , Prada Diddier , Mendoza Julia , Castro Clementina , de Leon David Cantu , Oñate Luis F. , Perez Delia , Mohar Alejandro , Herrera Luis A. 
Published: August 2014

Abstract
Introduction: MAD1, a protein of the mitotic spindle assembly checkpoint (SAC), recognizes MAD2 through two leucine zippers, transporting and activating MAD2, which promotes a metaphase arrest signal. A SNP of Mad1 was found to affect the SAC function that could be involved in a bad response to therapeutic agents that alter the dynamics of microtubules. Objective: To investigate the relationship of the polymorphism Mad1 1673 GA (rs1801368) with the efficiency of the SAC and the generation of aneuploidies, and with the therapeutic response of patients with ovarian cancer. Methods: The polymorphism was evaluated in 144 healthy individuals and 91 patients. The mitotic arrest and the presence of errors in segregation were analyzed in cultured human lymphocytes treated with nocodazol and paclitaxel. Errors in segregation were also evaluated in 27 biopsies of patients. Results: Allele frequencies in healthy individuals were G: 50, A: 50, while in the patients, they were G: 38%, A: 62% (p&lt;0.05). The percentage of cells with mitotic arrest was higher in GG cells (p&lt;0.05). The frequency of micronuclei and nondisjunction events increased in AA cells (p&lt;0.05). Tumors from polymorphic patients had a higher percentage of aneuploid cells (p&lt;0.05). The GG patients showed a higher biochemical response, optimal cytoreduction and sensitivity to the treatment. There were no differences in progression-free or overall survival between both groups. Conclusions: the polymorphism Mad1 1673 GA affects the SAC functionality, increasing the frequency of aneuploid cells. This polymorphism modifies the response to agents that alter the dynamics of microtubules in patients with ovarian cancer.
Citation Format: Miguel Santibañez, Dolores Gallardo, Flavia Morales, Alejandro Lopez, Diddier Prada, Julia Mendoza, Clementina Castro, David Cantu de Leon, Luis F. Oñate, Delia Perez, Alejandro Mohar, Luis A. Herrera. The MAD1 1673 GA polymorphism alters the function of the mitotic splindle assembly checkpoint and is asociated with a worse response to induction chemotherapy and sensitivity to treatment in patients with advanced epithelial ovarian 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 1780. doi:10.1158/1538-7445.AM2013-1780