bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-104: Excited electrons in melanin induce cyclobutane dimers in the dark
Authors: Premi Sanjay , Wallisch Silvia , Mano Camila , Weiner Adam , Bacchiocchi Antonella , Wakamatsu Kazumasa , Bechara Etelvino , Halaban Ruth , Douki Thierry , Brash Douglas E. 
Published: August 2015

Abstract
Sunlight-induced melanomas contain UV-signature mutations, which are caused by cyclobutane pyrimidine dimers (CPD). These photoproducts are typically created picoseconds after a UV photon is absorbed at adjacent thymines or cytosines. However, using immunohistochemistry, mass spectrometry, and RNAi, we find that melanocytes generate CPD for &gt;3 hours after exposure to UVA or UVB, wavelengths found in sunlight and in tanning beds; these “dark CPD” constitute the majority of CPD induced. Using pharmacologic inhibitors, single-photon counting, and specific energy acceptors, we elucidated the mechanism. The process begins when UV-induced superoxide and nitric oxide combine to form peroxynitrite, one of the few biological molecules capable of exciting an electron. Excitation creates a quantum triplet state in the skin pigment melanin that has the energy of a UV photon but induces CPD by transferring its energy to DNA in a radiation-independent manner. Melanin is evidently carcinogenic as well as protective. These findings may underlie the dependence of UV-induced and spontaneous skin cancers on melanin type. The results also validate the long-standing suggestion that chemical generation of excited electronic states - the source of bioluminescence in lower organisms - is important in mammalian biology.
Citation Format: Sanjay Premi, Silvia Wallisch, Camila Mano, Adam Weiner, Antonella Bacchiocchi, Kazumasa Wakamatsu, Etelvino Bechara, Ruth Halaban, Thierry Douki, Douglas E. Brash. Excited electrons in melanin induce cyclobutane dimers in the dark. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-104. doi:10.1158/1538-7445.AM2015-LB-104
Abstract LB-105: Methanol extract of Cochrorus olitorus protects against potassium dichromate toxicity in albino rats
Authors: Osifeso Olabode O. , Akinwumi Kazeem A. , Adedoja Ayobami W. 
Published: August 2015

Abstract
Hexavalent chromate compounds are human carcinogens that pose great health hazard in several parts of the world especially in developing countries. In addition, an effective cure eludes the world. The study therefore evaluates the usefulness of the leafy vegetable and herb; Cochrorus olitorus (CO) against potassium chromate K2Cr2O7. Negative control animals were fed distilled water, while the positive control rats received K2Cr2O7 once per week. Test rats were exposed to 25, 50 and 100 mg/Kg body weight of CO alone for 42 days and / or 12 mg/kg body wt of K2Cr2O7 once per week before the animals were sacrificed. The frequency of micronucleated polychromatic erythrocytes (mPCEs) was monitored in bone marrow cells while aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine levels were assessed in the serum. Haematological parameters were also monitored in test and control animals. The phytochemical analysis of CO was also carried out. K2Cr2O7 significantly (P&lt;0.05) increased the levels of mPCE, AST, ALT, creatine, total white blood cells and lymphocytes as compared with the control. While percentage pack cell volume and neutrophils were reduced. In contrast, treatment with the different doses of CO restored the markers towards the levels of the negative control. Methanolic extract of CO is rich in flavonoids, saponins, anthraquinnones, terpernoid and phenols which may be responsible for the protection observed in this study. Our results suggest that methanol extract of CO has potentials in the treatment/management of chromate toxicity.
Note: This abstract was not presented at the meeting.
Citation Format: Olabode O. Osifeso, Kazeem A. Akinwumi, Ayobami W. Adedoja. Methanol extract of Cochrorus olitorus protects against potassium dichromate toxicity in albino rats. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-105. doi:10.1158/1538-7445.AM2015-LB-105
Abstract LB-106: Fusogenic-oligoarginine peptide-mediated silencing of the CIP2A oncogene suppresses oral cancer tumor growth in vivo
Authors: Alexander-Bryant Angela , Dumitriu Anca , Attaway Christopher , Yu Hong , Jakymiw Andrew 
Published: August 2015

Abstract
Intracellular delivery and endosomal escape of functional small interfering RNAs (siRNAs) remain major barriers limiting the clinical translation of RNA interference (RNAi)-based therapeutics. Recently, we demonstrated that a endosome-disruptive peptide we synthesized termed, 599, could enhance the intracellular delivery and bioavailability of siRNAs designed to target the CIP2A oncoprotein (siCIP2A) into oral cancer cells and consequently inhibit oral cancer cell invasiveness and anchorage-independent growth in vitro. Thus, to further assess the therapeutic potential of the 599 peptide in mediating RNAi-based therapeutics for oral cancer and its prospective applicability in clinical settings, the objective of the current study was to determine whether intratumoral dosing of the 599+siCIP2A complex could induce silencing of CIP2A and consequently impair tumor growth using a xenograft oral cancer mouse model. Our results demonstrated that the 599 peptide was able to protect siRNAs from degradation by serum and ribonucleases in vitro, confirming the stability of the 599+siRNA complex and its potential for in vivo utility. Moreover, 599 peptide-mediated delivery of siCIP2A to tumor tissue induced CIP2A silencing without any associated toxicity, consequently resulting in reduction of the mitotic index and significant inhibition of tumor growth. Together, these data suggest that the 599 peptide carrier could be a clinically effective mediator of RNAi-based cancer therapeutics.
Citation Format: Angela Alexander-Bryant, Anca Dumitriu, Christopher Attaway, Hong Yu, Andrew Jakymiw. Fusogenic-oligoarginine peptide-mediated silencing of the CIP2A oncogene suppresses oral cancer tumor growth in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-106. doi:10.1158/1538-7445.AM2015-LB-106
Abstract LB-124: Tumor-educated platelets allow for multiclass liquid biopsy-based diagnosis of cancer
Authors: Best Myron , Sol Nik , Kooi Irsan , Nilsson Jonas , Westerman Bart , Ylstra Bauke , Dorsman Josephine , Smit Egbert , Verheul Henk , Reijneveld Jaap , Tannous Bakhos , Wesseling Pieter , Würdinger Thomas 
Published: August 2015

Abstract
Background: Cancer diagnosis is frequently hampered by limited access to adequate tissue of the primary tumor or of metastatic lesions. To overcome such limitations, the use of blood-based liquid biopsies has been suggested. Blood represents a biosource of tumor-educated platelets (TEPs) that sequester biomolecules during tumor growth, thereby altering the platelet mRNA profile.
Methods: Blood platelet samples of 175 patients with cancer covering five tumor types (40 non-small cell lung cancer, 39 glioblastoma, 37 colorectal cancer, 35 pancreatic cancer, and 24 breast cancer) and of 52 healthy donors were isolated from whole blood by differential centrifugation. Total RNA was isolated, subjected to SMARTer mRNA amplification and submitted for whole transcriptome mRNA sequencing on the Illumina platform. Healthy donors, pan-cancer, and individual cancer classes were distinguished by a self-learning support vector machine (SVM) algorithm, using transcripts with moderate to high expression.
Results: The 227 blood platelet samples were successfully sequenced and demonstrated a good intersample correlation of the detected mRNAs. Based on mRNA profiles, all tumor samples were clearly distinguished from healthy individuals: the pan-cancer SVM-supported classification test reached a sensitivity of 97% and a specificity of 92% to distinguish cancer patients from healthy controls. Also, all patients without overt metastases were correctly predicted as cancer patients. Moreover, a multiclass cancer diagnostics TEP-test, to distinguish multiple tumor subclasses and healthy controls provided an overall accuracy of 70%, far exceeding random classification. In addition, we distinguished HER2-positive, and mutant KRAS and EGFR tumors from their wild-type counterparts. Also, patients with metastatic tumors in lung, brain, and liver were accurately diagnosed according to the tumor in the tissue of origin.
Conclusion: Molecular interrogation of TEP-based liquid biopsies may leverage cancer diagnostics. TEPs provide a circulating biosource for pan-cancer, multiclass, and molecular cancer classification. Of interest, this tool might also allow for blood-based highly sensitive early-stage cancer screening.
Citation Format: Myron Best, Nik Sol, Irsan Kooi, Jonas Nilsson, Bart Westerman, Bauke Ylstra, Josephine Dorsman, Egbert Smit, Henk Verheul, Jaap Reijneveld, Bakhos Tannous, Pieter Wesseling, Thomas Würdinger. Tumor-educated platelets allow for multiclass liquid biopsy-based diagnosis of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-124. doi:10.1158/1538-7445.AM2015-LB-124
Abstract LB-125: The identification of FOXA1/ERα pathway modulators for the treatment of hormone-based therapy resistant breast cancer
Authors: roffey jon , Lejeune Aurore , Barnard Michelle , Stock Julie , Wong Ai Ching , McKelvie Jenny , Holmes Kelly , Carroll Jason , Myatt Stephen 
Published: August 2015

Abstract
Estrogen receptor alpha (ERα) is expressed in ∼75% of breast cancers where it binds and regulates specific target genes which drive cancer cell proliferation. Hormone-based treatments such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors prevent estrogen signalling through the ERα, but in many cases resistance to these therapies develops. FOXA1 is a pioneer factor for ERα that is required to facilitate ERα binding to its target genes and its expression is considered to be a defining gene that characterizes ERα positive luminal breast cancers. Here we show that FOXA1 is an essential gene in ERα positive, tamoxifen resistant and aromatase-resistant breast cancer cell lines suggesting inhibitors that target the FOXA1/ERα pathway could have broad utility in these settings. To this end we performed a cell-based screen to identify novel small molecule regulators of FOXA1/ERα pathway activity. Our novel cell-based assay allowed us to screen over 180, 000 discrete compounds in a high through-put manner. Counter screens and phenotypic profiling in FOXA1 positive and negative breast cancer cell lines were used to remove non-specific compounds and direct ERα modulators. Second batches of confirmed actives were profiled through the screening cascade and by using ChIP assays we have observed a reduction in FOXA1 binding at the chromatin that is commensurate with a similar loss of ERα binding, demonstrating for the first time pharmacological modulation of FOXA1/ERα occupancy at the chromatin level.
Citation Format: jon roffey, Aurore Lejeune, Michelle Barnard, Julie Stock, Ai Ching Wong, Jenny McKelvie, Kelly Holmes, Jason Carroll, Stephen Myatt. The identification of FOXA1/ERα pathway modulators for the treatment of hormone-based therapy resistant breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-125. doi:10.1158/1538-7445.AM2015-LB-125
Abstract LB-131: In vivo chromosomal engineering with the CRISPR/Cas9 model: a new frontier for mouse modeling
Authors: Maddalo Danilo 
Published: August 2015

Abstract
Introduction: Chromosomal rearrangements are often detected in several types of cancer and result in expression of aberrant genes with oncogenic functions. In spite of their importance in tumor formation, modeling such rearrangements has been proven challenging and requires heavy and long germline manipulation.
Purpose of the study: in this study we propose to induce chromosomal rearrangements in vivo by delivering the CRISPR/Cas9 system making use of viral vectors.
Experimental procedures: for in vitro studies we transfected NIH/3T3 cells with plasmids expressing the Cas9 protein and the specific sgRNA. For in vivo delivery of the CRISPR/Cas9 system to the lung of adult mice we made use of Adenoviral vectors containing the Cas9 and two sgRNAs expressed under the control of two independent U6 promoters. Imaging of the lungs was performed with μCT scan.
Results: two sgRNAs to direct the endonuclease Cas9 to the intron 19 of Alk and the intron 14 of Eml4 to induce the Eml4-Alk inversion were designed to induce Eml4-Alk inversion, detected in a subset of patients with non-small cell lung cancer (NSCLC). Co-delivery of the sgRNAs and the Cas9 resulted in the expected rearrangements, indicating that two sgRNAs and the endonuclease are sufficient to induce chromosomal rearrangements in vitro. For in vivo delivery to the lung of adult mice, we generated an adenoviral system for the concomitant delivery of the Cas9 and the two sgRNAs (Ad-EA) or the Cas9 alone (Ad-Cas9). Within 8 weeks post-infection with Ad-EA, mice developed lung adenomas while mice infected with Ad-Cas9 were tumor free. All the tumors carried the genomic inversion Eml4-Alk and were negative for p63 and positive for TTF-1 resembling the histological feature of NSCLC. Finally we tested the sensitivity of the tumors to the ALK/MET inhibitor crizotinib, used in therapy for the treatment of ALK+ NSCLC. Radiological and histological analysis showed in all cases tumor regression, indicating that our CRISPR-induced mouse model closely resembles human NSCLC.
Conclusion: In conclusion the strategy here presented expands significantly our possibility of modeling cancers driven by chromosomal rearrangements and represents an opportunity to test novel targeted therapies and thee mechanisms leading to drug resistance.
Citation Format: Danilo Maddalo. In vivo chromosomal engineering with the CRISPR/Cas9 model: a new frontier for mouse modeling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-131. doi:10.1158/1538-7445.AM2015-LB-131
Abstract LB-141: Specific and potent silencing of K-Ras by asymmetric silencing RNA (aiRNA) reveals addiction of cancer stem cells to mutant K-Ras amplification
Authors: Oishi Jun , Umehara Hiroki , Jesuraj Nithya , Barbulovic Jelena , Sun Xiangao , Li Chiang J. 
Published: August 2015

Abstract
K-Ras, the first oncogene identified in human cancer, is mutated in about 30% of human solid tumors. K-Ras protein, a small membrane-bound GTP-binding protein, acts as a molecular switch to transduce cell proliferation signals. Activating mutations of K-Ras lock the Ras protein into the hyper-active GTP-bound state, resulting in the activation of numerous signaling pathways that control cell survival and proliferation. Ras is also an important oncoprotein in many cancers where it is not mutated since Ras can be functionally activated through aberrant activation of other signal transduction elements. Activated K-Ras proteins are, therefore, found in a large proportion of all human cancers, and occupy a central position of interest.
Hypermalignant cancer cells, termed cancer stem cells (CSCs), that are highly tumorigenic and metastatic have been isolated from cancer patients with a variety of tumor types and found to have high stemness properties. These stemness-high cancer cells are hypothesized to be fundamentally responsible for cancer metastasis and relapse. Furthermore, a number of stemness genes, such as beta-catenin, nanog, Sox2, Oct3/4 have been implicated in cancer cell stemness. The role of oncogenes such as K-Ras in cancer cell stemness, however, is not clear.
To elucidate the role of K-Ras in the maintenance of cancer cell stemness, we employed asymmetric silencing RNA technology (aiRNA) which is able to silence target genes with high potency and precision. Moreover, aiRNA technology can be readily applied to CSCs. Here we report, to our surprise, that CSCs are not simply addicted to activating mutations of K-Ras, or activation of downstream regulators of the Ras pathway. However, CSCs with amplified mutant K-Ras are highly sensitive to K-Ras silencing. Moreover, the DNA copy number of the mutant K-Ras directly predicts the sensitivity of CSCs to K-Ras silencing. Our studies suggest that amplified mutated K-Ras is required for the maintenance of malignancy and cancer cell stemness, which may have significant implications for understanding the connections between oncogenes and cancer cell stemness, and for developing cancer stem cell inhibitors.
Citation Format: Jun Oishi, Hiroki Umehara, Nithya Jesuraj, Jelena Barbulovic, Xiangao Sun, Chiang J. Li. Specific and potent silencing of K-Ras by asymmetric silencing RNA (aiRNA) reveals addiction of cancer stem cells to mutant K-Ras amplification. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-141. doi:10.1158/1538-7445.AM2015-LB-141
Abstract LB-144: Derivation of a model of cancer stem cell from human induced pluripotent stem cells
Authors: Kasai Tomonari , Hoshikawa Kenta , Takejiri Shuto , Ikeda Masashi , Kumon Kazuki , Sanchez Calle Anna , Vaidyanath Arun , Mizutani Akifumi , Ling Chen , Seno Masaharu 
Published: August 2015

Abstract
The existence of cancer stem cell (CSC) has been considered as one of the important reason as to why patients have a poor prognosis. However, heterotopic transplantation of embryonic stem cells and induced pluripotent stem cells has been shown to form teratoma, but not malignant teratoma. Since the microenvironment niche is playing a significant role for the proper differentiation of stem cells, the cancerous niche should drive stem cells into malignant cells in vivo. According to this hypothesis, we tried to generate cancer cells from human induced pluripotent stem (hiPS) cells. For the conversion into CSC, the conditioned medium from different human cancer cell lines was collected from confluent dishes and filtered using 0.22 micrometer filter. Then, hiPS cells, without MEF feeder cells, were maintained in the conditioned medium (CM) in the ratio of 1:1. The medium was changed every day with CM for 4 weeks. hiPS cells with the complete medium were used as control. For transplantation studies, 10^4 cells were suspended in HBSS and were xenotransplantated into NOD-SCID mice. After 3 months, tumors were excised and fixed in 10% neutral formalin buffer solution, or subjected to primary culture. The converted cells and primary cultured cells formed spheroids in suspension culture, and had tumorigenicity in vivo. The stemness of living cells was checked under fluorescent microscopy observation with rBC2LCN-FITC staining. The RNAs were extracted from converted cells and microarray analysis was perfomed. The RNA expression patterns of cell lines were visualized by sphered self-organizing map (sSOM) analysis. The sSOM analysis perfomed based upon various parameters shows the converted CSCs can be characterized into various cell types. Utilizing this method, we successfully established two different hiPS-CSC lines using CM from A172 and RERF-LC-KJ.
The comprehensive understanding of cancer could be realized as the heterogeneity of cancer tissues is clarified and their component cells are identified. This study will lead to the development of the true personalized therapy of cancer in the future.
Citation Format: Tomonari Kasai, Kenta Hoshikawa, Shuto Takejiri, Masashi Ikeda, Kazuki Kumon, Anna Sanchez Calle, Arun Vaidyanath, Akifumi Mizutani, Chen Ling, Masaharu Seno. Derivation of a model of cancer stem cell from human induced pluripotent stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-144. doi:10.1158/1538-7445.AM2015-LB-144
Abstract LB-149: A novel strategy to inhibit CpG island hypermethylation and restore BRCA1 expression
Authors: Han Yoo Jeong , Zhang Jing , Prat Aleix , Yoshimatsu Toshio , Gomez-Vega Maria , Kwon John , Perou Charles M. , Kannanganattu Prasanth , Olopade Olufunmilayo I. 
Published: August 2015

Abstract
BRCA1 promoter methylation is observed in 20-60% of sporadic triple negative breast cancer (TNBC) and may be an important mechanism contributing to the loss of BRCA1 function in sporadic TNBC and other cancers with low BRCA1 expression. Demethylation and consequent reactivation of tumor suppressor genes are rational approaches being used in the treatment of cancer. However, currently available nucleoside-based DNMT inhibitors affect genome-wide DNA methylation and cannot specifically target tumor suppressor genes like BRCA1. Here, we describe a novel approach to modulate local DNA methylation by silencing a neighboring long non-coding RNA (lncRNA) which tethers DNMT1 at the BRCA1 genomic locus.
The human genomic region encompassing the BRCA1 gene is complex and includes two protein coding genes (BRCA1 and NBR1), a non-coding RNA gene (NBR2), and a pseudogene of BRCA1 (BRCA1P1), within a ∼170kb region of chromosome 17q21. The BRCA1 gene on the minus strand is located head-to-head with NBR2 on the plus strand, whereas BRCA1P1 on the minus strand is located head-to-head with NBR1 on the plus strand. The promoter between the BRCA1 and NBR2 genes and that between the BRCA1P1 and NBR1 genes are bidirectional, expressing transcripts in opposite directions through convergent transcription. The BRCA1P1 pseudogene was generated by a recent evolutionary event: partial duplication of BRCA1 gene followed by insertion of a processed pseudogene of RPLP1. It expresses a chimeric lncRNA retained in nuclei. Interference with the nuclear expression of BRCA1P1 lncRNA using a specific anti-sense oligonucleotide (ASO) decreased the promoter methylation of BRCA1 and increased BRCA1 expression. RNA immunoprecipitation (RIP) assays revealed DNMT1 interactions with BRCA1 mRNA and BRCA1P1 lncRNA at the locus. Chromosome conformation capture (3C) will assess whether there is a long-range interaction between the BRCA1 and BRCA1P1 promoters through DNMT1 and mediators. Our data support a long-range cis-regulation of BRCA1 expression by neighboring BRCA1P1 lncRNA through an interaction with DNMT1 at the locus. Depleting BRCA1P1 with ASO could be developed as a therapeutic method to inhibit BRCA1 promoter methylation and restore BRCA1 expression.
Citation Format: Yoo Jeong Han, Jing Zhang, Aleix Prat, Toshio Yoshimatsu, Maria Gomez-Vega, John Kwon, Charles M. Perou, Prasanth Kannanganattu, Olufunmilayo I. Olopade. A novel strategy to inhibit CpG island hypermethylation and restore BRCA1 expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-149. doi:10.1158/1538-7445.AM2015-LB-149