bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-050: Patient-derived tumor xenografts in humanized NSG mice: a model to study immune responses in cancer therapy
Authors: Wang Minan , Keck James G. , Cheng Mingshan , Cai Danying , Shultz Leonard , Palucka Karolina , Banchereau Jacques , Bult Carol , Huntress Rick 
Published: August 2015

Abstract
Mouse models are frequently used to test the therapeutic efficacy of anti-cancer drugs. However, the translation of murine experimental data to treatments for patients with cancer often fails due to significant differences between the species, including the differences in the immune system. Our goal is to bridge this gap and to establish an in vivo preclinical model of human tumor immunotherapy by engrafting immunodeficient mice expressing a partial human immune system with human tumor implants. Humanized NOD-scid IL2Rγ (null) (hu-NSG) mice were initially generated by transplanting NSG mice with human CD34+ hematopoietic stem and progenitor cells (HSPCs) which support human hematopoietic and immune system development. Hu-NSG mice develop functional human T cells and B cells with high levels of TCR excision circles, complex TCR repertoire diversity and antigen-specific T cell proliferative responses. Several types of patient-derived tumors (non small cell lung cancer, sarcoma, triple negative breast cancer and invasive bladder cancer) were successfully implanted into HLA mismatched hu-NSG mice. Tumor growth curves show a delay in tumor growth in hu-NSG compared to non-humanized NSG mice. In a colon cancer xenograft model, treatment with chemotherapy agent (5-FU) or with a therapeutic antibody directed against VEGF (Avastin) resulted in decreased tumor growth. In addition to PDX tumors we have also tested human cancer cell lines. Tumor growth was observed in all hu-NSG mice implanted with human ovarian tumor cell line SKOV3-Luc-D3 cells at different time points post HSPC engraftment, showing no evidence of tumor rejection. Thus, our model of humanized mice bearing tumor-derived xenografts provides opportunities to study both the safety and efficacy of current cancer therapies.
Citation Format: Minan Wang, James G. Keck, Mingshan Cheng, Danying Cai, Leonard Shultz, Karolina Palucka, Jacques Banchereau, Carol Bult, Rick Huntress. Patient-derived tumor xenografts in humanized NSG mice: a model to study immune responses in cancer therapy. [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-050. doi:10.1158/1538-7445.AM2015-LB-050
Abstract LB-054: Normal stem cell divisions, cancer incidence, and driver gene mutations
Authors: Tomasetti Cristian , Vogelstein Bert 
Published: August 2015

Abstract
Cancer arises through the sequential accumulation of mutations in oncogenes and tumor suppressor genes. We show that the incidence of many cancers is strongly correlated (0.80; P &lt; 1.8 × 10-6) with the lifetime number of divisions of the normal stem cells maintaining that tissue's homeostasis. These results suggest that only ∼35% of the variation in cancer incidence among tissues is attributable to environmental factors or inherited predispositions. Moreover, we derive an approach to assess the evidence for environmental and inherited factors that contribute to a given cancer type vs. other cancer types.
The slope of the correlation noted above suggests that the number of driver gene mutations required to develop cancer must be smaller than what was previously estimated. We describe a novel approach to derive this estimate that combines conventional epidemiologic studies with genome-wide sequencing data. In two well-documented cancer types (lung and colon adenocarcinomas), we find that no more than three sequential mutations are needed.
Finally, we explore the role of chance and aging in acquiring the driver gene mutations required to develop cancer. We provide novel experimental evidence, in both mice and humans, of an unexpected relationship between the dynamics of division rates in normal tissues and age-specific cancer incidence. These data and analyses provide a firm basis for understanding the role of random, replicative mutations during stem cell division in cancer incidence.
Citation Format: Cristian Tomasetti, Bert Vogelstein. Normal stem cell divisions, cancer incidence, and driver gene mutations. [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-054. doi:10.1158/1538-7445.AM2015-LB-054
Abstract LB-059: Opposing roles for protein tyrosine kinase 6 (PTK6) in colon cancer
Authors: Mathur Priya S. , Gierut Jessica J. , Xicola Rosa M. , Llor Xavier , Tyner Angela L. 
Published: August 2015

Abstract
Background: Protein Tyrosine Kinase 6 (PTK6, also called BRK) is a non-receptor tyrosine kinase expressed in differentiated epithelial cells of the skin, gastrointestinal tract, and prostate. Disruption of the Ptk6 gene led to impaired intestinal differentiation and increased intestinal proliferation in mice. However, PTK6 also has a tumor-promoting role in the colon, as disruption of the Ptk6 gene impaired carcinogen-induced STAT3 activation and tumorigenesis in mice. PTK6 also promotes survival of human colon cancer cell lines following DNA damaging treatments including γ-irradiation and chemotherapeutic drugs via STAT3 activation.
Results: We examined and manipulated colon cancer cell lines to understand these two seemingly contradictory roles for PTK6 in the colon. The human colon adenocarcinoma cell lines SW480 and SW620 represent a primary colon tumor and a metastasis from the same patient, respectively. PTK6 is highly expressed in SW480 cells and significantly reduced in SW620 cells. Active PTK6, phosphorylated on tyrosine residue 342, is not detectable in either cell line. Stable knockdown of PTK6 in SW480 cells results in an epithelial-to-mesenchymal transition (EMT), evidenced by decreased E-cadherin expression and increased ZEB-1 and Vimentin; as well as increased migration, wound-healing, and anchorage-independent growth of cells in culture. Additionally, knockdown of PTK6 led to increased in vivo tumorigenesis of xenograft cells in nude mice. Ectopic expression of wild-type PTK6 in SW620 cells drives the reverse process (MET), demonstrating a rescue of the EMT phenotype. When a constitutively active PTK6 construct is expressed in SW620 cells, it promotes activation of cytoplasmic oncogenic targets and downstream effectors, STAT3, FAK, BCAR1 and ERK5. Analysis of patient tissues demonstrates a downregulation of mRNA and protein levels, as well as a change in protein localization in tumor versus normal tissues; while PTK6 is detectable in the nuclei of differentiating normal cells it is excluded from nuclei in colon tumors.
Conclusions: Our studies indicate that PTK6 promotes the epithelial phenotype to antagonize the EMT in a kinase-independent manner and a kinase switch activates PTK6 to promote oncogenic signaling. PTK6 protein localization may function to regulate its specific role. Further examination of the complex role of this kinase could allow for a more nuanced understanding of colon cancer initiation and progression for the development of novel treatments.
Citation Format: Priya S. Mathur, Jessica J. Gierut, Rosa M. Xicola, Xavier Llor, Angela L. Tyner. Opposing roles for protein tyrosine kinase 6 (PTK6) in colon 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-059. doi:10.1158/1538-7445.AM2015-LB-059
Abstract LB-061: Bmi1 is required for the initiation of pancreatic cancer through an Ink4a-independent mechanism
Authors: Schofield Heather , Bednar Filip , Collins Meredith , Yan Wei , Zhang Yaqing , Shyam Nikhil , Eberle Jaime , Olive Kenneth , Bardeesy Nabeel , Nakada Daisuke , Simeone Diane , Morrison Sean , Pasca di Magliano Marina 
Published: August 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in the United States. Many characteristic mutations in PDAC are known, but this information has so far failed to produce the development of effective treatments, highlighting the need for deeper understanding of the processes that drive tumorigenesis.
B-cell specific Moloney murine leukemia virus insertion site 1 (Bmi1), a Polycomb repressive group protein, is upregulated in PDAC and associated with poor prognosis. Our lab has shown that despite an oncogenic K-ras mutation, mice with pancreas specific loss of Bmi1 do not develop precancerous lesions, termed PanINs (Pancreatic Intraepithelial Neoplasia). This lack of PanIN development was also seen in the presence of pancreatitis, which is usually known to synergize with oncogenic K-ras to speed PanIN development. In other cancer types, Bmi1's effect on tumorigenesis was mechanistically linked to its regulation of the Ink4a/ARF genetic locus. However, we found that in PDAC, PanIN initiation was independent of Bmi1 control this locus. Further, impairment in the regulation of ROS generation was seen in vitro in pancreatic cancer cell lines lacking Bmi1. Regulating ROS generation is a vital step in the neoplastic process and has been shown in other systems to be controlled by Bmi1.
Overall, in this work we have shown that expression of the Polycomb group protein Bmi1 is necessary for the initiation of pancreatic precancerous lesions, and that the mechanism of Bmi1 requirement is independent of its repression of the Ink4a/ARF genetic locus. Given the recent pre-clinical development of a Bmi1 inhibitor, this work could provide rationale for future treatment of pancreatic cancer, a truly devastating disease.
Citation Format: Heather Schofield, Filip Bednar, Meredith Collins, Wei Yan, Yaqing Zhang, Nikhil Shyam, Jaime Eberle, Kenneth Olive, Nabeel Bardeesy, Daisuke Nakada, Diane Simeone, Sean Morrison, Marina Pasca di Magliano. Bmi1 is required for the initiation of pancreatic cancer through an Ink4a-independent mechanism. [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-061. doi:10.1158/1538-7445.AM2015-LB-061
Abstract LB-071: Kub5-Hera/RPRD1B controls CDK1 regulation and synthetic lethality to PARP1 inhibition
Authors: Motea Edward A. , Fattah Farjana , Xiao Ling , Girard Luc , Rommel Amy , Morales Julio , Patidar Praveen , Porter Andrew , Minna John , Boothman David 
Published: August 2015

Abstract
Aberrant CDK1 regulation induces impulsive proliferation as well as genomic and chromosomal instability in cancer cells. However, the mechanism of how CDK1 is regulated at the transcriptional level, especially under pathological conditions (e.g. cancer), remains elusive. Here, we show that Kub5-Hera (K-H), a known transcription termination factor, plays a novel role in promoting CDK1 transcription to mediate DNA repair and cellular response to PARP1 inhibition in various cancer cell lines. At the molecular level, we demonstrate via luciferase reporter assays and mutagenesis studies that K-H binds the phospho-Serine 2-containing C-terminal domain (CTD) of RNA Pol II, which is then recruited to the cell-cycle homology region (CHR) of the CDK1 promoter to efficiently stimulate CDK1 transcription. Mechanistically, the loss of K-H concomitantly reduces CDK1 mRNA/protein expression levels, which consequently compromises homologous recombination (HR)-mediated DNA repair due to the lack of BRCA1 phosphorylation for efficient function. Intriguingly, loss of K-H stimulates PARP1 activity needed for cancer cell survival. Genetic and pharmacological ablation of PARP1 activity in BRCA-proficient cells with aberrant K-H reduction leads to synthetic lethality, which is reversed by re-expression of wild-type K-H but not the mutant with attenuated RNAPII binding. The mechanistic insights gained from this study should lay foundation toward promising new tumor biology-based targets (i.e., K-H as a novel therapeutic target) and innovative strategies to reduce normal tissue toxicity, increase tumor control, and expand the use of PARP1 inhibitors (e.g., Rucaparib) against BRCA-proficient cancers with aberrant K-H loss.
Citation Format: Edward A. Motea, Farjana Fattah, Ling Xiao, Luc Girard, Amy Rommel, Julio Morales, Praveen Patidar, Andrew Porter, John Minna, David Boothman. Kub5-Hera/RPRD1B controls CDK1 regulation and synthetic lethality to PARP1 inhibition. [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-071. doi:10.1158/1538-7445.AM2015-LB-071
Abstract LB-074: The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc
Authors: Sun Xiao-Xin , He Xia , Yin Li , Sears Rosalie , Dai Mushui 
Published: August 2015

Abstract
c-Myc protein stability and activity are tightly regulated by the ubiquitin-proteasome system. Aberrant stabilization of c-Myc contributes to many human cancers. c-Myc is ubiquitinated by SCFFbw7 and several other ubiquitin ligases, whereas it is deubiquitinated and stabilized by ubiquitin-specific protease (USP) USP28. The bulk of c-Myc degradation appears to occur in the nucleolus. However, whether c-Myc is regulated by deubiquitination in the nucleolus is not known. Here, we report that the nucleolar deubiquitinating enzyme USP36 is a novel c-Myc deubiquitinase. USP36 interacts with and deubiquitinates c-Myc in cells and in vitro, leading to the stabilization of c-Myc. This USP36 regulation of c-Myc occurs in the nucleolus. Interestingly, USP36 interacts with the nucleolar Fbw7γ, but not the nucleoplasmic Fbw7α. Yet, it abolished c-Myc degradation mediated both by Fbw7γ and by Fbw7α. Consistently, knockdown of USP36 reduces the levels of c-Myc and suppresses cell proliferation. We further show that USP36 itself is a c-Myc target gene, suggesting that USP36 and c-Myc form a positive feedback regulatory loop. High expression levels of USP36 are found in a subset of human breast and lung cancers. Altogether, these results identified USP36 as a crucial and bono fide deubiquitinating enzyme controlling c-Myc's nucleolar degradation pathway.
Citation Format: Xiao-Xin Sun, Xia He, Li Yin, Rosalie Sears, Mushui Dai. The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc. [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-074. doi:10.1158/1538-7445.AM2015-LB-074
Abstract LB-083: Regulation of the mitotic centrosome by heat shock protein 70
Authors: Fang Chieh-Ting , Kuo Hsiao-Hui , Yih Ling-Huei 
Published: August 2015

Abstract
A functional centrosome is essential for the assembly of a bipolar mitotic spindle and accurate chromosome segregation. Loss of centrosome integrity frequently occurs in transformed cells or in tumor tissues. Pathways maintaining the quality control of proteins are known to regulate the biogenesis and duplication of the centrosome. In this study, we explored the role of heat shock protein 70 (HSP70), an essential molecular chaperone for protein quality control, on maintaining the centrosome integrity during mitosis by treating cells with a HSP70 inhibitor or transducing cells with HSP70-specific shRNA. The effects of these treatments on mitosis progression, mitotic spindle assembly, and cell viability were investigated. Our results showed that inhibition or depletion of HSP70 disrupted microtubule nucleation and polymerization, induced abnormal mitotic spindles, and interfered with mitosis progression. In addition, HSP70 accumulated at the spindle pole and co-localized with γ-tubulin and pericentrin during mitosis. Loss of centrosomal HSP70 impeded the recruitment of pericentriolar components essential for centrosome maturation. These results indicate that HSP70 is required for the maintenance of a functional mitotic centrosome to support the assembly a bipolar mitotic spindle.
Citation Format: Chieh-Ting Fang, Hsiao-Hui Kuo, Ling-Huei Yih. Regulation of the mitotic centrosome by heat shock protein 70. [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-083. doi:10.1158/1538-7445.AM2015-LB-083
Abstract LB-084: A role of long interspersed nuclear element-1 (LINE-1) for telomere maintenance in cells with alternative lengthening of telomeres
Authors: Aschacher Thomas , Wolf Brigitte , Kienzl Philip , Enzmann Florian , Messner Barbara , Holzmann Klaus , Bergmann Michael M. 
Published: August 2015

Abstract
LINE-1 elements (L1s, long interspersed nuclear elements-1) are abundant retrotransposons in the eukaryotic genome that are primarily known for facilitating aberrant recombination. Here we show the involvement of L1 in telomere maintenance in cells using the less characterized alternative lengthening of telomeres (ALT) mechanism. Interestingly, ALT cells show significantly higher expression levels of L1 when compared to TA cells. Knock-down (KD) of L1 in ALT cell lines was associated with reduced length of telomeres, an increase in telomere dysfunction foci, a reduced expression of ALT characteristics such as c-circles and ALT associated PML bodies, and a decreased growth. On the other hand, overexpression of L1 in ALT cell lines lead to a higher rate of c-circles and increased length of telomeres. LINE-1 not only bound to the C-strand of telomeric DNA but also to telomere-repeat-containing RNA (TERRA), a multifunctional component of human telomeres that is highly expressed in ALT cells and has been described to be involved in telomere stabilization. Whereas L1-KD decreased overall TERRA, L1 overexpression increased this RNA. Moreover, L1 KD abrogated the nuclear retention of TERRA. Moreover, the L1-ribonucleoprotein can use the polyadenylated form of TERRA as a template to generate telomere-specific DNA. Thus, L1 appears to contribute to telomere maintenance by a mechanism involving TERRA, either by ensuring its nuclear localization or by using this RNA as a template for the generation of telomere-specific DNA. Our findings now render L1 proteins a promising target in cancer therapy by interfering with telomere lengthening in ALT cells.
Citation Format: Thomas Aschacher, Brigitte Wolf, Philip Kienzl, Florian Enzmann, Barbara Messner, Klaus Holzmann, Michael M. Bergmann. A role of long interspersed nuclear element-1 (LINE-1) for telomere maintenance in cells with alternative lengthening of telomeres. [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-084. doi:10.1158/1538-7445.AM2015-LB-084
Abstract LB-098: Antitumor studies: Design, synthesis, antitumor activity and molecular docking study of novel 2-deoxo-2-substituted-5-deazaalloxazines
Authors: Mahmoud Sawsan A. , Mohamed Mosaad S. , Abou Taleb Nageh A. , Nagamatsu Tomohisa , Ali Hamed I. 
Published: August 2015

Abstract
Cancer is the major threat to the public health worldwide, thereby we have a considerable interest to get potential antitumor agents via computational design, synthesis, functional elucidation, and biological evaluation of different deazaalloxazine analogs. Many of these compounds revealed higher selectivities against different tumor cell lines.
In the study the structure activity relationships (SAR) of the proposed derivatives was investigated, by applying structure based drug design (SBDD) using most advanced molecular modeling tool programs, namely: AutoDock 4.2 and Accelrys Discovery studio 2.0. These computational approaches aim to increase the speed and efficiency in the drug discovery process. The reasonable drug candidates were subjected to the chemical synthesis and biological in vitro test against different tumor cell lines. The docking study of the synthesized and the rationally designed derivatives was carried out using PTKs as target enzymes which was early reported as a proposed pathway for inhibition of cancer. The main outcome of this study is the synthesis of novel 2-methylthio, 2-(substituted alkyl amino), 2-(heterocyclic substituted), 2-amino, 2,4-dioxo and 2-deoxo-5-deazaalloxazine derivatives. Their antitumor activities against human T-cell acute lymphoblastoid leukemia cell line (CCRF-HSB-2), human oral epidermoid carcinoma cell line (KB), human breast cancer cell line (MCF-7) and human cervical cancer cell line (Hela) have been investigated in vitro. Many compounds showed promising antitumor activities. Furthermore, AutoDock study has been done by binding of the 5-deazaalloxazine analogs into c-kit PTK (PDB code: 1t46), where a good correlation between their IC50 and AutoDock binding free energy was exhibited.
Citation Format: Sawsan A. Mahmoud, Mosaad S. Mohamed, Nageh A. Abou Taleb, Tomohisa Nagamatsu, Hamed I. Ali. Antitumor studies: Design, synthesis, antitumor activity and molecular docking study of novel 2-deoxo-2-substituted-5-deazaalloxazines. [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-098. doi:10.1158/1538-7445.AM2015-LB-098
Abstract LB-099: A high-throughput screen of approved drugs uncovers a synergistic interaction targeting prostate cancer
Authors: Licciardello Marco P. , Markt Patrick , Klepsch Freya , Lardeau Charles-Hugues , Dürnberger Gerhard , Ivanov Vladimir , Colinge Jacques , Kubicek Stefan 
Published: August 2015

Abstract
Libraries of approved drugs contain some of the best studied small molecules and represent invaluable resources for drug repurposing and chemical biology studies. Access to comprehensive libraries of clinical compounds is limited and these collections are otherwise difficult to arrange. Using cheminformatics approaches we have assembled a non-redundant set of representative FDA-approved small molecules that we call the CeMM Library of Unique Drugs (CLOUD). The CLOUD covers the chemical and biological space of approved drugs, contains active forms of prodrugs, and can be screened at clinically relevant concentrations. In a combinatorial viability screen of the CLOUD we uncovered a synergistic interaction between two approved drugs. We show that the concomitant administration of these two small molecules induces apoptosis in the androgen receptor (AR)-dependent prostate cancer cell line LNCaP. Mechanistically, the combination affects AR signaling and the stability of the receptor itself. We are currently dissecting further aspects of the mechanism of action and performing in vivo experiments. Altogether, our data suggest that the combination of these two drugs can be repurposed for the treatment of prostate cancer.
Citation Format: Marco P. Licciardello, Patrick Markt, Freya Klepsch, Charles-Hugues Lardeau, Gerhard Dürnberger, Vladimir Ivanov, Jacques Colinge, Stefan Kubicek. A high-throughput screen of approved drugs uncovers a synergistic interaction targeting prostate 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-099. doi:10.1158/1538-7445.AM2015-LB-099