bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA03: DICER1: From ontogenesis to oncogenesis
Authors: Foulkes William D. , Wu Mona , Kock Leanne De , Witkowski Leora , Sabbaghian Nelly , Weber Evan , Hamel Nancy , Priest John R. 
Published: May 2015

Abstract
The DICER1 syndrome, also known as the pleuropulmonary blastoma familial tumor dysplasia syndrome (PPB-FTDS) (OMIM #601200), is a recently described entity comprising a number of rare to ultra-rare tumors arising mainly in childhood or adolescence. The most frequent and characteristic disorders are pleuropulmonary blastoma, cystic nephroma and ovarian Sertoli-Leydig cell tumors. Some aspects of the syndrome were identified in the 1970s and 1990s, but discovery in 2009 by Hill et al of heterozygous disease-associated germ-line DICER1 mutations in affected kindred brought the syndrome into focus. Several studies since 2009 have extended the phenotypes to include more common conditions such as multinodular goiter and Wilms tumor, as well as much rarer entities such as cervical embryonal rhabdomyosarcoma, pineoblastoma and pituitary blastoma. The critical molecular defect appears to be impairment of DICER1's RNase III endonuclease function, which normally would cleave precursor microRNAs to their final mature length. These microRNAs function by targeted silencing and/or degradation of specific messenger RNAs. DICER1 may be considered an unusual type of tumor suppressor gene, in that the first inherited “hit” usually cripples one allele completely, whereas a second somatic “hit” is nearly always limited to the RNase III domains (and is in fact often even more focused on the metal-binding domains of RNase IIIb). These second hits are most commonly a single base substitution leading to an amino acid change, which functionally impairs the protein without overall protein loss. In this presentation I will summarize the current knowledge on the role of DICER1 mutations in cancer and will describe the edges of the known associated phenotypes.
Citation Format: William D. Foulkes, Mona Wu, Leanne De Kock, Leora Witkowski, Nelly Sabbaghian, Evan Weber, Nancy Hamel, John R. Priest. DICER1: From ontogenesis to oncogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA03. doi:10.1158/1538-7445.CANSUSC14-IA03
Abstract IA11: New insights into DNA double-strand break responses
Authors: Kastan Michael B. 
Published: May 2015

Abstract
Repair of damaged DNA in cells is complicated by the necessity to repair the damage in the context of complex chromatin structures. Elucidation of molecular mechanisms of DNA repair in intact cells has been challenging. We developed a system that can rapidly induce DNA double strand breaks (DSBs) at defined endogenous sites in mammalian genomes and enables direct assessment of repair and monitoring of protein recruitment, egress, and modification at DSBs in viable cells. The tight regulation of the system also permits assessments of relative kinetics and dependencies of events associated with cellular responses to DNA breakage. Using chromatin immunoprecipitation, we found that nucleosomes are partially disassembled around DSBs during non-homologous end-joining repair in G1-arrested mammalian cells, characterized by a transient loss of the H2A/H2B histone dimer. Nucleolin, a protein with histone chaperone activity, interacts with RAD50 via its RGG domain and is rapidly recruited to DSBs in an MRE11-NBS1-RAD50 complex dependent manner. Down-regulation of nucleolin abrogates the nucleosome disruption, the recruitment of repair factors, and repair of the DSB, demonstrating for the first time the functional importance of nucleosome disruption in DSB repair and identifying a chromatin remodeling protein required for the process. Interestingly, the nucleosome disruption that occurs during DSB repair in cycling cells differs in that both H2A/H2B and H3/H4 histone dimers are removed. This complete nucleosome disruption is also dependent on nucleolin and is required for RPA recruitment to DSBs, a marker of DSB processing that is a requisite for homologous recombination repair. Since inhibition of nucleolin function blunts the DSB repair process, it has become a potential therapeutic target for radiosensitization of tumors. Similarly, small molecule inhibitors of PIKK kinases like ATM and DNA-PK have been developed and are potent radiosensitizers. The potential clinical use of such compounds will be discussed.
Citation Format: Michael B. Kastan. New insights into DNA double-strand break responses. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA11. doi:10.1158/1538-7445.CANSUSC14-IA11
Abstract IA12: Regulation of the RNF168-dependent response to DNA double-strand breaks
Authors: Orthwein Alexandre , Durocher Daniel 
Published: May 2015

Abstract
The chromatin-based response to DNA double-strand breaks (DSBs) is characterized by the accumulation of DNA repair factors and DNA damage signaling molecules within a large domain that surrounds the lesion. This response is largely dependent on ATM-dependent phosphorylation but also on chromatin ubiquitylation. Indeed, the RNF8 and RNF168 E3 ubiquitin ligases are necessary for the accumulation of proteins such as 53BP1, BRCA1 and RAD18 at sites of DNA damage. The critical importance of this pathway is manifested by the observation that biallelic mutations in the RNF168 gene results in an ataxia-telangiectasia-like syndrome referred to as RIDDLE. We are interested in understanding how this pathway is regulated and how ubiquitin-dependent protein interactions orchestrate the hierarchy of protein recruitment at sites of DNA lesions. I will present our current understanding on the regulation and organization of this signaling cascade and in particular, I will focus my presentation on addressing how the pathway underpinned by RNF168 is regulated during the course of the cell cycle.
Citation Format: Alexandre Orthwein, Daniel Durocher. Regulation of the RNF168-dependent response to DNA double-strand breaks. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA12. doi:10.1158/1538-7445.CANSUSC14-IA12
Abstract IA15: Amelioration of ionizing irradiation damage in Fanconi anemia (Fancd2-/- mice) by GS-nitroxide (JP4-039)
Authors: Greenberger Joel S. 
Published: May 2015

Abstract
Fancd2-/- mice derived from both the C57BL/6 and FEV/B background demonstrate bone marrow stromal cell radiosensitivity and paradoxical hematopoietic cell radioresistance. Fancd2-/- (B6) mouse long-term bone marrow cultures showed reduced longevity of hematopoiesis consistent with decreased capacity to handle oxidative stress. FA patients demonstrate an increased risk for hematopoietic and epithelial cancers, which are difficult to treat with radiotherapy due to intrinsic normal tissue radiosensitivity. Intraoral administration of GS-nitroxide (JP4-039) in F15 emulsion prior to head and neck irradiation significantly reduces the increased susceptibility of Fancd2-/- mice to oral cavity ulceration. Baseline biomarkers for oxidative stress related proteins in oral cavity and bone marrow of Fancd2-/- mice compared to heterozygote and normal littermates (B6) and FVB/N were exacerbated by oral cavity irradiation. Suppression of femur marrow hematopoiesis by head and neck irradiation, was also increased in Fancd2-/- mice, but was ameliorated by JP4-039/F15 intraoral administration, as were gene transcripts, proteins, and DNA promoter demethylation. Amelioration of normal tissue radiosensitivity by organ specific radioprotective mitochondrial targeted antioxidants is effective in both DNA repair defective and wild type murine epithelial tissues.
Citation Format: Joel S. Greenberger. Amelioration of ionizing irradiation damage in Fanconi anemia (Fancd2-/- mice) by GS-nitroxide (JP4-039). [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA15. doi:10.1158/1538-7445.CANSUSC14-IA15
Abstract IA20: A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest
Authors: Hayashi Makoto T. , Karlseder Jan 
Published: May 2015

Abstract
Telomere shortening and disruption of telomeric components are pathways that induce telomere deprotection. Here we describe another pathway, where prolonged mitotic arrest induces damage signals at telomeres in human cells. Exposure to microtubule drugs, kinesin inhibitors, proteasome inhibitors or the disruption of proper chromosome cohesion resulted in the formation of damage-foci at telomeres. Induction of mitotic telomere deprotection coincided with dissociation of TRF2 (Telomere Repeat binding Factor 2) from telomeres, telomeric 3′-overhang degradation and ATM (Ataxia Telangiectasia Mutated) activation, and could be suppressed by TRF2 overexpression or inhibition of Aurora B kinase. Normal cells that escape from prolonged mitotic arrest halted in the following G1 phase, whereas cells lacking p53 continued to cycle and became aneuploid. We propose a telomere dependent mitotic duration monitoring system that reacts to improper progression through mitosis and will discuss the molecular details and implications of this pathway.
Citation Format: Makoto T. Hayashi, Jan Karlseder. A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA20. doi:10.1158/1538-7445.CANSUSC14-IA20
Abstract A11: Cyclosporin A promotes tumor angiogenesis in a calcineurin-independent manner by increasing mitochondrial reactive oxygen species
Authors: Zhou Alice Yao , Ryeom Sandra W. 
Published: May 2015

Abstract
The commonly used immunosuppressant cyclosporin A (CsA), a potent calcineurin inhibitor, significantly increases the incidence of cancer in organ transplant patients. Calcineurin signaling is an important mediator of VEGF signaling in endothelial cells. Negative regulation of calcineurin by its endogenous inhibitor, Down Syndrome Candidate Region-1 (DSCR1), suppresses tumor growth and angiogenesis, in contrast to the effect observed after long-term CsA treatment. Despite the significance of calcineurin signaling in endothelial cells, the consequences of CsA on tumor angiogenesis has not been investigated. Using an in vivo model of skin carcinogenesis, we show that long-term CsA treatment promotes tumor growth and angiogenesis. Treatment of endothelial cells in vitro with CsA increases proliferation and migration in a calcineurin-independent manner and is associated with increased mitochondrial reactive oxygen species. Co-treatment with antioxidants significantly abrogated CsA-induced endothelial cell activation. Furthermore, mice treated with antioxidants were protected against CsA-mediated tumor progression. Taken together, these findings show that CsA functions independent of calcineurin to potentiate tumor growth by promoting tumor angiogenesis via mitochondrial reactive oxygen species production. This work identifies a previously undescribed mechanism underlying a significantly adverse off-target effect of CsA and suggests that co-treatment with antioxidants may inhibit the tumor promoting effects of CsA.
Citation Format: Alice Yao Zhou, Sandra W. Ryeom. Cyclosporin A promotes tumor angiogenesis in a calcineurin-independent manner by increasing mitochondrial reactive oxygen species. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A11. doi:10.1158/1538-7445.CHTME14-A11
Abstract A13: Hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis by regulating VEGF and S100A8 production
Authors: Ahn G-One , Kim Young-Eun , Hong Beom-Ju , Bok Seoyeon , Lee Chan-Ju , Kim Hak Jae , Kim Il Han , Seita Jun , Weissman Irving , Brown J Martin 
Published: May 2015

Abstract
Myeloid cells (cells that give rise to monocytes and macrophages) are a critical component in the solid tumor microenvironment, promoting angiogenesis and tumor recurrence to therapies. Recent literature have extensively demonstrated that hypoxia-inducible factor (HIF) is a key transcription factor in myeloid cells in responding to hypoxic stimuli including solid tumors and inflammation by secreting various cytokines and growth factors.
Although a number of studies have reported that hypoxia exposure to primary macrophages induces HIF-1 activation and subsequent vascular endothelial growth factor (VEGF) production, there had been no mouse model to demonstrate this phenomenon. To better understand the role of transcriptional activation of HIF in pathological macrophages, we have created a new strain of myeloid-specific knockout (KO) mice targeting HIF pathways using hS100A8 as the myeloid promoter. S100A8 is an intracellular calcium binding protein and its expression has been heavily detected in pathological macrophages of many diseases including solid tumors, inflammatory bowel disease, obesity, and rheumatoid arthritis.
Upon generating mice deficient for von Hippel Lindau (pVHL) tumor suppressor, the negative regulator of HIF, in myeloid cells, we observed erythema and increased VEGF expression in the bone marrow lysate. Moreover, these mice exhibited an enhanced angiogenesis in the subcutanouesly implanted matrigel plugs, which was accompanied by increased VEGF-VEGFR2 signaling in matrigel. We further found that these phenotypes were dependent on transcriptional activation of HIF-1 as a pharmacological or genetic inhibition of HIF-1α completely suppressed the phenotypes in mice deficient for pVHL in myeloid cells. Importantly, we found that HIF-1 activation in myeloid cells regulate not only VEGF but also S100A8 production and identified that monocytes were the major effector driving angiogenesis.
Together these results suggest that transcriptional activation of HIF-1 in myeloid cells plays a critical role in promoting angiogenesis. We are currently investigating how HIF-1 in myeloid cells regulates tumor microenvironment thereby affecting tumor progression.
Citation Format: G-One Ahn, Young-Eun Kim, Beom-Ju Hong, Seoyeon Bok, Chan-Ju Lee, Hak Jae Kim, Il Han Kim, Jun Seita, Irving Weissman, J Martin Brown. Hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis by regulating VEGF and S100A8 production. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A13. doi:10.1158/1538-7445.CHTME14-A13
Abstract A21: Thrombin-processed Ecrg4 recruits myeloid cells and induces anti-tumorigenic inflammation
Authors: Lee Jisook , Borboa Alexandra , Baird Andrew , Eliceiri Brian 
Published: May 2015

Abstract
Myeloid cells regulate tumor angiogenesis and promote tumor invasion, yet few strategies exist to exploit their presence to reverse the overall immunosuppressive tumor microenvironment. Based on bioinformatic mining of sentinel genes encoding biologically active peptides, we have recently identified Ecrg4 (Esophageal Cancer-Related Gene 4), as a novel secreted pro-inflammatory mediator of macrophage activation. While higher Ecrg4 expression levels correlate with improved survival in cancers of the esophagus, prostate and breast, indicating a role as a candidate tumor suppressor gene, we have demonstrated that the biological activity of Ecrg4 in cancer functions through a paracrine mechanism, in which Ecrg4 regulates myeloid cells in brain tumors. Moreover, mutational analysis reveals that the biological activity of Ecrg4 is dependent on a thrombin-processing site at the C-terminus, inducing monocyte invasion in vivo and in vitro, demonstrating its role as a novel chemoattractant. Here we establish Ecrg4 as a thrombin-processed chemoattractant using subcutaneous tumor models. Ecrg4 gene delivery or Ecrg4 (133-148) peptide administration to tumor reduced melanoma progression through mobilization and activation of myeloid cells to tumor site. Furthermore, in Ecrg4-knockout mice, myeloid cell recruitment is impaired, leading to increased tumor burden. Together, these results identify Ecrg4 as a paracrine factor that is chemotactic for monocytes, with translational potential as an anti-tumor therapeutic.
Citation Format: Jisook Lee, Alexandra Borboa, Andrew Baird, Brian Eliceiri. Thrombin-processed Ecrg4 recruits myeloid cells and induces anti-tumorigenic inflammation. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A21. doi:10.1158/1538-7445.CHTME14-A21
Abstract A25: SOCS3 deficiency in myeloid cells promotes prostate tumor development
Authors: Yu Hao , Liu Yudong , McFarland Braden C. , Benveniste Etty N. , Qin Hongwei 
Published: May 2015

Abstract
Suppressor Of Cytokine Signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway, and have been implicated as functioning as tumor suppressors, particularly SOCS3. We have previously demonstrated that specific deletion of SOCS3 in myeloid cells leads to heightened activation of STAT3 and downstream STAT3 target gene expression. STAT3 activation has been strongly implicated in contributing to prostate cancer progression and metastasis. STAT3 signaling in myeloid cells has been demonstrated to attenuate anti-tumor immunity. Thus, we evaluated the impact of SOCS3 deletion in myeloid cells in a murine prostate tumor model. We demonstrate that prostate tumor growth is significantly enhanced in myeloid-specific SOCS3-deficient mice, which correlates with elevated levels of Myeloid Derived Suppressor Cells (MDSC) in both the spleen and tumor microenvironment, and less CD8+ T-cell infiltration in tumors. Furthermore, SOCS3-deficient bone-marrow-derived mononuclear cells exhibit heightened STAT3 activation and are preferentially differentiate into MDSC phenotype. Importantly, we identify granulocyte-colony stimulating factor (G-CSF) as a critical factor secreted by the prostate tumor microenvironment that promotes development of Gr-1+CD11b+ cells via a STAT3-depentent pathway. Abrogation of tumor-derived G-CSF reduced the proliferation and accumulation of Gr-1+CD11b+ cells and inhibited prostate tumor growth. Therefore, the tumor-derived cytokine, G-CSF, is a prospective candidate upstream of the STAT3/SOCS3 pathway in MDSC differentiation from the bone marrow. These findings highlight the critical function of SOCS3 as a negative regulator of MDSC development and function, which may contribute to tumor suppressor attributer of SOCS3.
Citation Format: Hao Yu, Yudong Liu, Braden C. McFarland, Etty N. Benveniste, Hongwei Qin. SOCS3 deficiency in myeloid cells promotes prostate tumor development. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A25. doi:10.1158/1538-7445.CHTME14-A25
Abstract A55: Tumor-associated fibroblasts: A new target for cancer treatment
Authors: Hamilton Chase , Shelton Shary , Kakarala Kiran , Thomas Sufi Mary 
Published: May 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a 50% rate of local failure with current standard of care. We recently reported that patient-derived tumor associated fibroblasts (TAF) facilitate HNSCC proliferation and metastasis to the cervical lymph node and lung of mice. Although the paracrine molecular interactions between HNSCC and TAFs have not been fully described, we demonstrated that TAFs (and not HNSCC) secrete hepatocyte growth factor (HGF), a ligand for the c-Met receptor on HNSCC cells. Further, activation of the HGF-c-Met pathway increased HNSCC growth and invasion. In addition, we demonstrated that HNSCC cells induce the expression of HGF from TAFs. We hypothesized that inhibition of TAF-secreted HGF would reduce HNSCC proliferation, invasion and migration. We tested the efficacy of ficlatuzumab (AV-299) a humanized HGF inhibitory immunoglobulin G1 (IgG1) monoclonal antibody in mitigating TAF-induced HNSCC progression. . Ficlatuzumab exhibits antitumor effects in xenograft models as a single agent and has been tested in patients with non-small cell lung cancer in a phase I setting. The antitumor efficacy of HGF neutralization has not been tested in the context of TAFs in HNSCC. Our data demonstrate that ficlatuzumab is effective in mitigating TAF-induced HNSCC proliferation, migration and invasion through inhibition of the c-met pathway in HNSCC.
Citation Format: Chase Hamilton, Shary Shelton, Kiran Kakarala, Sufi Mary Thomas. Tumor-associated fibroblasts: A new target for cancer treatment. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A55. doi:10.1158/1538-7445.CHTME14-A55