bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1263: Cellular senescence in Hodgkin's lymphoma
Authors: Gopas Jacob , Zurgil Udi , Zeev Estee , Benharoch Daniel , Ezratty Jodi , Shubinsky Giora , Livneh Etta 
Published: August 2015

Abstract
Hodgkin's lymphoma (HL), a B cell originated malignancy of the immune system, is one of the most frequent lymphomas in the Western world. Although the rate of cure is high, about 20-35% of patients relapse, and about half of them eventually die of the disease or treatment-related late toxicities and secondary malignancies. Conceptually novel treatment strategies are thus needed, particularly for this category of patients. The malignant cells, called Hodgkin and Reed-Sternberg (HRS) cells, only make up 1-2% of the total tumor cellularity; the remaining mass comprising a mixed infiltrate population is thought to be recruited to the lymph node by HRS-driven pro-inflammatory signals. The origin of the pro-inflammatory signals remains elusive, and represents a critical gap in our knowledge of the pathogenesis of HL. We propose that a sub-population of HRS cells, which we call herein large RS cells, have characteristics of senescent cells, and, thus produce large amounts of inflammatory mediators (the so-called “senescence-associated secretory phenotype”, or SASP). Senescence is characterized by permanent cell cycle arrest and loss of proliferative capacity, despite continued viability and metabolic activity. We show that the senescence markers the cell cycle inhibitors p16INK4a and p21Cip1 are expressed in large RS cells in all HL biopsies examined. Moreover, the large RS cells are negative for Ki-67 staining, demonstrating that these cells have ceased to proliferate. We also show that large, ‘RS-like’ cells in a HL-derived line, L428, stained for the characteristic senescence marker β-galactosidase (β-gal). Oxidative stress and chemotherapy increased the proportion of β-gal positive large RS cells. Furthermore, we show that the large RS cells secrete high levels of cytokines. We suggest that these senescent RS cells may be responsible, at least in part, for creating a pro-inflammatory microenvironment, promoting HL pathogenesis, and mediating chemo-resistance in relapsed disease. Understanding the pathways important for the establishment of senescence in HRS cells, as well gaining insight into targetable mechanisms for the eradication of these cells, will provide new therapeutic approaches for HL patients with recurrent or chemo-resistant disease.
Citation Format: Jacob Gopas, Udi Zurgil, Estee Zeev, Daniel Benharoch, Jodi Ezratty, Giora Shubinsky, Etta Livneh. Cellular senescence in Hodgkin's lymphoma. [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 1263. doi:10.1158/1538-7445.AM2015-1263
Abstract 1268: Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration
Authors: Buchheit Cassandra , Angarola Brittany , Steiner Allison , Weigel Kelsey , Schafer Zachary 
Published: August 2015

Abstract
Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Due to the inherent invasive nature of IBC cells, we hypothesized that IBC cells could evade detachment-induced apoptosis (anoikis), and rely on tightly regulated intracellular signaling pathways to do so. Here we demonstrate that in contrast to normal mammary epithelial cells, IBC cells robustly survive in ECM-detached conditions. ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment, suggesting overexpression/hyperactivation of these oncogenes is vital for IBC evasion of anoikis. Downstream of ErbB2 and EGFR, ERK/MAPK signaling was found to protect cells from anoikis by phosphorylating Bim-EL at serine 59. This phosphorylation of Bim-EL results in a physical interaction between Bim-EL, LC8, and Beclin-1 and prevents Bim-EL from localizing to the mitochondria and promoting cell death. Mutation of the serine 59 site results in increased cell death and a diminished capacity to form a protein complex with LC8 and Beclin-1. Bim-EL knockdown also rescued ECM-detachment-induced death in IBC cells, suggesting Bim-EL is necessary for the induction of anoikis in IBC cells. Interestingly, Bim-EL levels were found to be elevated in ECM-detached IBC cells and present in a significant percentage of IBC patient samples, despite their evasion of anoikis. Therefore, the sequestration of Bim-EL away the mitochondria provides a compelling rationale for how IBC cells survive in the presence of high Bim-EL levels. Furthermore, this mechanism provides a unique and novel opportunity for chemotherapeutic approaches aimed at freeing the already elevated Bim-EL levels from sequestration to specifically induce cell death in IBC cells.
Citation Format: Cassandra Buchheit, Brittany Angarola, Allison Steiner, Kelsey Weigel, Zachary Schafer. Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration. [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 1268. doi:10.1158/1538-7445.AM2015-1268
Abstract 1269: Role of ribosomal protein, Rpl22 in regulating leukemic transformation
Authors: Patel Nehal Solanki , Kushnir Noa Greenberg , Rao Shuyun , Peri Suraj , Rhodes Michele , Nagahawatte Panduka , Mullighan Charles , Wiest David L. 
Published: August 2015

Abstract
Inactivation of ribosomal proteins (RP) is known to cause diseases called ribosomopathies, which are often associated with abnormal hematopoiesis and an increased risk for development of leukemia. Our laboratory has recently reported an important link between inactivation of one such ribosomal protein, Rpl22, and poor survival in T cell acute lymphoblastic leukemia (T-ALL) patients. Preliminary bioinformatic analysis shows that RPL22 is lost in ∼10% of pediatric T-ALL patients, who exhibit a more aggressive disease course. Deletion of the RPL22 locus is also enriched in the early T-cell precursor (ETP-ALL) subset of T-ALL patients, which exhibit a more aggressive disease course. Thus, RPL22 loss appears to be a marker for poor outcome in pediatric T-ALL patients. While RP inactivation has previously been linked to increased cancer risk, the mechanistic basis for this linkage remained unclear. We have recently demonstrated that inactivation of Rpl22 promotes leukemic transformation by activating NF-κB and inducing the stem cell gene, LIN28B. Nevertheless, the molecular link between Rpl22 inactivation and the induction of NF-κB activity remained unclear. We have now determined that inactivation of Rpl22 activates NF-κB signaling by exacerbating ER stress responses. Indeed, Rpl22 loss results in hyperactivation of the PERK-EIF2a-ATF4 stress pathway, which is known to activate NF-κB. We have demonstrated that knockdown of PERK using shRNA abrogates the activation of NF-κB in Rpl22 mutant cells and returns Lin28B expression levels to baseline. This reduction in Lin28B eliminates the predisposition to transformation exhibited by Rpl22 mutant cells, as evidenced by decreased formation of colonies in soft agar. Taken together, these data suggest that RPL22 inactivation may serve as a negative prognostic indicator in T-ALL and that pharmacologic targeting of ER stress pathways may represent a novel therapeutic alternative in this molecularly-defined subclass of T-ALL.
Citation Format: Nehal Solanki Patel, Noa Greenberg Kushnir, Shuyun Rao, Suraj Peri, Michele Rhodes, Panduka Nagahawatte, Charles Mullighan, David L. Wiest. Role of ribosomal protein, Rpl22 in regulating leukemic transformation. [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 1269. doi:10.1158/1538-7445.AM2015-1269
Abstract 1271: MDM2 small molecule inhibitors synergize with chemotherapeutics to attenuate senescence-driven inflammatory secretion
Authors: Schaum Nicholas , Almirah Fatouma , Scott Gary , Benz Christopher , Campisi Judith , Davalos Albert R. 
Published: August 2015

Abstract
An attractive therapeutic approach for treatment of cancers with wild-type (wt) p53 is the emergent class of small molecule MDM2 inhibitors, including the imidazoline nutlin-3 and more potent spiro-oxindole MI-63. Both compounds rapidly increase intracellular wt p53 levels and induce apoptosis or a senescence growth arrest, depending on the target cell. A critical question in the clinical development of MDM2 inhibitors is their potential for normal tissue toxicity owing to their ability to cause p53-dependent apoptosis or cellular senescence. Recent work suggest senescent cells exhibit a senescence-associated secretory phenotype (SASP) that can stimulate cancer progression. We critically examined the effect of MDM2 small molecule inhibitors Nutlin-3a and MI-63 on non-senescent and senescent cells. Both compounds caused normal cells to undergo a transient growth arrest. Continuous incubation with MDM2 small molecule inhibitors caused normal cells to exhibit some hallmarks of senescence (arrested growth, SA-β-Gal expression and secretion of High Mobility Group Box 1 protein), but the cells resumed growth upon removal of the MDM2 inhibitors. Senescent cells cultured with MDM2 inhibitors failed to resume growth upon removal of the compounds, as expected. However, their SASP was markedly dampened, as determined by multiplex ELISA assays. Since NF-κB and IL-1α are major drivers of the SASP, we examined their status in senescent cells cultured with MDMD2 inhibitors. The small molecule MDM2 inhibitors significantly reduced NF-κB activity and IL-1α mRNA expression in senescent cells. Our data suggest using combinatorial therapy of chemotherapeutics or irradiation and MDMD2 small molecule inhibitors may provide a potent therapeutic strategy to promote apoptosis of p53 positive tumor cells after radio- or chemo-therapy and attenuate the potentially deleterious effects of the SASP.
Citation Format: Nicholas Schaum, Fatouma Almirah, Gary Scott, Christopher Benz, Judith Campisi, Albert R. Davalos. MDM2 small molecule inhibitors synergize with chemotherapeutics to attenuate senescence-driven inflammatory secretion. [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 1271. doi:10.1158/1538-7445.AM2015-1271
Abstract 1273: Relation between tumor-associated macrophage (TAM) subsets and CD47 expression on squamous cell carcinoma of the head and neck (SCCHN) in tumor microenvironment
Authors: Sakakura Koichi , Takahashi Hideyuki , Chikamatsu Kazuaki 
Published: August 2015

Abstract
Introduction: In general, TAM is classified into M1 producing Th1 cytokines and M2 secreting IL-10. Numerous reports have demonstrated that M2 infiltration to tumor microenvironment associates with local immunosuppression and proliferation of cancer cells. In this study, we investigated phagocytic potentials of M1 and M2 in SCCHN in relation to the expression of CD47 molecule, which is known as “Don't eat me” signal against macrophage (Mϕ).
Material and Methods: CD68 (pan-Mϕ marker) positive CD163 (M2 marker) negative M1 (derived with GM-CSF and IFN-γ) and CD68+CD163+M2 (derived with M-CSF and IL-10) were induced from positively selected CD14+ cells in PBMC from a healthy donor. Phagocytosis of CD47+/CD47-SCCHN cell lines labeled with CFSE by M1/M2 were assessed using multi-color flow cytometry. Suppressions of the phagocytosis by neutralizing anti-CD47 antibody were also evaluated. Furthermore, we examined CD68, CD163 and CD47 expressions immunohistochemically in 74 cases of oral squamous cell carcinoma, and relation between Mϕ counts or CD47 expression on cancer cells and clinicopathological parameters or prognoses.
Results: M1 derived from PBMC showed higher phagocytic potential comparing to M2. Phagocytosis of M1 was dose-dependently inhibited by anti-CD47 neutralizing antibody, however M2 phagocytosis was not suppressed. In immunohistochemical analysis, while CD47 was expressed in almost half cases of oral cancer, CD47 expression did not correlate to the numbers of total Mϕ nor M2. Patients with high CD47 expression on cancer cells, increasing number of total Mϕ or M2 showed significantly shorter overall survival.
Conclusion: Only M1 showed CD47-dependent phagocytosis of CD47-expressed cancer cells in vitro. While CD47 expression on patient samples did not correlate with number of total Mϕ or M2, each of them independently showed significant association with prognosis. Various mechanisms were presumed between CD47 expression on SCCHN cells and tumor-infiltrating Mϕ subsets.
Citation Format: Koichi Sakakura, Hideyuki Takahashi, Kazuaki Chikamatsu. Relation between tumor-associated macrophage (TAM) subsets and CD47 expression on squamous cell carcinoma of the head and neck (SCCHN) in tumor microenvironment. [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 1273. doi:10.1158/1538-7445.AM2015-1273
Abstract 128: Tyrosine 823 in the activation loop of c-Kit regulates the transforming capacity of the oncogenic mutant D816V and its sensitivity to kinase inhibitors
Authors: Agarwal Shruti , Kazi Julhash U. , Mohlin Sofie , Påhlman Sven , Rönnstrand Lars 
Published: August 2015

Abstract
Oncogenic mutations in c-Kit have been shown to lead to ligand-independent receptor activation and contribute to transformation. A substitution of an aspartate for a valine at position 816 (D816V) is one of the most commonly found oncogenic c-Kit mutation and is found in more than 90% of cases of mastocytosis and in a subgroup of germ cell tumors, core-binding factor acute myeloid leukemia and mucosal melanomas. Previous studies have shown that the D816V mutation causes a structural change in the activation loop resulting in weaker binding of the activation loop to the juxtamembrane domain, leading to a release of the negative constraint it poses on kinase activity. Here we have investigated the role of Y823 in the activation loop of c-Kit and its role in oncogenic transformation by c-Kit/D816V. Although dispensable for the kinase activity of c-Kit/D816V, the presence of Y823 was shown to be crucial for cell proliferation and survival. Furthermore, mutation of Y823 selectively down-regulated the Ras/Erk and Akt pathways. It also led to decreased phosphorylation of STAT5 and reduced the transforming capacity of D816V/c-Kit in vitro. The sensitivity to kinase inhibitors, such as dasatinib and nilotinib, was decreased in cells expressing c-Kit/Y823F/D816V compared to cells c-Kit/D816V. Mice injected with cells expressing c-Kit/D816V/Y823F displayed significantly reduced tumor size as well as tumor weight compared to controls. Finally, microarray array analysis, comparing c-Kit/Y823F/D816V cells with cells expressing c-Kit/D816V, demonstrate that mutation of Y823 causes up-regulation of pro-apoptotic genes whereas genes of survival pathways are down-regulated. Thus, phosphorylation of Y823 is not necessary for kinase activation, but essential for the transforming ability of the c-Kit/D816V mutant.
Citation Format: Shruti Agarwal, Julhash U. Kazi, Sofie Mohlin, Sven Påhlman, Lars Rönnstrand. Tyrosine 823 in the activation loop of c-Kit regulates the transforming capacity of the oncogenic mutant D816V and its sensitivity to kinase inhibitors. [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 128. doi:10.1158/1538-7445.AM2015-128
Abstract 1283: In situ activity of tumor specific CTL is a prognostic factor in colorectal cancer
Authors: Stamova Slava , Reissfelder Christoph , Gossmann Christina , Braun Marion , Bonertz Andreas , Walliczek Ute , Koch Moritz , Benner Axel , Jäger Dirk , Halama Niels , Khazaie Khashayarsha , Weitz Jürgen , Beckhove Philipp 
Published: August 2015

Abstract
The extent of T cell infiltrates in the primary tumor is one of the most important prognostic factors in colorectal cancer (CRC). Still, a putative causal role of T cell infiltrates for prolonged patient survival remains unclear. To answer this question, we studied the presence and functional activity of tumor infiltrating lymphocytes (TIL) together with their specificity in CRC patients and correlated the obtained results to long term survival.
We have utilized intracytoplasmic cytokine staining, conjointly with human leukocyte antigen (HLA)- multimers loaded with peptides derived from tumor antigen (TA), as well as antigen specific cytokine secretion assays, to demonstrate that tumor necrosis factor alpha (TNFα) expression characterizes a population of TA specific, in situ active cytotoxic T cells. TNFα was increased in CRC tumors only when patients develop spontaneous systemic T cell responses, as elucidated by IFN-γ Elispot, and this increase correlated with the number of TNFα expressing tumor infiltrating T cells. Based on these observations we concluded that intratumoral TNFα can be a direct indicator of the in situ functionality of tumor specific effector T cells in CRC.
In accordance, intratumoral TNFα concentration was an independent long term prognostic factor in a retrospective multivariate analysis of a cohort of 102 CRC patients involving various other immune parameters, such as CD4+, CD8+ T cell infiltration, presence of regulatory T cells or mast cells.
In conclusion, our findings provide evidence for a causal relationship between T cell infiltrates and improved survival in CRC patients as the prognostic impact of T cell infiltrates depends on small subpopulations of in situ active TA specific T cells. Furthermore TNFα, as an indicator for the functionality of TIL, might be better and more accurate prognostic parameter in CRC than mere T cell infiltration.
Citation Format: Slava Stamova, Christoph Reissfelder, Christina Gossmann, Marion Braun, Andreas Bonertz, Ute Walliczek, Moritz Koch, Axel Benner, Dirk Jäger, Niels Halama, Khashayarsha Khazaie, Jürgen Weitz, Philipp Beckhove. In situ activity of tumor specific CTL is a prognostic factor in colorectal 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 1283. doi:10.1158/1538-7445.AM2015-1283
Abstract 1288: Does an increased underlying immune/inflammatory response in healthy females put them at a higher risk for thyroid cancer
Authors: Singh Karnika , Jones Melanie , Moscatello Augustine , Shin Edward , Tiwari Raj , Geliebter Jan 
Published: August 2015

Abstract
The SEER (Surveillance, Epidemiology, and End Results Program) and American Cancer Society data indicate that the incidence of papillary thyroid cancer is ∼ 3 times greater in females, as compared to males. The American Cancer Society estimates that out of a total of ∼62,980 new thyroid cancer cases in 2014, approximately 47,790 of these will be women. There is strong evidence that supports the role of estrogen in the pathogenesis of thyroid cancer. Estrogen also plays a critical role in the inflammatory process. For example, mouse models have demonstrated that in vivo exposure to estrogen promotes an inflammatory response, including the enhanced secretion of Th-1 related cytokines (IFNγ, IL-12, IL-1β) and inflammatory chemokines (MCP-1 and MCP-5). Studies in rats and mouse models have shown that females exhibit stronger humoral and cellular immune responses as compared to males. As the association between inflammation and cancer is widely accepted, we hypothesize that an underlying immune and inflammatory response in the normal female thyroid puts it at a higher risk of developing cancer. The Cancer Genome Atlas (TCGA) provides a means to assess gender differences at the molecular level. Using the SUBIO platform version 1.17 (SUBIO Inc., Amami Island, Japan), we performed bioinformatics and statistical analyses on the Level 3 RNA-Seq data available in the TCGA Data Portal. Differential gene expression analysis of 39 normal thyroid samples (26 females and 13 males) revealed that out of the 20,531 genes analyzed, 73 genes exhibited &gt;2 fold increased expression in females vs. males (p-value, 0.05). Of these 73 genes, 10 genes were involved in immune response and inflammation. We are currently analyzing expression levels of these genes on the RNA and protein levels. Such analysis will help us to elucidate a possible link between the gender disparity in thyroid cancer and inflammation.
Citation Format: Karnika Singh, Melanie Jones, Augustine Moscatello, Edward Shin, Raj Tiwari, Jan Geliebter. Does an increased underlying immune/inflammatory response in healthy females put them at a higher risk for thyroid 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 1288. doi:10.1158/1538-7445.AM2015-1288