bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY17-03: Inferring cell death networks from biochemical data
Authors: Sorger Peter K. , Spencer Sabrina , Gaudet Suzanne , Aldridge Bree , Flusberg Deborah , Bachman John , Sims Josh 
Published: June 2012

Abstract
The responses of cells to extracellular ligands results in a series of complex spatiotemporal changes in protein levels and state that vary considerably from one cell to the next. I will discuss our attempts to understand the biochemical mechanisms underlying these phenomena with a focus on TRAIL and Fas ligand in human tumor cells. These molecules are prototypical inducers of receptor-mediated (extrinsic) apoptosis and TRAIL is a first-in-class investigational therapeutic. I will discuss the development and application of computational methods for constructing, managing, calibrating and validating detailed kinetic models of core apoptotic process. With these methods we aim to go beyond the informal pictorial models that currently dominating molecular biology and create probabilistic mathematical constructs that assign rigorous “degrees of belief” to specific biochemical hypothesis given prior knowledge and a specific set of empirical data.
I will discuss why some TRAIL-treated human cells die within ∼40 min, some only after 12 hr and yet others live indefinitely. We have explored three explanations for these differences: (i) genetic or epigenetic variation (ii) the involvement of one or more biochemical processes subject to stochastic fluctuation (iii) transient but deterministic differences in cell state. I will illustrate how all three interact on different time scales to determine those aspects of cellular physiology that are highly invariant and those that are variable and I will present a modeling framework for understanding the impact of specific protein factors in cell-to-cell variability. A key conclusion from this work is that variability in the responses of cells to drugs is inherent to the stochastic operation of the biochemical pathways that anti-cancer drugs target. Fractional killing is one inevitable consequence.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY17-03. doi:10.1158/1538-7445.AM2011-SY17-03
Abstract SY19-02: Role of the Tim-3 and PD-1 pathways in T cell exhaustion and antitumor immunity
Authors: Anderson Ana C. 
Published: June 2012

Abstract
The immune response plays an important role in fighting cancer; however, mechanisms of immune suppression in tumor-bearing hosts hinder productive antitumor immunity. T cell dysfunction or exhaustion is one such mechanism. PD-1 has been identified as a marker of dysfunctional or exhausted T cells in chronic disease states and blockade of PD-1/PD-1L interactions has been shown to partially restore T cell function. Recently, Tim-3 has also been identified as a marker of exhausted T cells. We have found that Tim-3 is expressed on both CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) in mice bearing solid tumors (4T1, CT26, and B16). All CD8+ Tim-3+ TILs co-express PD-1 and Tim-3+PD-1+ TILs represent a predominant fraction of the CD8+ T cells infiltrating tumors. CD8+Tim-3+PD-1+ TILs exhibit the most severe exhausted phenotype as defined by failure to proliferate, produce IL-2, TNFα and IFNγ. We have further found that combined immunotherapeutic targeting of the Tim-3 and PD-1 pathways is more effective in controlling tumor growth than targeting either pathway alone. Indeed, 50% of the mice receiving combination immunotherapy exhibited complete tumor regression. We have examined whether combined targeting of Tim-3 and PD-1 restores effector function to TILs and have found that culture of TILs in vitro in the presence of anti-Tim-3 plus anti-PD-L1 antibodies augments IFNγ production. In addition, T cells isolated from the tumor-draining lymph nodes of mice treated in vivo with anti-Tim-3 and anti-PD-L1 antibodies exhibit restored tumor antigen-specific T cell responses compared to those isolated from mice treated with control immunoglobulins. Collectively, our data support that combined targeting of the Tim-3 and PD-1 signaling pathways is highly effective in restoring antitumor immunity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY19-02. doi:10.1158/1538-7445.AM2011-SY19-02
Abstract SY23-01: Early endosomes: Platforms for the induction of oncogenic phenotypes
Authors: D'Souza-Schorey Crislyn 
Published: June 2012

Abstract
Oncogenic signaling markedly impacts the adhesive and migratory potential of tumor cells. Many of the resulting cellular changes are elicited by coordinated alterations in endosomal membrane trafficking. Although long regarded as a means for cells to internalize nutrients and cell surface molecules, emerging evidence suggests that the endosomal circuitry is also an essential platform for signal transduction and a conduit for the transport of cellular machinery, including adhesion proteins and signaling molecules, appropriate compartmentalization of which appears to be essential for eliciting changes that accompany disease progression. The disruption of epithelial glandular architecture and the acquisition of aggressive invasive phenotypes, two hallmarks of tumor progression, exemplify the above paradigm. Our efforts are directed at elucidating and defining the role of ARF6-coupled endocytic pathways in the acquisition of migratory/invasive phenotypes. Recent work using three-dimensional basement membrane cultures of renal and mammary epithelial cells reveals that the formation of signaling endosomes during glandular cyst morphogenesis, serve as platforms for hyperactive receptor signaling leading to the disruption of epithelial cysts and generation of certain tumorigenic phenotypes. We are also investigating the structural and molecular changes at the invasive front of tumor cells. Our recent studies, and others, have shown that selective sorting of specific cargo such as the membrane-type proteases along early endocytic recycling pathways, is tightly coupled to the biogenesis and function of invasive structures such as invadopodia and microvesicles. Invadopodia are actin-rich protrusions that form at the adherent cell surface and mediate pericellular proteolysis. Microvesicles, generated by the outward budding and fission of the plasma membrane, facilitate the horizontal transfer of bioactive molecules and are now thought to have vital roles in tumor invasion and metastasis, inflammation and stem-cell expansion. Since endosomes confer spatial and temporal dimensions to oncogenic signaling, understanding the interplay between endocytic trafficking and the activation of invasive cell programs could provide new and important insights into the progression toward pathophysiological states.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY23-01. doi:10.1158/1538-7445.AM2011-SY23-01
Abstract SY25-01: Functional genomics, transformation, and resistance
Authors: Hahn William C. 
Published: June 2012

Abstract
Recent advances in genomics now make it possible to consider enumerating all of the genetic lesions in specific cancers. While these approaches will yield critical information regarding the identify, number, and types of alterations found in human tumors, a complementary approach to decipher the molecular basis of malignant transformation depends upon the application of genome scale tools to annotate the function of genes involved in cancer initiation and progression. Over the past several years, we have developed genome scale RNAi libraries and open reading frame expression libraries that permit a systematic evaluation of genes involved in cancer initiation and maintenance. Using these libraries, we have now performed screens in a panel of human cancer cell lines to systematically identify cancer vulnerabilities. By combining these functional approaches with information derived from mapping the structural abnormalities present in cancer genomes, we have identified several new oncogenes that contribute to cancer development. In addition, many commonly occurring and well-validated oncogenes and tumor suppressor genes remain refractory to molecularly targeted therapies. An alternative strategy for targeting such cancer drivers is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Through the use of systematic RNAi screens, we have identified several genes that act as synthetic lethal partners to known oncogenes. Taken together, these studies suggest that combining forward and reverse genetic approaches with information derived from the cancer genome characterization projects will yield a comprehensive list of cancer vulnerabilities and establish a general approach for the rational identification of oncogenic and co-dependent pathways in cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY25-01. doi:10.1158/1538-7445.AM2011-SY25-01
Abstract SY27-01: Colon commensals and cancer
Authors: Sears Cynthia L. 
Published: June 2012

Abstract
A clear intersection between the infectious diseases and oncology fields has emerged from our understanding that many cancers arise in the setting of chronic infection. Roughly one-third of cancers worldwide, particularly epithelial cancers, are associated with identified single microbial infections, leading to the conceptual paradigm that chronic infection with specific microbes cause these cancers independent of other components of the ambient microbial community. Among epithelial cancers, colon cancer is the second leading cancer killer of adults in the United States but specific microbial contributors have not yet been identified. Rather, we now understand that the colon is home to one of the most dense and diverse communities of bacteria in the body and that we are each remarkably unique in our bacterial makeup, reinforcing the contrasting view that the microbial contribution to colon cancer pathogenesis may lie in the composition of the colon microbiome. This talk will explore the scientific data supporting differing paradigms for how the colonic flora may contribute to colon oncogenesis. Specific, usually commensal, members of the colonic microbiome and the mechanisms by which they may initiate and/or promote colon tumors with be discussed with a particular emphasis on enterotoxigenic Bacteroides fragilis (ETBF). B. fragilis not only colonizes most humans but is the leading anaerobe in human disease. ETBF is a molecular subset of B. fragilis distinguished by secretion of a zinc-dependent metalloprotease toxin. In murine models, ETBF is a potent inducer of colonic tumors. Tumor induction by ETBF is dependent, in part, on a specific host immune response involving IL-17-producing CD3+CD4+ T cells. A framework for utilizing this knowledge to better understand the pathogenesis of colon cancer and to develop new approaches to colon cancer prevention and/or therapy will be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY27-01. doi:10.1158/1538-7445.AM2011-SY27-01
Abstract A10: L1236, a Hodgkin and Reed-Sternberg cell line, stimulates monocytes in vitro to differentiate into M2-like macrophages
Authors: Lee Kim Yee , Chong Siew Meng , Lim Yaw Chyn 
Published: June 2012

Abstract
The microenvironment of classical Hodgkin lymphoma (cHL) is characterized by a small number of malignant Hodgkin and Reed-Sternberg (HRS) cells embedded in a background rich with infiltrating immune cells. HRS cells and the surrounding cellular infiltrates are believed to produce soluble and membrane-bound factors that are essential for the survival and proliferation of HRS cells. Steidl et al (2010) have reported that an increase in the number of tumor associated macrophages in cHL correlates with poor prognosis. However, little is known about the molecular crosstalk between macrophages and HRS cells in cHL. This study aims to examine in-vitro the influence of HRS cells on monocyte activation and differentiation.
Freshly isolated human monocytes were co-cultured with L1236 cells, a HRS cell-line, under standard culture conditions. At the end of 8 days in culture, we examined the influence of HRS cells on monocyte survival and differentiation. In addition, we determined the activation and differentiation status of the co-cultured monocyte by assessing the cells for CD206 and IL-10 expression. The role of IL-4Rα and Macrophage colony-stimulating factor (M-CSF) receptor on HRS cell-induced monocyte differentiation was examined using antibody blocking assay. We also examined consented cHL patient samples for the presence of CD206/CD68 double positive macrophages by immunofluorescent staining.
Our data showed that L1236 cells are able to enhance the survival of monocytes in vitro. In the presence of L1236 cells, monocytes differentiated into alternatively activated, M2-like macrophages which expressed CD206 and IL-10. The observed enhanced survival, and differentiation to M2-like macrophages, was mediated by soluble factors secreted by the L1236 cells. The survival of co-cultured monocytes is enhanced by signalling through the M-CSF receptor. In contrast, the differentiation to M2-like macrophages is in part, regulated by signals generated via IL-4Rα. Finally, the presence of CD68/CD206 double positive macrophages was detected in three out of four cHL patient samples.
We conclude that HRS cells secrete soluble factors that can in vitro directly modulate monocyte survival and differentiation to a CD206+ M2 macrophage phenotype.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A10.
Abstract A12: AmotL2 linking hypoxia to invasion
Authors: Mojallal Mahdi , Zheng Yujuan , Hultin Sara , Holmgren Lars 
Published: June 2012

Abstract
Hypoxia has been shown to be a bad prognostic marker correlating with metastasis and poor survival. Furthermore, in response to antiangiogenic therapy hypoxic tumor cells become invasive and form metastasis. Malignant tumor cells undergo epithelial-mesenchymal transition (EMT) and become depolarized. A protein important for apicobasal polarity during tumor progression is Crumbs3 (crb3). Silencing of Crumbs3 disrupts epithelial cell polarity and possibly promotes metastasis. AmotL2, a gene regulated by hypoxia, associates to the Crb3/Pals/Patj polarity complex via its PDZ-binding motif (unpublished data).
Here we show that AmotL2 disrupts apicobasal polarity resulting in the development of an invasive phenotype.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A12.
Abstract A3: p53-dependent release of alarmin HMGB1 is a central mediator of senescent phenotypes
Authors: Davalos Albert R. , Kawahara Misako , Malhotra Gautam K. , Huang Jiahao , Ved Urvi , Rodier Francis , Beausejour Christian , Coppe Jean Philippe , Campisi Judith 
Published: June 2012

Abstract
Cellular senescence irreversibly arrests the proliferation of cells at risk for malignant transformation in part through activities of the transcriptional regulator and tumor suppressor p53. Cells that senesce owing to DNA damage also secrete many biologically active factors, including inflammatory cytokines such as IL-6. Some data suggest that the senescence associated secretory phenotype (SASP) creates a tumor permissive environment. However, we find that senescent cells secrete a potent bioactive molecule—High Mobility Group Box 1 (HMGB1) protein, which is unusual in having two distinct functions. Intracellularly, it binds chromatin and modulates transcription, including stimulating p53 activity. In addition, necrosis or microbial infection causes HMGB1 leakage or active secretion, respectively, whereupon it functions as an extracellular alarmin to signal tissue damage and promote tissue regeneration, stem cell recruitment and immune activation. We show that HMGB1 is largely nuclear in non-senescent human and mouse fibroblasts and epithelial cells, but is actively exported from the nucleus and secreted by senescent cells. In culture and in vivo, HMGB1 re-localization occurred prior to the appearance of other hallmarks of senescence, and depended on the function of p53, but not the upstream p53 activator ATM, which distinguished HMGB1 secretion from the SASP. Aged mice or human sera contained significantly higher levels of circulating HMGB1 compared to sera from young mice or human subjects. Disruption of HMGB1 stoichiometry, either by overexpression or depletion, induced a p53-dependent senescence growth arrest, but only HMGB1 overexpression, not HMGB1 depletion, promoted IL-6 secretion. Senescence-associated secretion required endogenous and secreted HMGB1 because deletion of endogenous HMGB1— or addition of an HMGB1 blocking antibody – attenuated IL-6 secretion. Recombinant HMGB1 protein induced IL-6 secretion in cells depleted, but not harboring, endogenous HMGB1. Depletion of endogenous HMGB1 promoted NF-κ B transcriptional activity in cells cultured with recombinant HMGB1. Our findings identify a novel biological setting (senescence), independent of necrosis or microbial infection, in which HMGB1 secretion occurs in vitro and in vivo, and link senescence-dependent HMGB1 redistribution to p53 activity and inflammatory cytokine secretion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A3.
Abstract A33: A whole genome RNAi screen identifies BRD7 and BAF180 as p53 regulators required for senescence
Authors: Burrows Anna E. , Smogorzewska Agata , Elledge Stephen J. 
Published: June 2012

Abstract
Multiple tumor-suppressor mechanisms exist to promote genomic stability. One such mechanism is cellular senescence. In response to DNA damage and oncogenic stimuli, the senescence program, including the p53 and Rb pathways, is activated to prevent the proliferation of damaged cells and their potential oncogenic transformation.
We are performing a pooled whole genome shRNA screen in primary human fibroblasts to identify novel components of the senescence machinery. In addition to many known senescence regulators including cell cycle and DNA damage response factors, we have also uncovered many genes of unknown function. From this screen we have identified SWI/SNF components BRD7 and BAF180 as novel regulators of replicative and oncogene-induced senescence.
Both BRD7 and BAF180 are required for p53 transcriptional activity toward a subset of target genes including p21, and BRD7 physically interacts with p53. Overexpression of BRD7 induces premature senescence and p21 expression, highlighting its regulatory role in this pathway. We also show that BRD7 is required for expression of p21 in p53-independent contexts, such as in response to TGF-β and 1α,25(OH)2D3 (vitamin D) in epithelial cells. Lastly, BRD7 and BAF180 are deletion targets in human cancer, suggesting that their loss may provide additional mechanisms to antagonize p53 function in cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A33.
Abstract A4: Hodgkin and Reed-Sternberg cells secrete soluble factors to modulate endothelial cell-T cell interactions in classical Hodgkin lymphoma
Authors: Fhu Chee Wai , Chong Siew Meng , Yap Celestial , Graham Anne , Lim Yaw Chyn 
Published: June 2012

Abstract
Introduction: Classical Hodgkin lymphoma (CHL) is characterized by the presence of a minority of malignant Hodgkin and Reed-Sternberg cells (H-RS cells) surrounded by an abundant mixed inflammatory infiltrate that includes CD4+ T helper 2 cells, regulatory T cells and CD8+ cytotoxic T cells. The mechanisms exploited by HRS cells to influence T cell recruitment into the involved lymph nodes are still unknown.
Objective: The aim of this study is to elucidate whether H-RS cells can induce endothelial cell activation to modulate T cell recruitment in CHL.
Procedures: Fresh cell culture supernatant (C/S) from the H-RS cell line, KM-H2, was used to stimulate endothelial cells (EC) in-vitro. Controls were EC incubated in medium alone; or with 10ng/ml TNF-α Up-regulation of adhesion molecule expression was assessed by ELISA and FACS. Using the transwell migration system and the parallel plate flow chamber apparatus respectivel, the ability of these stimulated EC to support T cell interactions in-vitro was assessed under static and defined flow conditions. Signaling pathways involved in C/S induced EC activation were examined by western blotting.
Results: KM-H2 C/S-stimulated EC up-regulate ICAM-1, VCAM-1 and E-selectin to levels comparable to those of TNF-α-stimulated EC. Both C/S-stimulated EC and TNF-α stimulated-EC support naïve and memory T-cell interactions under defined flow conditions. Furthermore, both CD4+ naïve and memory T cell demonstrated enhanced transmigration across C/S-stimulated EC monolayers in response to SDF-1α, as compared to TNF-α-stimulated or unstimulated EC.
The activation of EC by KM-H2 C/S is dependent on the NFkB pathway. Blocking of p65 nuclear translocation by the specific IκBα phosphorylation inhibitor (BAY11-8075) abrogated the stimulatory effect of C/S on EC. Phosphorylation of ERK, p38 and JNK were also detected in the KM-H2 C/S stimulated EC. Intracytoplasmic expression of TNF-α was detected in KM-H2 cells.
The bioactivity assay showed that the TNF-α sensitive cell line, L929 is sensitive to KM-H2 C/S. However, treatment of cells with TNF-α neutralizing antibody did not effectively prevent L929 cell death, nor inhibit the stimulatory effect of KM-H2 C/S on EC.
Conclusion: Our data suggest that the malignant Hodgkin and Reed-Sternberg cells secrete soluble mediators that modulate endothelial cell function and influence recruitment of T cells into the cHL lesion. While the C/S induced EC activation is dependent on the NFkB pathway, our data suggest that the dominant mediator involved is not TNF-α.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A4.