bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4974: IL-1 receptor-associated kinase-1 and -4 expression in Hodgkin lymphoma
Authors: Giffi Victoria S. , Younger Kenisha M. , Singh Zeba , Chen Qing , Davila Eduardo , Kimball Amy S. 
Published: August 2015

Abstract
BACKGROUND: The Toll-like receptor (TLR) mediates nuclear factor kappa B (NFkB) activation in lymphocytes using a family of intermediary proteins called IL-1 receptor associated kinase (IRAK). Mutations within and upregulation of this pathway have been described in the carcinogenesis of non-Hodgkin lymphoma (NHL), but it is not known whether IRAK proteins are present in Hodgkin lymphoma (HL). Furthermore, Epstein-Barr virus (EBV) has been shown to activate NFkB in HL but its association with proteins upstream of NFkB is not described.
METHODS: 1. We performed Western blots on two Hodgkin Reed-Sternberg (HRS) cell lines to detect total IRAK-1 and -4, and phospho-IRAK-1 and -4 (the activated forms). 2. Archived lymph node biopsy samples from Hodgkin lymphoma patients diagnosed at the University of Maryland were stained for IRAK-4.
RESULTS: 1. IRAK-1, IRAK-4, p-IRAK-1 and p-IRAK-4 were present in the malignant HRS cells in two HRS cell lines (HDLM-2 and KM-H2). 2. Seventeen lymph node biopsy samples showed marked positivity for IRAK-4 (mean of 2.3 on a 0-4 scale), as well as lesser positivity in surrounding reactive lymphocytes and histiocytes (mean of 1.6). The only sample to achieve a staining level of 4 was of mixed cellularity subtype, and was EBER-positive and HIV-negative.
CONCLUSIONS: The IRAK proteins are present in the malignant HRS cells of Hodgkin lymphoma. Further work will examine IRAK-1, and phospho-IRAK-1 and -4 in the lymph node samples. Future studies should also examine whether IRAK causes downstream NFkB activation in HL as it does in NHL, and whether HRS cells depend on IRAK's presence for survival. A possible association with EBV infection will also be investigated. IRAK is a targetable protein with inhibitors available, so this and future studies may reveal new therapeutic strategies in relapsed Hodgkin lymphoma.
Citation Format: Victoria S. Giffi, Kenisha M. Younger, Zeba Singh, Qing Chen, Eduardo Davila, Amy S. Kimball. IL-1 receptor-associated kinase-1 and -4 expression in Hodgkin 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 4974. doi:10.1158/1538-7445.AM2015-4974
Abstract 4976: Inhibition of eIF4B suppresses the growth and induces the apoptosis of Bcr-Abl positive cells
Authors: Chen Ke , Yang Jian-Ling , Guo Guijie , Chen Jilong 
Published: August 2015

Abstract
Alterations in translation are associated with various human malignancies, but the precise pathogenic processes and mechanistic underpinnings remain to be better understood. The oncogenic tyrosin kinase Bcr-Abl, which is believed to induce chronic myelogenous leukemia (CML), could cause the dysregulation of mRNA translation initiation by activating a series of signal pathways. Eukaryotic initiation factor 4B (eIF4B), a critical element in the assembly of translation initiation complex, has been shown to anticipate in Bcr-Abl-mediated tumorigenesis. eIF4B is activated through Ser422 phosphorylation by several pathways including JAK/STAT/Pim and PI3K/AKT/mTOR. Such redundant activation provides mechanistic bases for the less potent antitumor consequences under single-pathway targeted therapy. Interestingly, profound synergy was observed against cell survival and tumor growth and greater decrease of eIF4B Ser422 phosphorylation was detected upon the combination of Pim and mTOR inhibitors. Knockdown of eIF4B would increase the dependence of Bcr-Abl positive cells on Pim and mTOR signaling and then sensitize cells to the synergistical effect mediated by the combined inhibition. In addition, inhibiting mTOR pathway by shRNA targeting AKT or mTOR renders cells dependent on Pim pathway and knockdown Pim1 would sensitize cells to mTOR inhibitor. Thus, eIF4B acts as a prominent role in Bcr-Abl-driven pathogenesis by playing as the convergent point of these pathways which are active in Bcr-Abl positive tumors. Our results reveal a novel mechanism by which Bcr-Abl-induced cellular transformation can be blokced and provides a rationale for combination therapy targeting the dysregulation of translation for CML.
Note: This abstract was not presented at the meeting.
Citation Format: Ke Chen, Jian-Ling Yang, Guijie Guo, Jilong Chen. Inhibition of eIF4B suppresses the growth and induces the apoptosis of Bcr-Abl positive 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 4976. doi:10.1158/1538-7445.AM2015-4976
Abstract 4986: Distinct temporal regulation of RET isoform internalization: Roles of clathrin and AP2
Authors: Crupi Mathieu Joseph François , Yoganathan Piriya , Bone Leslie N. , Lian Eric , Fetz Andrew , Antonescu Costin N. , Mulligan Lois M. 
Published: August 2015

Abstract
The RET receptor tyrosine kinase is an important contributor to kidney and enteric nervous system development. In normal development, RET signaling regulates cell proliferation, migration, survival and differentiation, but RET is also implicated in growth and spread of several human cancers. Activating mutations of RET are drivers of inherited and sporadic thyroid cancers, while expression of wildtype RET receptors in breast and pancreatic cancers has been associated with enhanced tumor invasion, metastasis and poor disease prognosis. RET is expressed as two major isoforms, RET9 and RET51, that have unique 9 or 51 amino acid C-terminal tails, respectively. These isoforms induce unique phosphorylation patterns on intracellular tyrosine residues, differentially bind downstream signalling proteins, and possess different intrinsic abilities to cause cellular transformation. We have previously shown that RET isoforms are internalized from the cell surface into endosomal compartments in response to glial cell line derived neurotrophic factor (GDNF) ligand stimulation, but the specific mechanisms of RET trafficking remain to be elucidated. Here, we used total internal reflection fluorescence microscopy to demonstrate that RET internalization occurs through clathrin coated pits (CCPs). Activated RET receptors colocalize with clathrin, but not caveolin, at sites of CCPs. The RET51 isoform is rapidly and robustly recruited to CCPs upon GDNF stimulation, while RET9 recruitment occurs more slowly and is less pronounced. We showed that the clathrin-associated adaptor protein complex 2 (AP2) is important for RET internalization. Our data establish that interactions with the AP2 complex promote RET receptor internalization via clathrin-mediated pathways but that RET9 and RET51 have distinct internalization kinetics that may contribute to the functional differences between RET isoforms which are critical to regulating RET's contribution to tumorigenesis and normal development. These data may also have clinical importance, as they characterize key regulatory events for an important oncogene that may in future indicate biologically relevant targets for therapeutic interventions in RET-associated tumors.
Citation Format: Mathieu Joseph François Crupi, Piriya Yoganathan, Leslie N. Bone, Eric Lian, Andrew Fetz, Costin N. Antonescu, Lois M. Mulligan. Distinct temporal regulation of RET isoform internalization: Roles of clathrin and AP2. [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 4986. doi:10.1158/1538-7445.AM2015-4986
Abstract 4990: The RET receptor Y791F variant activates the kinase but diminishes ligand responsiveness
Authors: Fetz Andrew , Crupi Mathieu J.F. , Lian Eric , Hyndman Brandy D. , Mulligan Lois M. 
Published: August 2015

Abstract
The RET receptor tyrosine kinase is essential for normal development of the kidneys and enteric nervous system, and is also implicated in several human pathologies. Gain-of-function mutations in RET are associated with the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN 2), where single amino acid substitutions lead to constitutive RET activation in the absence of its ligands of the glial cell line-derived neurotrophic factor (GDNF) family. Conversely, loss-of-function RET mutations are associated with Hirschsprung disease, a congenital abnormality of the enteric nervous system. Previous studies have identified a specific substitution variant of a phenylalanine for tyrosine at amino acid 791 in the RET kinase domain in both cancer and Hirschsprung disease patients. Thus, the functional implications of this variant and its contributions to these diverse phenotypes are not clear. Here, we have explored the role of MEN 2-associated RET mutations in RET-mediated cell invasion and migration. We showed that GDNF-stimulation promotes RET-mediated cell migration and that a GDNF-chemotactic gradient significantly increased invasion of cells expressing wild type RET or a MEN2B (M918T) mutant RET form. However, we found that a GDNF gradient did not enhance invasion of cells expressing RET-Y791F. Consistent with this, we showed that MEN 2-associated RET mutants M918T and Y791F were phosphorylated in the absence of GDNF and stimulated downstream signaling pathways. GDNF treatment further increased phosphorylation of the RET-M918T but not RET-Y791F proteins, suggesting that RET-Y791F has reduced responsiveness to GDNF ligand. Our results suggest that despite constitutive activation of RET signaling, cells expressing the Y791F variant may possess a diminished capacity to recognize and respond to GDNF in the cell microenvironment. This may be linked to a disturbance in the directional migration of cells expressing the mutant receptor thus contributing to the phenotypic variability observed.
Citation Format: Andrew Fetz, Mathieu J.F. Crupi, Eric Lian, Brandy D. Hyndman, Lois M. Mulligan. The RET receptor Y791F variant activates the kinase but diminishes ligand responsiveness. [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 4990. doi:10.1158/1538-7445.AM2015-4990
Abstract 4991: RET and integrins cooperate in cell-microenvironment response
Authors: Lian Eric , Crupi Mathieu J.F. , Cockburn Jessica G. , Wagner Simona M. , Goel Anirudh , Mulligan Lois M. 
Published: August 2015

Abstract
The RET receptor tyrosine kinase is expressed in neural crest-derived cell types, where it is activated by soluble ligands of the Glial Cell-derived Neurotrophic Factor (GDNF) family and signals through multiple downstream pathways, contributing to cell growth, survival, and migration during embryonic development. In addition to its normal developmental roles, oncogenic mutations or aberrant expression of RET are also linked to tumour spread and metastasis in multiple human tumour types. Thus, a consistent feature of RET involvement in these disease processes is its contribution to directional cell motility. We have previously shown that RET-mediated cell-adhesion and migration requires multiple members of the integrin family of cell adhesion molecules, including integrin β1 (ITGB1) and β3 (ITGB3) subunits, however the regulation of cell migration and invasion by RET and integrins has not been explored.
In this study, we showed that GDNF-mediated RET activation induced rapid ITGB1 and ITGB3 activation with transiently increased cell adhesion, followed by enhanced cell protrusion formation and reduced adhesion typical of more migratory cells. In addition, we showed that directional cell migration in response to GDNF requires the presence of both extracellular matrix and a GDNF concentration gradient. Our data also suggest that ITGB1 and ITGB3 play complementary but non-compensatory roles in the initiation of RET-mediated cell migration and invasion, and that the inhibition of either ITGB1 or ITGB3 resulted in impaired migration and invasion in both 2D and 3D culture conditions. We have also shown that multiple signaling pathways downstream of RET are involved in these processes and that these pathways contribute differently to migration in 2D vs 3D microenvironments. These data highlight the ability of tumour cells to leverage different signaling pathways to mediate cell migration and invasion downstream of RET, and reveal ways in which cooperation between RET and integrins might affect aspects of tumour progression. Our data, together with other studies which have shown combination therapy targeting integrins and RTKs to be more effective than monotherapy, suggest that adjuvant treatment with agents targeting integrin function may further enhance therapeutic options for tumours where RET is expressed.
Citation Format: Eric Lian, Mathieu J.F. Crupi, Jessica G. Cockburn, Simona M. Wagner, Anirudh Goel, Lois M. Mulligan. RET and integrins cooperate in cell-microenvironment response. [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 4991. doi:10.1158/1538-7445.AM2015-4991
Abstract 4992: Nicotinic acetylcholine receptor α5 mediates low-dose nicotine-dependent regulation of tumorigenesis in lung adenocarcinoma cells
Authors: Wang Mong-Lien Lotus , Hsu Yi-Fan , Liu Chih-Hsuan , Wu Cheng-Wen 
Published: August 2015

Abstract
The concept that lung adenocarcinoma is less related to smoking behavior than lung squamous cell carcinoma may be due to the fact that a considerable number of LAC patients do not have smoking habit. However, this argument may mislead the effect of tobacco smoke on LAC because it ignores the potential effects of environmental smoking that cause second hand smoking in non-smokers. In Taiwan, 70% of female LAC patients would encounter heavy smokers either at home or in working place, suggesting that environmental smoke may have substantial effects than we thought. Transcriptional deregulation at the chromosome 15q25 locus revealed an association between the gene encoding CHRNA5 with lung adenocarcinoma risk. It has been showed that overexpression of the genes encoded in this locus in mice increased the sensitivity to nicotine. In this report, we found that nAChR α5, but neither nAChR α7 or nAChR α9 that have been respectively shown to mediate tumorigenic alterations in lung SCC and breast cancer cells, was differentially expressed between tumor and non-tumor specimens of LAC patient specimens. Knockdown of nAChR α5 in LAC cell lines resulted in decreased cell proliferation rate as well as cell migrating and invasive capabilities. In these nAChR α5-knockdown cells, low dose (10 nM) nicotine was not able to significantly increase cell proliferation and motility, while low dose nicotine enhanced both abilities of cells when nAChR α5 expressed. Colony formation assay indicated that nAChR α5 maintained cell survival and prevent contact inhibition in LAC cells when encountering low serum stress condition. Through molecular analysis, we showed that nAChR α5 positively regulates epithelial-mesenchymal transition factors such as Snail and Slug, and negatively regulates E-cadherin. Animal experiment showed a severely suppressed tumor growth in mice transplanted with LAC cells with nAChR α5 being knocked down, in comparison to mice transplanted with parental cells. These data demonstrated a crucial role of nAChR α5 in low-dose nicotine-dependent regulation of tumorigenesis in LAC. It is, for the first time, a study of mechanism in response to low dose nicotine that implies the regulatory pathway underlying the effect of environmental nicotine.
Citation Format: Mong-Lien Lotus Wang, Yi-Fan Hsu, Chih-Hsuan Liu, Cheng-Wen Wu. Nicotinic acetylcholine receptor α5 mediates low-dose nicotine-dependent regulation of tumorigenesis in lung adenocarcinoma 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 4992. doi:10.1158/1538-7445.AM2015-4992
Abstract 5001: High dose IL-2 (HDIL-2) results in increased PD-1 expression on CD45RA-CCR7-CD8+ and CD45RA-CCR7-CD4+ T cells in melanoma patients
Authors: Diller Maggie L. , Maio Susan , Eysmans Cabell E. , Lawson David , Delman Keith A. , Kudchadkar Ragini R. , Ford Mandy L. 
Published: August 2015

Abstract
Introduction: HDIL-2 is associated with long-term remissions in Stage IV melanoma in less than 10% of patients. We hypothesized that HDIL-2 alters the expression of PD-1 on T cell subsets in melanoma patients.
Methods: Samples were collected after written consent under an IRB approved protocol. Peripheral blood was collected at baseline and serially post-treatment at 24, 48, 72, and 96 hours from 6 patients with advanced stage melanoma undergoing HDIL-2. All patients were treatment naïve with regards to anti-PD-1 and anti-CTLA4 therapies. PBMCs were isolated and underwent intracellular cytokine and extracellular receptor staining. Co-signaling molecule expression was analyzed via flow cytometry. Statistical analysis was performed using paired t tests via Prism 6.0e software.
Results: HDIL-2 was associated with a preferential loss of effector memory (TEM; CD45RA-CCR7-) CD4+ and CD8+ T cells and a relative enrichment of naïve (CD45RA+CCR7+) CD4+ and CD8+ T cells in the blood during the first 3 days of treatment. On day 4, frequencies of CD4+ and CD8+ TEM had returned to baseline. Importantly, PD-1 expression was significantly increased on day 4 post-treatment on CD8+ TEM relative to baseline (22.1% +/- 13.2% on day 4 compared to 13.4% +/- 7.4% at baseline; p = 0.04). This finding was also true for CD4+ TEM (11.4% +/- 6.1% on day 4 compared to 6.1% +/- 3.7% at baseline, p = 0.04). PD-1 expression was not statistically different within the other CD4+ and CD8+ memory T cell subsets including: naïve, central memory (CD45RA-CCR7+), or TEMRA (CD45RA+CCR7-) lymphocytes.
Conclusion: These results demonstrate that HDIL-2 is associated with an increase in expression of PD-1 on TEM cells in patients with advanced melanoma suggesting a possible mechanism contributing to the limited efficacy of HDIL-2 in most patients. It is known that TEM cells function by migrating to peripheral tissues, and that CD8+ TEM cells are found specifically in metastatic melanoma lesions. Importantly, our findings illustrate a potential synergistic effect between HDIL-2 and PD-1 blockade. Upregulation of PD-1 and the chronologic pattern in which its expression changes under the effects of HDIL-2 provide a mechanistic rationale for testing the combination of HDIL-2 and anti-PD-1 therapy in patients with advanced melanoma.
Citation Format: Maggie L. Diller, Susan Maio, Cabell E. Eysmans, David Lawson, Keith A. Delman, Ragini R. Kudchadkar, Mandy L. Ford. High dose IL-2 (HDIL-2) results in increased PD-1 expression on CD45RA-CCR7-CD8+ and CD45RA-CCR7-CD4+ T cells in melanoma patients. [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 5001. doi:10.1158/1538-7445.AM2015-5001
Abstract 5006: Elucidating the mechanism of bile acid-induced activation of estrogen receptor β in colorectal adenocarcinoma
Authors: Trujillo Jesse 
Published: August 2015

Abstract
In previous studies, Ursodeoxycholic Acid (UDCA) was investigated as a chemopreventive drug for the prevention of colorectal adenoma recurrence. These studies revealed that the efficacy of UDCA was gender-specific. The use of UDCA in men significantly lowered the odds of advanced lesions in men, but significantly increased the odds of advanced lesions in women, more specifically, in females who were younger, obese, or whose diet was high in fat. The gender specific role of UDCA led us to investigate this bile acids’, along with deoxycholic acid's (DCA), ability to activate the estrogen receptor in colon cancer.
Estrogen receptor β (ERβ) is the predominant estrogen receptor in both normal and malignant human colon tissue, and loss of ERβ has been shown to be critical for tumor cell differentiation. Elevated concentrations of bile acids have previously been shown to promote colon cancer and growing evidence indicates that these molecules play a vital role in regulating cell signaling and gene expression. In our current studies, through western blot and qRT-PCR analysis, we have shown that DCA-treated HT-29 colorectal adenocarcinoma cells significantly induce the phosphorylation of ERβ, as well as increase gene expression of the pS2 estrogen response element (ERE). UDCA was also shown to induce phosphorylation of ERβ, but much later than DCA. However, UDCA increases gene expression of pS2 at much earlier time points than DCA. In addition, we have also shown that when pre-treating HT-29 cells with the MEK 1/2 inhibitor, PD98059, bile acid-induced phosphorylation of ERβ is significantly reduced, along with ERE gene up-regulation. Collectively, this data suggests that bile acids are inducing the activation of ERβ through a ligand-independent mechanism via the MAPK signaling cascade.
Citation Format: Jesse Trujillo. Elucidating the mechanism of bile acid-induced activation of estrogen receptor β in colorectal adenocarcinoma. [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 5006. doi:10.1158/1538-7445.AM2015-5006
Abstract 5010: A versatile tool to study immune checkpoint therapeutics: Syngenic tumor mouse models in vivo
Authors: Schaefer-Obodozie Cynthia , Jantscheff Peter , Moor Sandra , Hoffmann Steffen , Saso Tihomir , Schaechtele Christoph , Weber Holger 
Published: August 2015

Abstract
Checkpoint inhibitor treatment is a common therapy of various cancer types, however, clinical data indicate that patients only partially respond to this regiment due to attenuated anti-tumor immune response. Thus, it has been recognized as important to consider the immune response already during preclinical drug development in animal experiments to anticipate such clinical drawbacks. Although immune-humanized models using human leukocytes in immuno-compromised mice may provide a starting point, syngenic mice models appear to be the better method of choice, reflecting the whole spectrum of a functional immune system. Here, we report on the establishment of syngenic mouse models for breast, colon, kidney and skin cancer both for subcutaneous and orthotopic implantation. Analyzing untreated as well as checkpoint inhibitor treated mice, we will present data on tumor growth kinetics as well on the distribution of immune cells such as Treg cells, M1/M2 macrophages and M/PMN-MDSCs in tumor and spleen tissue based on multi-color flow-cytometric analysis. These data may help to select a suitable model for testing new drug candidates and define a sensitive combination therapy to support the anti-tumor immune defense in addition to checkpoint inhibitor treatment.
Citation Format: Cynthia Schaefer-Obodozie, Peter Jantscheff, Sandra Moor, Steffen Hoffmann, Tihomir Saso, Christoph Schaechtele, Holger Weber. A versatile tool to study immune checkpoint therapeutics: Syngenic tumor mouse models 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 5010. doi:10.1158/1538-7445.AM2015-5010