tbuckley/cabot-search huggingface dataset:
Abstract 4761: Translational regulation by eIF4E and its contribution to tamoxifen resistance in breast cancer
Authors: Chun Gong, Ka Chun Mok, Yuen-Nei CHEUNG, Pui-Sum Man, EWF Lam, Ui-Soon Khoo
Journal: Cancer Research (2016)

Abstract Breast cancer is one of the prevalent causes of cancer in women and its occurrence has been rising in the last few decades. Two thirds of breast cancer patients are ER-positive and can receive tamoxifen (TAM) treatment. Unfortunately, many of the patients eventually develop resistance to tamoxifen. Identifying a molecular marker associated with tamoxifen resistance would help in designing better therapeutic strategies to overcome this. In eukaryotes, translation initiation is the most regulated step. Abnormal translation machinery underlies a variety of human diseases including cancers. Eukaryotic translation initiation factor 4E (eIF4E) is the least abundant initiation factor and is believed to be the rate limiting step for translation initiation. Overexpression of eIF4E in cells selectively promotes translation of mRNAs involved in cell proliferation, apoptosis and tumor progression. Recently, eIF4E overexpression has been implicated in drug resistance in melanoma1. We hypothesized that eIF4E may also be involved in tamoxifen resistance. The aim of this study was to characterize the role of eIF4E in tamoxifen resistance and identify novel molecular targets that may be translationally regulated. Immunohistochemistry (IHC) staining of eIF4E showed up-regulation in human breast cancer samples compared with non-tumor counterparts. In silico analysis predicted that ERá and FOXM1 have a long and highly structured 5’-UTR, which are sensitive to the expression level of eIF4E. Polysomal fractionation confirmed that ERá and FOXM1 mRNA were more actively translated in MCF7 than in MCF10A. The correlation between eIF4E and ERá/FOXM1 were further confirmed in tissue microarray (TMA). The role of eIF4E in conferring TAM resistance was studied by MTT assays. Overexpression of eIF4E induced TAM resistance while knockdown eIF4E sensitized cells to TAM. Additionally, overexpression of eIF4E upregulated ERá/FOXM1 expression at protein level while knockdown eIF4E downregulated their expression at protein level. Our results show that eIF4E induced TAM resistance possibly through translational regulation of ERá/FOXM1. eIF4E is a promising biomarker for anti-estrogen drug responsiveness and a future therapeutic target for treating drug resistant breast cancer patients. Reference: 1. Zhan Y, et al. The role of eIF4E in response and acquired resistance to vemurafenib in melanoma J Invest Dermatol. 2015 May;135(5):1368-76. (2178 characters without spaces) Citation Format: Chun Gong, Ka Chun Mok, Yuen-Nei CHEUNG, Pui-Sum Man, EWF Lam, Ui-Soon Khoo. Translational regulation by eIF4E and its contribution to tamoxifen resistance in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4761.
Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis
Authors: Hsin-Yuan Cheng, Dalia E. Gaddis, Runpei Wu, Chantel McSkimming, LaTeira D. Haynes, Angela M. Taylor, Coleen A. McNamara, Mary Sorci-Thomas, Catherine C. Hedrick
Journal: Journal of Clinical Investigation (2016)

ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol accumulation and alters T cell homeostasis, which may contribute to progression of atherosclerosis. Here, we investigated how the selective loss of ABCG1 in T cells impacts atherosclerosis in LDL receptor-deficient (LDLR-deficient) mice, a model of the disease. In LDLR-deficient mice fed a high-cholesterol diet, T cell-specific ABCG1 deficiency protected against atherosclerotic lesions. Furthermore, T cell-specific ABCG1 deficiency led to a 30% increase in Treg percentages in aorta and aorta-draining lymph nodes (LNs) of these mice compared with animals with only LDLR deficiency. When Abcg1 was selectively deleted in Tregs of LDLR-deficient mice, we observed a 30% increase in Treg percentages in aorta and aorta-draining LNs and reduced atherosclerosis. In the absence of ABCG1, intracellular cholesterol accumulation led to downregulation of the mTOR pathway, which increased the differentiation of naive CD4 T cells into Tregs. The increase in Tregs resulted in reduced T cell activation and increased IL-10 production by T cells. Last, we found that higher ABCG1 expression in Tregs was associated with a higher frequency of these cells in human blood samples. Our study indicates that ABCG1 regulates T cell differentiation into Tregs, highlighting a pathway by which cholesterol accumulation can influence T cell homeostasis in atherosclerosis.
CADAVERIC RENAL-TRANSPLANTATION (CRT) WITHOUT PREVIOUS CHRONIC DIALYSIS TREATMENT AS AN ALTERNATIVE APPROACH IN THE TREATMENT OF END STAGE RENAL-DISEASE
Authors: Adam Tegzess, Sytze Meijer, WJ van Don, F van der Woude, Mjh Slooff, WJ Sluiter, A Donker
Journal: Kidney International (1986)
Associations of Methylene Tetrahydrofolate Reductase Polymorphism and Methotrexate-Related Toxicities in Korean Treated for Malignant Lymphoma
Authors: Hyangmin Park, Dok Hyun Yoon, Youngcheon Song, Heese Kim, Youngseol Huh, Shin Kim, Seongsoo Jang, Chan-Jeoung Park, Hyun-Sook Chi, Chan-Sik Park, Jooryung Huh, Sang-wook Lee, Cheolwon Suh
Journal: Blood (2011)
Treatment and Outcomes of Acute Myocardial Infarction Complicated by Shock After Public Reporting Policy Changes in New York
Authors: James M. McCabe, Stephen W. Waldo, Kevin F. Kennedy, Robert W. Yeh
Journal: JAMA Cardiology (2016)

In 2006, New York began excluding patients with cardiogenic shock from the publicly reported percutaneous coronary intervention (PCI) risk-adjusted mortality analyses.To examine the effects of the New York shock-exclusion policy change on rates of revascularization and mortality for patients with acute myocardial infarction (AMI) complicated by cardiogenic shock.This study used several comprehensive statewide hospitalization databases to identify patients with AMI and shock from January 1, 2002, through December 31, 2012, in New York and a series of comparator states (Massachusetts, Michigan, and New Jersey from January 1, 2002, through December 31, 2012, and California from January 1, 2003, through December 31, 2011). Data analysis was performed from October 1, 2015, to March 15, 2016.A difference-in-differences approach was used to evaluate whether the likelihood of receiving PCI and surviving to discharge differed after the policy change in New York in 2006 compared with comparator states that did not enact such a change.Among 45 977 patients with AMI and cardiogenic shock (11 298 in New York), 21 974 (47.8%) underwent PCI. The mean (SD) age of the patients was 69.7 (13.2) years, and 18 139 (39.5%) were female. After adjusting for patient factors, patients in New York were significantly more likely to undergo PCI after the public reporting policy changes than they were previously (adjusted relative risk [aRR], 1.28; 95% CI, 1.19-1.37; P < .001) compared with a 9% increase in comparator states during the same period (aRR, 1.09; 95% CI, 1.05-1.13; P < .001; interaction P < .001). Nevertheless, rates of PCI remained lower in New York compared with comparator states throughout the study period. The adjusted risk of in-hospital death among patients in New York with AMI and shock decreased significantly faster after the policy change (aRR, 0.76; 95% CI, 0.72-0.81; P < .001) compared with comparator states (aRR, 0.91; 95% CI, 0.87-0.94; P < .001; interaction P < .001).The exclusion of patients with ongoing cardiogenic shock from New York PCI public reports in 2006 was associated with a significant increase in the use of PCI for cardiogenic shock and a concomitant decrease in in-hospital mortality, exceeding simultaneously observed trends in the comparator states. However, rates of PCI for AMI and shock were lower in New York throughout the study. Alterations in policies related to reporting mortality outcomes after cardiovascular procedures may have significant implications for physician behavior and the public health.
Abstract 3856: The atomic basis for paclitaxel sensitization following loss of CRMP2 phosphorylation in ovarian cancer cells
Authors: Yiyan Zheng, Ritika Sethi, Frank von Delft, Ahmed Ashour Ahmed
Journal: Cancer Research (2016)

Abstract The chemotherapeutic agent paclitaxel increases cancer cell microtubule stability, induces mitotic arrest and cancer cell death and improves survival of cancer patients. However, in ovarian and other cancers, it only elicits a response in less than half of patients who receive it. We have previously shown that enhancing microtubule stability in cells prior to paclitaxel treatment, further increases paclitaxel-induced microtubule stability and cancer cell death (Ahmed et al., Cancer Cell, 2007;12:514 and Ahmed et al., Cancer Research 2011;71:5806). We now report that the microtubule-associated protein CRMP2, and FER kinase are expressed in almost half of high-grade serous ovarian cancers and that inhibiting the phosphorylation of CRMP2 by FER is sufficient for enhancing paclitaxel-induced microtubule stability and cytotoxicity in multiple ovarian cancer cell lines. We are also able propose a detailed mechanism underlying these observations. A combination of biochemistry, super-resolution fluorescence microscopy, total internal reflection fluorescence (TIRF) microscopy and electron microscopy reveals that CRMP2 induces microtubule nucleation, elongation, bundling and stability. Moreover, FER phosphorylates CRMP2 at 6 tyrosine residues, two of which (Tyr479 and Tyr499) are critical for modulating CRMP2 function; this agrees with site-directed mutagenesis in cancer cells which points to Tyr479 as a critical site for association between CRMP2 and microtubules. A comparison of the crystal structures of wild-type CRMP2 and Tyr479Glu/Tyr499Glu phosphomimetic mutants indicate that phosphorylation of these sites induces significant conformational changes that prevent CRMP2 from forming tetramers that are known to be critical for its microtubule bundling activity. This then leads us to propose a molecular model of how CRMP2 associates with microtubules, explaining how targeting CRMP2 phosphorylation can be exploited for enhancing the therapeutic efficacy of paclitaxel. Citation Format: Yiyan Zheng, Ritika Sethi, Frank von Delft, Ahmed Ashour Ahmed. The atomic basis for paclitaxel sensitization following loss of CRMP2 phosphorylation in ovarian cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3856.
Study of the impact of Charlson comorbidity index and hypertension on survival in patients with metastatic castration-resistant prostate cancer.
Authors: Jatinder Goyal, Gregory Russell Pond, Matt D. Galsky, Ryan Hendricks, Alexander C. Small, Che-Kai Tsao, Guru Sonpavde
Journal: Journal of Clinical Oncology (2013)

111 Background: Clinical and laboratory factors, i.e. visceral metastasis, anemia, LDH, PSA, PSA-doubling time, bone scan progression, pain, performance status (PS), are recognized to be prognostic factors for overall survival (OS) in metastatic castration resistant prostate cancer (mCRPC). We sought to determine if the Charlson comorbidity Index (CCI) and hypertension (HTN) provide prognostic information independent of these known factors. Methods: We retrospectively evaluated 221 patients with mCRPC treated with docetaxel plus prednisone (DP) combined with AT-101 (bcl-2 antagonist) or placebo on a randomized phase II trial. Both arms of the trial were combined since no differences in outcomes or toxicities were observed. Wilcoxon rank sum test and Fisher’s exact tests were used to compare data by comorbidity groups (CCI as a continuous variable, CCI = 6 vs. CCI ≥7 and HTN vs. no HTN). Cox regression analysis was done to identify whether CCI or HTN independently predicted OS after adjusting for trial stratification factors (pain, performance status), nomogram, risk-groups and PCWG-2 clinical sub-types. Results: CCI was 6 in 116 patients (52.7%) whereas it was 7 in 70 (31.8%), 8 in 23 (10.5%), 9 in (1.8%) and 10 in 7 patients (3.2%) respectively. HTN was present in 107 (48.6%) patients. Patients with HTN had increased CCI (mean CCI 7.0 vs. 6.43, p &lt; 0.001). Patients with CCI of ≥7 were older and exhibited worse ECOG-PS and anemia than patients with CCI of 6 (p&lt;0.05). CCI was not found to be independently predictive of OS on univariable and multivariable analyses. HTN alone or in combination with CCI was borderline significantly associated with OS (p~0.08) on both univariable and multivariable analyses. Conclusions: CCI did not predict OS independent of known prognostic factors in mCRPC. Age, performance status and anemia may adequately capture comorbidities in the context of mCRPC, given their association with higher CCI. Further analysis of HTN in a larger dataset may be warranted given its borderline independent association with OS.
Abstract LB-151: Positively selected enhancer elements endow tumor cells with metastatic competence
Authors: James J. Morrow, Tyler E. Miller, Alina Saiakhova, Michael M. Lizardo, Cynthia F. Bartels, Ian Bayles, Stevephen Hung, Arnulfo Mendoza, Jay T. Myers, Frederick Allen, Analisa DiFeo, Brian P. Rubin, Alex Y. Huang, Paul S. Meltzer, Lee J. Helman, Chand Khanna, Peter C. Scacheri
Journal: Cancer Research (2016)

Abstract Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in signature enhancer-histone marks between near-isogenic pairs of high and low lung-metastatic osteosarcoma cells. We term these regions Metastatic Variant Enhancer Loci (Met-VELs). Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster non-randomly, indicating that activity of these enhancers and their associated gene targets is positively selected. Osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors whose motifs are enriched in Met-VELs, and by knockdown of individual genes activated by Met-VELs. These observations have implications for the discovery and development of targeted anti-metastatic therapies. Citation Format: James J. Morrow, Tyler E. Miller, Alina Saiakhova, Michael M. Lizardo, Cynthia F. Bartels, Ian Bayles, Stevephen Hung, Arnulfo Mendoza, Jay T. Myers, Frederick Allen, Analisa DiFeo, Brian P. Rubin, Alex Y. Huang, Paul S. Meltzer, Lee J. Helman, Chand Khanna, Peter C. Scacheri. Positively selected enhancer elements endow tumor cells with metastatic competence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-151.
Abstract 478: A mouse model for highly metastatic, nonfunctioning pancreatic neuroendocrine tumors
Authors: Tanupriya Contractor, Shinta Kobayashi, Richard Clausen, Edaise da Silva, Laura Tang, Chang Chan, Chris R. Harris
Journal: Cancer Research (2016)

Abstract Pancreatic neuroendocrine tumors are generally classified as functioning or nonfunctioning. Patients with functioning tumors can have severe hypoglycemia because their tumors express high amounts of insulin as well as chromogranin A; fortunately, these tumors are seldom metastatic. Patients with nonfunctioning tumors express high amounts of chromogranin A but little insulin; unfortunately these tumors are highly metastatic to the liver. Nonfunctioning tumors are more common, and a more severe health issue. The highly studied RT2 B6 mouse, in which the SV40 T antigen is expressed from an insulin promoter in an inbred C57Bl/6 genetic background, is a model for functioning pancreatic neuroendocrine tumors: liver metastasis is uncommon in RT2 B6 mice, which are very hypoglycemic and often die when tumors are very small. We have changed the genetic background and are studying RT2 AB6F1 hybrid mice, which have a C57Bl/6 father and a mother from an A/J inbred background. RT2 AB6F1 mice are much less hypoglycemic, and these mice develop liver metastasis with high frequency. We have mated the hybrid AB6F1 mice to their littermates in order to map metastasis genes by F2 analysis, and have discovered that a locus at mouse chromosome 2qG1 links tightly to liver metastasis. One gene within this locus, InsM1, is less expressed in the primary tumors of mice with liver metastatic disease. InsM1 is also less expressed in primary tumors from humans with liver metastatic disease. Previous studies of InsM1 have shown that this protein maintains the differentiated status of pancreatic beta cells. We find that tumors from mice with low expression of InsM1 also express lower amounts of several distinctive markers of differentiated beta cells, but higher amounts of several markers of liver cells. These data suggest that dedifferentiation to stem cells, which can then redifferentiate to other cell types such as liver cells, promotes metastasis of pancreatic beta cell tumors. Intratumoral expression of liver markers may be a useful predictor of metastatic disease in these patients. Dedifferentiation of mature beta cells is also a mechanism by which type 2 diabetes occurs, so there may be similarities between these two diseases. Citation Format: Tanupriya Contractor, Shinta Kobayashi, Richard Clausen, Edaise da Silva, Laura Tang, Chang Chan, Chris R. Harris. A mouse model for highly metastatic, nonfunctioning pancreatic neuroendocrine tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 478.
Abstract 4430: Implication of the primary cilium in the Hedgehog pathway in colorectal cancer cells
Authors: Blanche Senicourt
Journal: Cancer Research (2016)

Abstract Background: The Hedgehog (HH) pathway is involved in the maintenance of numerous cell types both during development and in the adult. Often deregulated in cancers, its involvement in colorectal cancer has come into view during the last few years, although its role remains poorly defined. In most tissues, the HH pathway is highly connected to the primary cilium (PC), an organelle not expressed in the normal colonic epithelium which recruits the functional components and regulates the pathway. Aims: Since the intestinal epithelium is known to be a non-ciliated tissue, the HH pathway as related to the PC has not been explored. We investigated the presence of PC in colon cancer tumors and cell lines. Our hypothesis is that PC formation controls the HH activation that has been reported in numerous colon cancer studies. Materials and methods: We used cellular models to look at HH activation, focusing on the final effector Gli1. The link between PC and the HH pathway was shown by the recruitment of the Smo receptor in the PC. We looked for PC in a subset of 63 tumors from a Tissue Micro Array and in 4 colorectal cell lines by immunofluorescence using two well-known markers, acetylated α-tubulin and polyglutamylated tubulin. 3D deconvoluted pictures were obtained to characterize the shape and size of PC. Using cellular models we investigated HH pathway expression by qPCR. We assessed the functional link between HH pathway and PC through localization of the Smo receptor in the PC using immunofluorescence. Results: We observed the presence of the PC in the epithelium of primary colorectal tumors at all stages but not in their normal counterparts. Using human colorectal cancer cell lines we found a clear correlation between the presence of the PC and the expression of the final HH effector, GLI1, and provide evidence of a functional link between the two by demonstrating the recruitment of the SMO receptor to the PC membrane. Conclusion: We conclude that the PC directly participates in the HH pathway in colorectal cancer cells which is the first observation of PC expression in tumors arising from a non-ciliated tissue. Functional studies are required to determine the mode of action of this organelle in carcinogenesis. Citation Format: Blanche Senicourt. Implication of the primary cilium in the Hedgehog pathway in colorectal cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4430.
Abstract 2079: IONP-LPrA2 and PEG-LPrA2 therapies for triple negative breast cancer
Authors: Tia L. Harmon, Adriana Harbuzariu, Antonio Rampoldi, Courtney Dill, Viola Lanier, Danielle Daley-Brown, Crystal Lipsey, Cynthia Tchio, Lily Yang, Ruben Rene Gonzalez-Perez
Journal: Cancer Research (2016)

Abstract Background: Breast cancer (BC) is an epidemic in the US. It is estimated that there will be over 230,000 new BC diagnoses in 2016. Triple Negative Breast Cancer (TNBC) comprises ∼15% of BC cases and lacks targeted therapeutic options. Obesity and high leptin levels are associated with higher TNBC incidence and poorer patient outcomes. Overexpression of leptin and its receptor, Ob-R, induce BC cell growth and angiogenesis; therefore leptin/Ob-R may serve as a TNBC therapeutic target. We have developed a Leptin Peptide Receptor Antagonist, LPrA2, which effectively inhibits leptin signaling. To increase its efficacy LPrA2 was coupled to iron oxide nanoparticles (IONPs) and polyethylene glycol (PEG), and subsequently tested in vitro and in vivo in obese mice hosting syngeneic TNBC-like mammary tumors. Methods: The conjugation of LPrA2 to IONPs and PEG was confirmed by immunoblotting analysis. E0771, mouse BC cells, which are progesterone receptor and HER2 negative were made insensitive to estrogen stimuli by long-term treatment with Tamoxifen (TAM). Cell cycle and MTT assays were performed to determine the effectiveness of leptin signaling inhibition by conjugated LPrA2 in vitro. C57BL/6 female mice were fed a 60% fat diet to induce obesity. The obese mice were injected with E0771-TAM cells in the mammary fat pad and treated with IONP-LPrA2 and PEG-LPrA2 after tumor development. Obese mice treated with IONP-LPrA2 Scramble (Sc) and PEG-LPrA2 Sc served as negative controls. Results and Conclusion: IONP-LPrA2 and PEG-LPrA2 attenuated leptin signaling in vitro and decreased tumor growth and progression in vivo in comparison to the controls. These findings indicate that conjugated LPrA2 may serve as a targeted therapy for TNBC. IONP-LPrA2 may be especially useful in treating this more aggressive form of BC due to its ability to capture multiple LPrA2 peptides as well as its small and uniform particle size. Citation Format: Tia L. Harmon, Adriana Harbuzariu, Antonio Rampoldi, Courtney Dill, Viola Lanier, Danielle Daley-Brown, Crystal Lipsey, Cynthia Tchio, Lily Yang, Ruben Rene Gonzalez-Perez. IONP-LPrA2 and PEG-LPrA2 therapies for triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2079.
Hemopexin Gene Therapy Inhibits Inflammation and Vaso-Occlusion in Transgenic Sickle Cell Mice
Authors: Gregory M Vercellotti, Ping Zhang, Chunsheng Chen, Julia Nguyen, Fuad Abdulla, Phong Nguyen, Carlos Nowotny, Aman Irfanullah, Ann Smith, Clifford J. Steer, John D. Belcher
Journal: Blood (2015)