tbuckley/cabot-search huggingface dataset:
Abstract 3236: T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade
Authors: Duane Moogk, Lin Wang, Kaitao Li, Zhou Yuan, Jeffrey Weber, Iman Osman, Cheng Zhu, Michelle Krogsgaard
Journal: Cancer Research (2019)

Abstract Although much clinical progress has been made in harnessing the immune system to recognize and target cancer, there is still a significant lack of an understanding of how tumors evade immune recognition and the mechanisms that drive tumor resistance to both T cell and checkpoint blockade immunotherapy. Our objective is to understand how tumor-mediated signaling through inhibitory receptors, including PD-1, combine to affect the process of T cell recognition of tumor antigen and signal activation in melanoma patients. The broader goal of the project is to understand the basis of resistance to PD-1 blockade and potentially identify new molecular targets to enable T cells to overcome dysfunction mediated by multiple inhibitory receptors (IR). Our biophysical measurements have shown that that the activities of TCR-proximal signaling components affect T cell antigen recognition and sensitivity at the earliest stages of T cell stimulation. We have shown that T cell antigen recognition is influenced by PD-1 and other inhibitory receptors via Shp-1/2 by targeting CD28 and Lckby directly suppressing TCR-pMHC-CD8 binding. Phospho-proteomics and flow cytometry-based analysis of melanoma patient-derived T cells from PD-1 blockade responders and non-responders identified additional mediators, signaling components and pathways associated with blockade resistance. CRISPR/Cas9 mediated genome editing was utilized to determine if resistance is mediated by the continued signaling of multiple IRs by perturbing IR signaling in mouse models of PD-1 blockade.Targeting these interactions and understanding the basis of resistance to PD-1 blockade would potentially allow identification of novel biomarkers of resistance or new molecular targets to enable T cells to overcome dysfunction during PD-1 checkpoint blockade. Citation Format: Duane Moogk, Lin Wang, Kaitao Li, Zhou Yuan, Jeffrey Weber, Iman Osman, Cheng Zhu, Michelle Krogsgaard. T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3236.
Clinical significance of BRAF mutations in colorectal cancer: A retrospective study of one institution in a real-life population
Authors: L. Carnerero Córdoba, I. González Cebrián, C. Rodríguez González, E. González-Flores, V. Conde, M. Delgado Ureña, J. Jurado García, B. González-Astorga
Journal: Annals of Oncology (2019)
Application of High-Sensitivity Troponin in Suspected Myocardial Infarction
Authors: Johannes T. Neumann, Raphael Twerenbold, Francisco Ojeda, Nils A. Sörensen, Andrew R. Chapman, Anoop S.V. Shah, Atul Anand, Jasper Boeddinghaus, Thomas Nestelberger, Patrick Badertscher, Arash Mokhtari, John W. Pickering, Richard W. Troughton, Jaimi Greenslade, William Parsonage, Matthias Mueller-Hennessen, Tommaso Gori, Tomas Jernberg, Niall Morris, Christoph Liebetrau, Christian Hamm, Hugo A. Katus, Thomas Münzel, Ulf Landmesser, Veikko Salomaa, Licia Iacoviello, Marco M. Ferrario, Simona Giampaoli, Frank Kee, Barbara Thorand, Annette Peters, Rossana Borchini, Torben Jørgensen, Stefan Söderberg, Susana Sans, Hugh Tunstall-Pedoe, Kari Kuulasmaa, Thomas Renné, Karl J. Lackner, Andrew Worster, Richard Body, Ulf Ekelund, Peter A. Kavsak, Till Keller, Bertil Lindahl, Philipp Wild, Evangelos Giannitsis, Martin Than, Louise A. Cullen, Nicholas L. Mills, Christian Mueller, Tanja Zeller, Dirk Westermann, Stefan Blankenberg
Journal: New England Journal of Medicine (2019)

Data regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes.
Abstract P042: Association of Epigenetic Age Acceleration and Adverse Cardiac Mechanics: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Sadiya S Khan, Tao Gao, Yinan Zheng, Laura A Colangelo, Brian Joyce, Norrina B Allen, Sanjiv J Shah, Lei Liu, Wei Zhang, Jun Wang, Joao Lima, Philip Greenland, Donald M Lloyd-Jones, Lifang Hou
Journal: Circulation (2018)

Background: Prevalence of diastolic dysfunction increases significantly with aging and becomes more prevalent in middle-age to older adulthood. DNA methylation markers of aging have been identified and integrated into an epigenetic age (EA) score, which has been demonstrated to be associated with cardiovascular morbidity and mortality. Epigenetic age acceleration (EAA) is the residual value of EA methylation markers regressed on chronologic age (CA), and is thus independent of CA. Therefore, we sought to examine the association of a previously identified DNA methylation molecular signature in blood (EAA) with cardiac mechanics. Methods: A subset of participants in the CARDIA cohort (n=1200) randomly selected (balanced on race and sex) underwent genome-wide DNA methylation profiling with the Illumina EPIC array from exam year 15 (2000-01 [age 33-45 years]) for calculation of EA and EAA. Echocardiography was completed at exam year 25 (2010-11 [age 43-55]). We used linear regression to examine the association of EA and EAA with parameters of cardiac mechanics. Models were adjusted for age, race, sex, education, study center, and Y15 cardiovascular risk factors (heart rate, body mass index, hypertension, hyperlipidemia, diabetes, and smoking). Results: Mean age of participant was 45.4±3.5 years, 52% female, and 41% black. DNA methylation markers of aging (EA and EAA) were associated with tissue Doppler measures of diastolic function, but not with parameters of left ventricular structure and systolic function ( Table ). Conclusions: EA and EAA are associated with changes in cardiac structure and function. Abnormalities in cardiac structure and function are an important intermediate phenotype prior to the development of symptomatic heart failure, and additional longitudinal research should examine DNA methylation markers as potential mediator of or novel biomarker for incident heart failure in young to middle-age adults.
Image Gallery: A case of Harlequin and Horner syndromes
Authors: F.Y.H. Kwok, K. Scharrer
Journal: British Journal of Dermatology (2019)

Funding sources: none. Conflicts of interest: none to declare. Dear Editor, An 11‐year‐old child without previous injury was referred for the lack of left hemifacial flushing and sweating when exercising (a). An ophthalmologist identified left eye miosis and partial ptosis (b). Magnetic resonance imaging (MRI) of the head, neck and upper chest showed no suspicious lesions or vascular malformations. Harlequin syndrome is attributed to disruption of the sympathetic chain, leading to unilateral anhidrosis and paleness. Examination of the cranial nerves, neck and chest is essential, and then complemented with ophthalmology review and MRI to rule out structural causes.1 This case demonstrates the overlapping features of dysautonomia in both Harlequin and Horner syndromes.2
Abstract 2250: Combinational markers of neoantigen intratumor heterogeneity and neoantigen burden predict progression-free survival for lenvatinib plus PD-1 blockade in patients with intrahepatic cholangiocarcinoma
Authors: Jianzhen Lin, Yiying Liu, Xu Yang, Yi Bai, Junyu Long, Junyu Long, Yongchao Li, Jiaqian Wang, Dongxu Wang, Xiaobo Yang, Mei Guan, Li Huo, Jie Pan, Ke Hu, Zhibo Gao, Haitao Zhao
Journal: Cancer Research (2019)

Abstract Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignant neoplasm derived from biliary epithelial cells. Although many targetable gene alterations have been identified, there has no molecular targeted drug available for these patients at present, which may be due to the high intratumor heterogeneity (ITH) of ICC. Previous studies have demonstrated that some ICC patients could be benefited from immune checkpoint inhibitors (ICIs), but the predictive biomarkers are still unknown. We used whole exome sequencing to evaluate the impact of neoantigen ITH and tumor neoantigen burden (TNB) in 45 ICC patients, in which 15 patients were treated by anti-PD1 inhibitor combined with lenvatinib. The median neoantigen and clonal neoantigen load of these patients were 0.65 and 0.29 per Mb, respectively. The median neoantigen ITH index was 0.45, with a range from 0.02 to 1. Survival analysis of those patients who received the combined treatment revealed significantly longer progression-free survival (PFS) in patients with higher TNB and low neoantigen ITH (9.5 vs 3.5 months, p=0.00583). Among the 30 patients without anti-PD1 combined therapy, there were 36.7% (11/30) ICC patients with high TNB and low neoantigen ITH, indicating these patients might be benefited from this combined therapy. One of these 45 patients had the highest TMB and TNB with high MSI and dMMR has the longest PFS (12 months) after the combined treatment. Besides, we found that the clonal KRAS mutation (G12D) occurred exclusively in patients with shorter PFS and OS and lower TMB and TNB, while the FLG mutation occurred only in patients with longer PFS and OS and higher TMB and TNB. These results indicated the potential relationship between mutations in KRAS and FLG and the levels of TMB and TNB, which needs to further investigation. Therefore, these data revealed that the high TNB and lower neoantigen ITH might be a promising marker for predicting the efficacy of the combination therapy of anti-PD1 inhibitor and lenvatinib in ICC patients. Citation Format: Jianzhen Lin, Yiying Liu, Xu Yang, Yi Bai, Junyu Long, Junyu Long, Yongchao Li, Jiaqian Wang, Dongxu Wang, Xiaobo Yang, Mei Guan, Li Huo, Jie Pan, Ke Hu, Zhibo Gao, Haitao Zhao. Combinational markers of neoantigen intratumor heterogeneity and neoantigen burden predict progression-free survival for lenvatinib plus PD-1 blockade in patients with intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2250.
Abstract LB-317: Use of <i>in vivo</i> microdialysis to evaluate biomarker levels in the tumor and tumor free flank of freely-moving PDX mice
Authors: Mariette Heins, Loreen Weichert, Sabine Gorynia, Gunnar Flik, Arash Rassoulpour
Journal: Cancer Research (2019)

Abstract The tumor microenvironment (TME) constitutes unique surroundings where cancer cells communicate with one another and with the host immune system by releasing a multitude of factors. Information about the physiological state of the TME can help in gaining a broader understanding of cancer biology and developing novel cancer therapeutics. Previous work has demonstrated the ability to use in vivo microdialysis to monitor the release of adenosine and its metabolites from murine cancer models. To further these findings, we used in vivo microdialysis to measure biomarkers in the patient-derived xenograft (PDX) cancer model. By using human tumor tissue models, we aim to bridge the gap between rodent models and human tumors to help develop better cancer therapeutics. The current set of studies used microdialysis in different PDX lines representing human tumor models (provided by CRL DRS Freiburg). Xenograft growth was monitored and upon a tumor volume &amp;gt; 400 mm3, the animals underwent surgical implantation of microdialysis probes in the tumor and the tumor-free flank. The implanted probes were perfused with dialysate fluid and samples from the both flanks were continuously collected over several hours. Levels of ATP, inosine and kynurenine metabolites were quantified by EIA or LC-MS/MS analysis. Analysis of microdialysate samples from tumor and tumor-free flank demonstrated differences in analyte levels between the two sampling sites within one animal indicating that the levels of ATP and metabolites measured in PDX tumors is unique to the tumor microenvironment. In addition, the various PDX models showed differences in biomarker levels between the different tumor types. There is a wide range of biomarkers which are important indicators of energy consumption and provide an insight in the differences in metabolic activity between the different xenografts. Moreover, these data demonstrate that microdialysis can be used to test targeted therapies and follow relevant biomarker levels over time. Thereby, providing better insight in effects of new therapeutic treatments within the patient specific tumor tissue itself. Citation Format: Mariette Heins, Loreen Weichert, Sabine Gorynia, Gunnar Flik, Arash Rassoulpour. Use of in vivo microdialysis to evaluate biomarker levels in the tumor and tumor free flank of freely-moving PDX mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-317.
Abstract 1521: Tumor-produced hyaluronan contributes to the formation tolerogenic immunosuppressive microenvironment
Authors: Paul R. Dominguez-Gutierrez, Paul Crispen, Sergei A. Kusmartsev
Journal: Cancer Research (2019)

Abstract Immunosuppressive ligand PD-L1 considered as a major player in mechanism of negative regulation of anti-tumor immune response and its expression is highly up-regulated in human and experimental tumors, including bladder cancer. Bladder cancer is characterized by aberrant hyaluronan metabolism resulting in increased HA production in tumor tissue. Hyaluronan or hyaluronic acid (HA) is a prominent component of tumor stroma/microenvironment. Membrane-bound or free extracellular HA favors tumor progression by inducing tumor cell motility, invasive properties, proliferation, production of growth factors and epithelial-mesenchymal transition. Here, we provide evidence that tumor-produced hyaluronan, one of the key tumor stroma components, contributes to the formation of tolerogenic/immunosuppressive tumor microenvironment and stimulated PD-L1 expression. We found that tumor-derived HA specifically binds to CD44 receptor expressed by myeloid precursors, such as myeloid-derived suppressor cells (MDSCs) and promotes its expansion with differentiation toward PD-L1-expressing F4/80+ macrophages. Inhibition of HA synthesis in tumor cells with pharmacologic inhibitor 4-MU, or blockade of CD44 signaling in myeloid cells with antagonistic anti-CD44 antibody, prevented the macrophage differentiation and tumor-induced up-regulation of PD-L1 expression. We also found that tumor-derived HA stimulated production of immunosuppressive and inflammatory factors IL-6, IL-10, TNF-alpha, IL-1beta and PGE2 by myeloid cells in CD44-dependent manner. Moreover, tumor-produced HA stimulated development of PD-L1-expressing macrophages in both murine and human myeloid cells. Our study reveals that tumors may evade the immune system by creating a protective tolerogenic “shield” in the form of tumor-produced HA, which binds to the CD44-expressing tumor-recruited MDSCs, stimulating production of immunosuppressive factors and promoting development of the PD-L1+ macrophages. Inhibiting of hyaluronan synthesis by tumors or targeting HA-CD44 signaling could provide an attractive approach to break tumor-induced immune tolerance and unleash the anti-tumor immune response. Citation Format: Paul R. Dominguez-Gutierrez, Paul Crispen, Sergei A. Kusmartsev. Tumor-produced hyaluronan contributes to the formation tolerogenic immunosuppressive microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1521.
Abstract P204: Tissue Plasminogen Activator (tPA) Eligibility for Acute Stroke in Urban and Rural Hospitals in North Carolina: The North Carolina Stroke Care Collaborative
Authors: Sara B Jones, Anna M Kucharska-Newton, Wayne D Rosamond
Journal: Circulation (2013)

Introduction: Thrombolytic therapy was approved over a decade ago for the treatment of acute ischemic stroke, yet administration remains infrequent in clinical practice partly due to pre- and in-hospital delays and patient contraindications. Reports of urban-rural differences in eligibility for and treatment with tPA are few. Understanding differences by hospital location may help identify quality improvement strategies unique to particular hospital systems, particularly those in non-metropolitan areas of North Carolina in which nearly one-third of the population resides. Methods: We included all acute ischemic strokes in the NC Stroke Care Collaborative, a voluntary state-wide quality improvement program, from Jan 2008 - Aug 2012 with valid, non-missing times from symptom onset to hospital arrival. Location of the 60 participating hospitals was classified as metropolitan, micropolitan, or smalltown using Rural-Urban Commuting Area codes. Rates of intravenous tPA eligibility and receipt were calculated by hospital location. Pre-hospital (onset to arrival) and CT (arrival to CT interpretation) delay times were compared using Wilcoxon tests. Reasons for non-eligibility by hospital location were compared using chi-squared statistics. Results: We identified 16,050 ischemic stroke patients (13,913 metropolitan, 1897 micropolitan, and 240 smalltown). Pre-hospital delay was longer among patients treated at smalltown compared with metropolitan hospitals (median hours [IQR] 3.8 [1.0-9.9] vs. 3.3 [1.3-8.2], p=0.04) but the proportion arriving within 2 hours of symptom onset was similar (38%). CT delay was slightly longer for patients at metropolitan compared with smalltown hospitals (1.1 [0.6-1.7] vs. 0.8 [0.5-1.2]; p&lt;0.0001). Thirty-eight percent (2004 of 5276) of patients arriving within 2 hours were eligible for tPA at metropolitan hospitals compared with 41% (304 of 741) at micropolitan and 46% (42 of 92) at smalltown hospitals (p=0.1). Patients in smalltown compared with metropolitan hospitals had higher rates of ineligibility due to advanced age (5% vs. 3%) and family/patient refusal (9% vs. 3%), whereas patients in metropolitan hospitals had higher rates of contraindications (35% vs. 12%) and rapid improvement/symptom resolution (20% vs. 12%). Rece ipt of tPA among eligible patients was highest in metropolitan (70%, 1399 of 2004) compared with micropolitan (37%, 113 of 304) and smalltown hospitals (33%, 14 of 42; p&lt;0.001). Conclusion: Receipt of tPA within 3 hours of symptom onset remains below guideline recommendations. Pre-hospital and CT delay times and eligibility for tPA were largely similar across hospital locations. Despite this, tPA administration was considerably lower at smalltown hospitals compared with hospitals in urban settings, suggesting the need for quality improvements targeted at smalltown hospitals that may have less stroke care capability.
Abstract 2702: Contribution of effector regulatory T cells to the regulation of antitumor immunity
Authors: Michael L. Dixon, Lin Luo, Jianmei W. Leavenworth
Journal: Cancer Research (2019)

Abstract Regulatory T cells (Treg) belonging to the FoxP3 lineage stringently control immune responses and self-tolerance. Follicular regulatory T (TFR) cells, an effector Treg (eTreg) subset, not only suppress cellular responses but also regulate the magnitude and quality of the germinal center (GC)-antibody (Ab) response through interactions with activated follicular helper T (TFH) cells and GC B cells. Although the Blimp1 transcription factor has been used as a phenotypic marker for eTreg, its contribution to the lineage stability and suppressive activity of eTreg, particularly TFR, has been clouded in uncertainty. In contrast to the current view that Blimp1 may have a negative impact on the TFR response, our recent analysis of mice that harbor a FoxP3-specific deletion of Blimp1 has shown that expression of Blimp1 in eTreg (including TFR) is essential for the maintenance of FoxP3 expression and stable eTreg suppressive phenotype. We then generated B16 melanoma model in these mice and investigated the impact of Blimp1 deficient eTreg on the tumorigenesis. These mice had delayed tumor growth compared to WT controls. The enhanced antitumor immunity in mice with Blimp1 deficient eTreg reflected reprogramming of unstable eTreg into T-cells with effector activity (Teff) specifically within the tumor and loss of suppression on TFH-Ab responses, leading to intratumoral TFH expansion, Ab deposition and enhanced CD8+ T-cell and NK cell effector function. Further analysis of mice expressing a conditional and tamoxifen-inducible Blimp1 deletion within the FoxP3+ lineage revealed the specific contribution of Blimp1 deficient TFR cells to antitumor immune response. These results suggest that induction of eTreg lineage instability provokes intratumoral eTreg conversion into Teff −a new source of effector activity by T-cells within the tumor and enhances robust Ab responses. The increased cellular and humoral responses cooperatively promote antitumor immunity. Insights from our studies may suggest new approaches to manipulate eTreg for better vaccines or combined immunotherapeutic approaches to melanoma or other types of cancer. Citation Format: Michael L. Dixon, Lin Luo, Jianmei W. Leavenworth. Contribution of effector regulatory T cells to the regulation of antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2702.