tbuckley/cabot-search huggingface dataset:
Abstract 18643: Proliferation and Endothelial to Mesenchymal Transition Contribute to Progressive Lesions in a Surgical Model of Pulmonary Vein Stenosis
Authors: Rachel D Vanderlaan, Yaqin Yana Fu, Jiaquan Zhu, Rie Montgomery, Haruki Ide, Mauro Lo Rito, Jason Maynes, John Coles, Christopher A Caldarone
Journal: Circulation (2016)

Introduction: The role of proliferation and endothelial-to-mesenchymal transition (EndMT) is poorly defined in progressive pulmonary vein stenosis (PVS). Hypothesis: Altered signaling leads to hype...
219P Outcomes of malignant pleural mesothelioma (MPM) patients (p) treated after first line chemotherapy (CT)
Authors: S. Cedres, F. Amair, A. Martinez-Marti, A. Navarro, N. Pardo, J. Remon-Masip, J.M. Miquel, G. Villacampa, R. Dienstmann, E. Felip Font
Journal: Journal of Thoracic Oncology (2018)
Exposure to Coxiella burnetii and risk of non-Hodgkin lymphoma: a retrospective population-based analysis in the Netherlands
Authors: Sonja E van Roeden, Fedor van Houwelingen, Chiel M J Donkers, Sander J Hogewoning, Marit M A de Lange, Wim van der Hoek, Linda M Kampschreur, Marc J M Bonten, Andy I M Hoepelman, Chantal P Bleeker-Rovers, Peter C Wever, Jan Jelrik Oosterheert
Journal: The Lancet Haematology (2018)
TCR repertoire sequencing of 254 resected non-small cell lung cancers to reveal TCR clonality in normal tissues compared to tumor tissues.
Authors: Alexandre Reuben, Rachel Gittelman, Jiexin Zhang, Erik Yusko, Chang-jiun Wu, Ryan O Emerson, Jianhua Zhang, Christopher Tipton, Marissa Vignali, Junya Fujimoto, Jaime Rodriguez-Canales, Stephen Swisher, John Heymach, Harlan Robins, J. Jack Lee, Andrew Futreal, Ignacio Ivan Wistuba, Jianjun Zhang
Journal: Journal of Clinical Oncology (2017)

11500 Background: The mechanisms underlying resistance to immune checkpoint blockade are poorly understood. Major efforts have been made to understand how mutations, through generation of neoantigens, may alter tumor immunogenicity and anti-tumor responses, particularly through T cell responses. However, the T cell repertoire and its interaction with cancers bearing specific molecular alterations have not been systemically studied. Methods: We delineated the landscapes in the T cell receptor (TCR) repertoire, immune infiltration (immunohistochemistry using multiple immune markers), genome (exome sequencing), epigenome (methylation array) and transcriptome (mRNA gene expression array) of 254 resected non-small cell lung cancers (NSCLC), matched normal lung tissues and peripheral blood mononuclear cells (PBMC). We report herein the preliminary analyses of TCR sequencing of NSCLC tumors and matched normal lung tissues. Results: We observed that: 1) Smaller tumors (smaller than median) had a higher T cell infiltrate (p = 0.0016) and higher entropy than larger tumors (p = 0.0098); 2) Tumors from ever/current smokers had higher T cell clonality than former/never-smokers (p = 0.005); 3) TCR clonality was positively correlated with mutational burden (p = 0.0026); 4) Compared to tumors, normal lung tissues demonstrated significantly less T cell infiltration (p = 2.1x10^-11), but a significantly higher clonality (p = 3.9x10^-7). Finally, many T cell clones, including major clones were shared between normal lung tissues and matched NSCLC tumors. Conclusions: Our preliminary data demonstrate the distinct immune microenvironment in different NSCLC tumors may be associated with particular clinicopathological features. The higher TCR clonality in normal lung tissues and overlap of T cell clones between normal lung and NSCLC tumors implies a significant proportion of tumor infiltrating T cells may be a function of constant exposure to mutagens rather than an anti-tumor response. Analysis of the peripheral TCR repertoire, the molecular landscape of these tumors and the association with immune profiling is underway.
Projected Costs of Informal Caregiving for Cardiovascular Disease: 2015 to 2035: A Policy Statement From the American Heart Association
Authors: Sandra B. Dunbar, Olga A. Khavjou, Tamilyn Bakas, Gail Hunt, Rebecca A. Kirch, Alyssa R. Leib, R. Sean Morrison, Diana C. Poehler, Veronique L. Roger, Laurie P. Whitsel
Journal: Circulation (2018)

Introduction: In a recent report, the American Heart Association estimated that medical costs and productivity losses of cardiovascular disease (CVD) are expected to grow from $555 billion in 2015 to $1.1 trillion in 2035. Although the burden is significant, the estimate does not include the costs of family, informal, or unpaid caregiving provided to patients with CVD. In this analysis, we estimated projections of costs of informal caregiving attributable to CVD for 2015 to 2035. Methods: We used data from the 2014 Health and Retirement Survey to estimate hours of informal caregiving for individuals with CVD by age/sex/race using a zero-inflated binomial model and controlling for sociodemographic factors and health conditions. Costs of informal caregiving were estimated separately for hypertension, coronary heart disease, heart failure, stroke, and other heart disease. We analyzed data from a nationally representative sample of 16 731 noninstitutionalized adults ≥54 years of age. The value of caregiving hours was monetized by the use of home health aide workers’ wages. The per-person costs were multiplied by census population counts to estimate nation-level costs and to be consistent with other American Heart Association analyses of burden of CVD, and the costs were projected from 2015 through 2035, assuming that within each age/sex/racial group, CVD prevalence and caregiving hours remain constant. Results: The costs of informal caregiving for patients with CVD were estimated to be $61 billion in 2015 and are projected to increase to $128 billion in 2035. Costs of informal caregiving of patients with stroke constitute more than half of the total costs of CVD informal caregiving ($31 billion in 2015 and $66 billion in 2035). By age, costs are the highest among those 65 to 79 years of age in 2015 but are expected to be surpassed by costs among those ≥80 years of age by 2035. Costs of informal caregiving for patients with CVD represent an additional 11% of medical and productivity costs attributable to CVD. Conclusions: The burden of informal caregiving for patients with CVD is significant; accounting for these costs increases total CVD costs to $616 billion in 2015 and $1.2 trillion in 2035. These estimates have important research and policy implications, and they may be used to guide policy development to reduce the burden of CVD on patients and their caregivers.
Circulating Tumor Cells in Breast Cancer Patients Treated by Neoadjuvant Chemotherapy: A Meta-analysis
Authors: François-Clément Bidard, Stefan Michiels, Sabine Riethdorf, Volkmar Mueller, Laura J Esserman, Anthony Lucci, Bjørn Naume, Jun Horiguchi, Rafael Gisbert-Criado, Stefan Sleijfer, Masakazu Toi, Jose A Garcia-Saenz, Andreas Hartkopf, Daniele Generali, Françoise Rothé, Jeffrey Smerage, Laura Muinelo-Romay, Justin Stebbing, Patrice Viens, Mark Jesus M Magbanua, Carolyn S Hall, Olav Engebraaten, Daisuke Takata, José Vidal-Martínez, Wendy Onstenk, Noriyoshi Fujisawa, Eduardo Diaz-Rubio, Florin-Andrei Taran, Maria Rosa Cappelletti, Michail Ignatiadis, Charlotte Proudhon, Denise M Wolf, Jessica B Bauldry, Elin Borgen, Rin Nagaoka, Vicente Carañana, Jaco Kraan, Marisa Maestro, Sara Yvonne Brucker, Karsten Weber, Fabien Reyal, Dominic Amara, Mandar G Karhade, Randi R Mathiesen, Hideaki Tokiniwa, Antonio Llombart-Cussac, Alessandra Meddis, Paul Blanche, Koenraad d'Hollander, Paul Cottu, John W Park, Sibylle Loibl, Aurélien Latouche, Jean-Yves Pierga, Klaus Pantel
Journal: JNCI Journal of the National Cancer Institute (2018)

We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker.We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study. Secondary end points included distant disease-free survival, locoregional relapse-free interval, and pathological complete response. All statistical tests were two-sided.Data from patients were collected before NCT (n = 1574) and before surgery (n = 1200). CTC detection revealed one or more CTCs in 25.2% of patients before NCT; this was associated with tumor size (P < .001). The number of CTCs detected had a detrimental and decremental impact on overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P < .001), but not on pathological complete response. Patients with one, two, three to four, and five or more CTCs before NCT displayed hazard ratios of death of 1.09 (95% confidence interval [CI] = 0.65 to 1.69), 2.63 (95% CI = 1.42 to 4.54), 3.83 (95% CI = 2.08 to 6.66), and 6.25 (95% CI = 4.34 to 9.09), respectively. In 861 patients with full data available, adding CTC detection before NCT increased the prognostic ability of multivariable prognostic models for overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P = .008).CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. It complements current prognostic models based on tumor characteristics and response to therapy.
Abstract 19579: The Incidence of Stroke and Pericardial Effusion after Pericardial Suture Ligation of the Left Atrial Appendage
Authors: Sandeep R Gangireddy, James O Coffey, Juan Viles-Gonzalez, Jakob S Koruth, Marc A Miller, Andre d'Avila, Srinivas Dukkipati, Vivek Y Reddy
Journal: Circulation (2012)

Introduction: Left atrial appendage closure (LAAC) is an effective alternative to warfarin in nonvalvular AF patients who are intolerant to oral anticoagulation. Our aim was to determine the incidence of stroke and pericardial effusion following pericardial suture ligation of the left atrial appendage. Methods: Retropspective analysis of 16 patients who underwent LAAC with an epicardial suture delivery system (LARIAT) at single center. Pericardial access was obtained using an anterior approach, followed by transeptal puncture. Epicardial and endovascular magnetic-tipped guidewires were then aligned, and the epicardial snare and suture were advanced over the left atrial appendage. After snare closure and suture deployment, TEE and fluoroscopy were used to confirm left atrial appendage exclusion. Patients were discharged on aspirin. Reported stroke or TIA events were confirmed by CT or MRI. Results: Of the 16 patients included, the mean age was 74.2 ±9.1, 56% of patients (9/16) were male, and the mean CHADS2 score was 3.6 ± 1.2; 11 patients (69%) had a prior stroke or TIA. These patients accumulated a total of 9.6 person-years of follow up (5.3 months ±7.7). LAAC was confirmed by repeat TEE at 1.95 ± 3.0 months, and 7/16 patients (44%, 95% CI 10-77%) experienced any size left atrial appendage leak, and 1/16 (6%, 95% CI 0-20%) experienced a large leak (≥3mm). After LAAC, 1/16 patients experienced a stroke. A 71 year old male (CHADS2 = 3) who was not on anticoagulation developed a central retinal artery occlusion 5 months post-procedure. The overall incidence of stroke or TIA was 6%, (95% CI 0-20%). After LAAC, 3/16 patients developed a pericardial effusion (19%, 95% CI 0-40%), of which 2 required pericardiocentesis. Conclusion: We observed a significant rate of pericardial effusion and symptomatic ischemic events after LAAC with an epicardial suture ligation system; further study is needed to assess its relative safety compared to alternate LAAC devices in patients intolerant to oral anticoagulation.
IgG response against prostate-related antigen as potential biomarker for personalized peptide vaccination in metastatic recurrent breast cancer.
Authors: Shuko Saku, Uhi Toh, Mina Okabe, Nobutaka Iwakuma, Shigeki Shichijo, Akira Yamada, Kyogo Itoh, Yoshito Akagi
Journal: Journal of Clinical Oncology (2017)

167 Background: The aim of this study is to identify the prognostic role of serum value of IgG antibody against prostate related-antigen (PRA), including prostate-specific antigen (PSA), prostate specific membrane antigen (PSMA), and prostate acid phosphatase (PAP) in mrBC patients. Methods: Peripheral blood samples of 77 patients with mrBC were analyzed for serum anti-PRA IgG levels before and after 6th and 12th PPV therapy prospectively. Most of the peptides used for PPV are derived from cancer associated antigens expressing in various types of advanced cancers, but the peptides derived from PRAs were not used in this study. Results: After PPV therapy, total serum levels of anti-PRA IgG were significantly increased in 31 mrBC patients (Group 1) compared with remaining 46 rmBC patients (Group 2). Either serum anti-PSA, anti-PAP, and/or anti-PMSA IgGs showed a significant increase in patients of Group 1 after 6th (p=0.045) and 12th PPV treatment (p &lt; 0.001), irrespective of their intrinsic subtypes. The median PFS and median OS of Group 1 patients were 8.1 and 14.3 months, while those of Group 2 patients were 5.1 and 10.8 months, respectively. Anti-PRA IgG levels were significantly associated with PFS (p=0.0073; HR: 0.37) and OS (p=0.025; HR: 0.43) between these two groups, whereas no significant relation was found with age, clinical response rate, and recurrent metastatic status. Conclusions: The Group 1 patients with elevated anti-PRA IgG may have better prognosis compared to Group 2 patients who showed no IgG elevation after PPV treatment for rmBC. These results indicated a clinical significance between pre-and post- treatment measurement of serum anti-PRA IgGs in mrBC patients receiving PPV therapy, and may be a useful prognostic marker for monitoring the outcome to PPV treatment of breast cancer.
Pan-cancer opportunities for off-label immunotherapy based on nonsynonymous mutation burden.
Authors: Todd Cory Knepper, Jamie K. Teer, Christine Marie Walko, Howard L. McLeod
Journal: Journal of Clinical Oncology (2017)

14 Background: In an effort to better predict which cancer patients (pts) are more likely to derive clinical benefit from immunotherapy, an association between increased non-synonymous mutation burden and likelihood of clinical response has been described. This study reports the mutation burden of pts with a variety of advanced cancers within a real-world clinical genomics database in order to highlight opportunities where off-label immunotherapy can be considered. Methods: For each solid cancer assayed by FoundationOne within Moffitt’s Clinical Genomic Action Committee (CGAC) database, a non-synonymous mutation burden was determined. Pts were then grouped by cancer type and descriptive statistics used to describe the mutation burden. For cancers with at least 5 cases, the percentage of pts with a non-synonymous mutation burden exceeding a threshold shown to be suggestive of clinical benefit from immunotherapy ( ≥ 13) is reported. The threshold was derived via linear regression from the “intermediate-high” mutation burden classification of the FoundationOne assay. Results: 520 pts received a FoundationOne test. The median non-synonymous mutation burden was 7 and the mean was 11.4. More pts with cancers that have demonstrated response to immunotherapy had a mutation burden exceeding the threshold (19.7% for lung – 45.0% for melanoma). Pt tumors from cancer types without immunotherapy indications sometimes (5.0% for salivary gland – 10.5% for breast and colorectal cancer) exceeded mutation threshold suggestive of benefit. Conclusions: A meaningful proportion of pts with cancer types without FDA-approved immunotherapies have a mutation burden for which immunotherapy may represent a clinical consideration. [Table: see text]
117P Feasibility of moderate hypofractionated image-guided thoracic irradiation for locally advanced node-positive non-small cell lung cancer patients with very limited lung function
Authors: F. Manapov, O. Roengvoraphoj, J. Taugner, M. Dantes, C. Wijaya, C. Belka, C. Eze
Journal: Journal of Thoracic Oncology (2018)
Regulation of Blood Pressure by Targeting Ca <sub>V</sub> 1.2-Galectin-1 Protein Interaction
Authors: Zhenyu Hu, Guang Li, Jiong-Wei Wang, Suet Yen Chong, Dejie Yu, Xiaoyuan Wang, Jia Lin Soon, Mui Cheng Liang, Yuk Peng Wong, Na Huang, Henry M. Colecraft, Ping Liao, Tuck Wah Soong
Journal: Circulation (2018)

L-type CaV1.2 channels play crucial roles in the regulation of blood pressure. Galectin-1 (Gal-1) has been reported to bind to the I-II loop of CaV1.2 channels to reduce their current density. However, the mechanistic understanding for the downregulation of CaV1.2 channels by Gal-1 and whether Gal-1 plays a direct role in blood pressure regulation remain unclear.In vitro experiments involving coimmunoprecipitation, Western blot, patch-clamp recordings, immunohistochemistry, and pressure myography were used to evaluate the molecular mechanisms by which Gal-1 downregulates CaV1.2 channel in transfected, human embryonic kidney 293 cells, smooth muscle cells, arteries from Lgasl1-/- mice, rat, and human patients. In vivo experiments involving the delivery of Tat-e9c peptide and AAV5-Gal-1 into rats were performed to investigate the effect of targeting CaV1.2-Gal-1 interaction on blood pressure monitored by tail-cuff or telemetry methods.Our study reveals that Gal-1 is a key regulator for proteasomal degradation of CaV1.2 channels. Gal-1 competed allosterically with the CaVβ subunit for binding to the I-II loop of the CaV1.2 channel. This competitive disruption of CaVβ binding led to CaV1.2 degradation by exposing the channels to polyubiquitination. It is notable that we demonstrated that the inverse relationship of reduced Gal-1 and increased CaV1.2 protein levels in arteries was associated with hypertension in hypertensive rats and patients, and Gal-1 deficiency induces higher blood pressure in mice because of the upregulated CaV1.2 protein level in arteries. To directly regulate blood pressure by targeting the CaV1.2-Gal-1 interaction, we administered Tat-e9c, a peptide that competed for binding of Gal-1 by a miniosmotic pump, and this specific disruption of CaV1.2-Gal-1 coupling increased smooth muscle CaV1.2 currents, induced larger arterial contraction, and caused hypertension in rats. In contrasting experiments, overexpression of Gal-1 in smooth muscle by a single bolus of AAV5-Gal-1 significantly reduced blood pressure in spontaneously hypertensive rats.We have defined molecularly that Gal-1 promotes CaV1.2 degradation by replacing CaVβ and thereby exposing specific lysines for polyubiquitination and by masking I-II loop endoplasmic reticulum export signals. This mechanistic understanding provided the basis for targeting CaV1.2-Gal-1 interaction to demonstrate clearly the modulatory role that Gal-1 plays in regulating blood pressure, and offering a potential approach for therapeutic management of hypertension.
Treatment Approaches for Malignant Pleural Effusion
Authors: Yukako Yagi, Kazuhiro Kosugi, Tetsuya Tanimoto
Journal: JAMA (2018)

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Differences in immune profiles of metastatic melanoma patients treated with anti-CTLA-4 and anti-PD-1 combined immunotherapy.
Authors: Tuba Nur Gide, Camelia Quek, Jason Madore, Alexander M. Menzies, Rebecca Dent, Matteo S. Carlino, Alex Guminski, Robyn Saw, John F. Thompson, James S. Wilmott, Richard A. Scolyer, Georgina V. Long
Journal: Journal of Clinical Oncology (2017)

51 Background: Immune checkpoint inhibitors targeting the cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) receptor have significantly improved the outcomes of metastatic melanoma patients resulting in durable response and longer overall survival. However, while some patients exhibit a complete response to immunotherapy, others have demonstrated little to no response. The aim of this study is to examine the immune cell subsets between the good and poor responders to anti-CTLA-4 and anti-PD-1 combined immunotherapy in order to determine potential mechanisms of response and resistance. Methods: Multiplex immunofluorescent staining was performed on pre-treatment formalin-fixed, paraffin-embedded (FFPE) tissue samples from good and poor responders ( n= 17; n= 11 good responders, n= 6 poor responders) for markers including CD8, PD-1, PD-L1, FOXP3 and SOX10. Spectral image analysis was conducted via the Vectra 3.0 imaging system. Quantitative analysis was carried out using the inForm software. Gene signatures associated with the T-cell signalling pathways were identified following RNA sequencing of FFPE samples. Results: Good responders displayed significantly higher levels of baseline intratumoural PD-1 and PD-L1 expression in comparison to the poor responders ( P= 0.01 and P= 0.01 respectively), highlighting their roles as predictive biomarkers of response. Additionally, the CD8 + T-cell to PD-L1 ratio was significantly higher ( P= 0.001) in the tumours of the poor responders, indicating a distinction in the CD8 + T-cell phenotypes between the good and poor responders. Furthermore, analysis of the RNA sequencing data revealed a panel of immune signatures that have been implicated in prognosis and responsiveness to immunotherapy in melanoma. Conclusions: In summary, these findings provide insight into the possible biomarkers of response and resistance to immunotherapy, thus improving our understanding of the mechanisms driving variations in response.
Bioactive thionic compounds and aromatic glycosides from Ligusticum chuanxiong
Authors: Xu Zhang, Bing Han, Ziming Feng, Jianshuang Jiang, Yanan Yang, Peicheng Zhang
Journal: Acta Pharmaceutica Sinica B (2018)

Three new thionic compounds, (S)-2-(2-carboxyl-2-hydroxyethylthio)-ferulic acid (1), (E)-2-methoxy-4-(3-(methylsulfonyl)prop-1-en-1-yl)phenol (2), and thiosenkyunolide C (3), together with two new aromatic glycosides (4 and 5) were isolated from the rhizome of Ligusticum chuanxiong Hort. Two known compounds (6 and 7) were also obtained. Their structures were elucidated based on extensive spectroscopic data (UV, IR, 1D and 2D NMR, and HR-ESI-MS). Furthermore the absolute configurations were established by comparison of their calculated and experimental circular dichroism spectra and by a dimolybdenum tetraacetate [Mo2(AcO)4]-induced circular dichroism procedure. All compounds were evaluated against lipopolysaccharide (LPS)-induced NO production in BV2 cells, and compounds 4 and 5 showed strong inhibitory activities with IC50 values of 2.03 and 3.09 µmol/L, respectively (positive control curcumin, IC50 = 6.17 µmol/L). In addition, compound 1 showed weak proteintyrosine phosphatase-1B (PTP1B) inhibitory activity.