tbuckley/cabot-search huggingface dataset:
Abstract 3580: Enhancing adoptive cell therapies through exogenous regulation
Authors: Celeste Richardson, Kutlu Elpek, Michelle Ols, Tariq Kassum, Steve Shamah
Journal: Cancer Research (2018)

Abstract Adoptive cell therapy with chimeric antigen receptor (CAR) modified T cells has demonstrated remarkable clinical efficacy in the treatment of certain B cell malignancies and more recently in multiple myeloma. However, in solid tumors, CAR-T therapy has been far less successful, likely due to the lack of robust CAR-T cell expansion, the immunosuppressive microenvironment, and clonal heterogeneity within these tumors. The trafficking of CAR-T cells to tumor sites provides an opportunity for selective delivery of cargo that can enhance CAR-T cell activity at the site of the tumor. Interleukin-12 (IL12) and membrane tethered interleukin-15 (mbIL15) have previously been shown to enhance CAR-T activity, yet the unregulated expression of either compromises safety and/or efficacy. The Obsidian Therapeutics platform equips engineered immune cells with new functionalities whose activity can be regulated via the administration of FDA-approved small-molecule drugs, putting dosing control back in the hands of the treating physician. We utilize small, fully human protein sequences called destabilizing domains (DDs) that confer reversible destabilization to a fused target protein. In the absence of ligand the fusion protein is degraded, whereas the presence of small molecule ligand restores expression and functionality. Furthermore, stabilization is titratable with small molecule ligand dose, providing finely tuned control over target protein expression and function. We have applied our technology to create DD-IL12 and DD-mbIL15 “cassettes” that provide exogenous regulation of cytokine activity when transduced into CAR-Ts for enhanced cellular function. We describe here the successful implementation of the DD technology in engineered primary human T cells and show small-molecule ligand controlled regulation of DD-IL12 and DD-mbIL15 protein expression in vivo in mouse models. These data demonstrate the feasibility of exogenous control over protein expression in primary human T cells for the development of next-generation CAR-T cell products with enhanced efficacy and more favorable safety profiles. Citation Format: Celeste Richardson, Kutlu Elpek, Michelle Ols, Tariq Kassum, Steve Shamah. Enhancing adoptive cell therapies through exogenous regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3580.
Abstract 5587: Sample quality control of cell-free DNA
Authors: Melissa H. Liu, Eva Graf
Journal: Cancer Research (2018)

Abstract Sequencing of cell-free DNA (cfDNA) extracted from blood specimens or other body fluids is possible due to the establishment of low input library protocols for next-generation sequencing workflows. Accurate quantification of cfDNA samples is essential to determine suitable input amounts for cfDNA library preparation prior to sequencing. The main component of cfDNA samples is the mononucleosome with a size around 170 bp, sometimes with additional species representing nucleosome multimers. Further, cfDNA samples may contain larger DNA fragments dependent on the donor's health status, preanalytical sample treatment, or extraction method. High molecular weight material can negatively influence library preparation and subsequently result in lower sequencing depth. Therefore, reliable quantification of cfDNA requires a method that separates DNA fragments by size, such as electrophoresis. This poster shows the use of a new cfDNA assay for the 2100 Bioanalyzer system as an add-on for the High Sensitivity DNA assay. The assay enables automated cfDNA quantification with pre-defined regions. Moreover, the results include sample purity as a score to qualify cfDNA samples according to their contamination level with high molecular weight material. The features of the assay are described with examples of typical sample patterns. Citation Format: Melissa H. Liu, Eva Graf. Sample quality control of cell-free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5587.
Abstract 5259: Cancer incidence in relation to body fatness in China: Evidence from a large population-based cohort study
Authors: Lu Wang, Guangfu Jin, Canqing Yu, Jun Lv, Yu Guo, Zheng Bian, Ling Yang, Yiping Chen, Zhibin Hu, Feng Chen, Zhengming Chen, Liming Li, Hongbing Shen
Journal: Cancer Research (2018)

Abstract Body fatness has been associated with several cancers in developed countries, but little is known in China. The purpose of this study was to examine the association between body fatness and cancer incidence, with different anthropometric measures, and compare their predicting values. Between June 2004 and July 2008, the China Kadoorie Biobank (CKB) study recruited 0.5 million adults aged 30-79 years from 10 geographically diverse areas across China, and followed up until December, 2015. Body-mass index (BMI), body fat percentage (BFP), waist circumference (WC), and waist-to-hip ratio (WHR) were measured at baseline. Cox regression yielded adjusted hazard ratios (HRs) associating incidence of all cancers and 15 site-specific cancers with different anthropometric measures, adjusting for education level, marital status, annual household income, alcohol consumption, smoking status and physical activity, and stratifying by age at risk, sex, and region. We compared the ability of cancer risk prediction between different anthropometric measures through a receiver operating characteristic (ROC) analysis. Among 508,362 participants, the overall mean (SD) BMI was 23.66 (3.38) kg/m2, 31.11% of men and 34.24% of women were overweight or obesity (BMI≥25.0kg/m2), and 4.41% of men and 4.26% of women were underweight (BMI&amp;lt;18.5kg/m2). 21,474 incident cancers were identified over an average of 8.94 years of follow-up. Each 5 kg/m2 increase in BMI was associated with an increased risk of endometrial (HR, 2.01; 95% CI, 1.72 to 2.35), postmenopausal breast (HR, 1.29; 95% CI, 1.18 to 1.40), colorectal (HR, 1.17; 95% CI, 1.10 to 1.25) and cervical (HR, 1.15; 95% CI, 1.03 to1.29) cancer, whereas it was associated with a reduced risk of oesophageal (HR, 0.73; 95% CI, 0.67 to 0.79), lung (HR, 0.78; 95% CI, 0.74 to 0.82), liver (HR, 0.85; 95% CI, 0.79 to 0.92), and stomach (HR, 0.88; 95% CI, 0.82 to 0.94) cancer. BMI was the best risk prediction measure for postmenopausal breast and endometrial cancer, whereas BFP were the best for oesophageal, lung, liver and stomach cancer, and WC and WHR did for colorectal cancer. BMI is related to the incidence of several cancers in China. Obesity and overweight, as well as underweight, contribute to the cancer incidence in China. Other anthropometric measures may add information for cancer-specific risk prediction. Citation Format: Lu Wang, Guangfu Jin, Canqing Yu, Jun Lv, Yu Guo, Zheng Bian, Ling Yang, Yiping Chen, Zhibin Hu, Feng Chen, Zhengming Chen, Liming Li, Hongbing Shen. Cancer incidence in relation to body fatness in China: Evidence from a large population-based cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5259.
Abstract 4472: Downregulation of POTEG predicts poor prognosis in esophageal squamous cell carcinoma
Authors: Yan Li
Journal: Cancer Research (2018)

Abstract POTE ankyrin domain family, member G (POTEG) belongs to POTE family. The POTE gene family encodes very closely related proteins that are highly expressed in prostate, ovary, testis, and placenta. Recent studies indicated that the POTE proteins have a pro-apoptotic function. To examine whether POTEG also underwent apoptosis in ESCC cancer cells and the functions of POTEG in the development of esophageal squamous cell carcinoma (ESCC), we determined the location and expression of POTEG in ESCC cancer cells. Clinical association studies determined that POTEG downregulation was associated with poor clinical outcomes. Ectopic re-expression of POTEG effectively suppressed the tumorigenesis and metastasis of ESCC cells in vitro and in vivo, including the inhibition of cell growth rate, foci formation, soft agar colony formation, migration, invasion and tumor formation in nude mice. Molecular analyses revealed that POTEG downregulated CDKs, leading to subsequent inhibition of Rb phosphorylation, and consequently arrested Cell Cycle at G1/S Checkpoint. Prospectively, POTEG can reduce the level of anti-apoptotic proteins, while promote the level of proapoptotic proteins and inducing apoptosis. On the other side, POTEG inhibit metastasis by reducing epithelial-mesenchymal transition in ESCCs. Taken together, our results revealed that POTEG has a pivotal function in ESCC pathogenesis, with possible use as a biomarker and intervention point for new therapeutic strategies. Citation Format: Yan Li. Downregulation of POTEG predicts poor prognosis in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4472.
Abstract 3787: Exploring the effect of chemotherapies on STING-dependent cytokine release
Authors: Richard D. Wilkinson, David I. Johnston, Eileen E. Parkes, Nuala McCabe, Richard D. Kennedy
Journal: Cancer Research (2018)

Abstract Introduction: Blockade of PD-1/PD-L1 has shown potent antitumor activity but these therapies are limited to certain diseases with higher intrinsic somatic mutation burden. A key research priority is now optimising response to these agents in diseases with limited clinical response. Activation of the cGAS-STING innate immune pathway has been identified as synergistic with anti-PD-1 therapy, and also a means of overcoming resistance to IO (immune-oncology therapy). We have reported activation of the cGAS-STING immune pathway as a result of cytosolic DNA released in response to intrinsic and extrinsic DNA damage, and that upregulation of PD-L1 in response to DNA damage is dependent on STING. Therefore, activating the STING pathway as a combination treatment with IO therapy could result in improved clinical responses. Experimental procedures: We perform qPCR analysis of the STING target genes, CXCL10/CCL5 after treatment with different classes of chemotherapy. We perform immunofluorescence to determine dsDNA translocation to the cytosol and the requirement of STING for this, an siRNA screening approach was used to identify the key nucleases involved in cytosolic dsDNA translocation and chemokines expression. Results: We observed increased expression of CXCL10/CCL5 gene expression following treatment with the topoisomerase I (irinotecan) and II (Doxorubicin and Etoposide) inhibitors. This chemokine expression was associated with increased expression of dsDNA in the cytosol. Using an siRNA approach, depletion of STING and the DNA nuclease MUS81 demonstrated abrogation of CXCL10/CCL5 expression following treatment with Doxorubicin. Conclusions: Here, we show that topoisomerase I and II inhibitors are the most potent chemotherapy at activating the cGAS-STING pathway and associated expression of interferon-dependent chemokines. We propose that combination therapies of topoisomerase I and II inhibitors with IO therapy will be effective in tumours which have had limited clinical response to single agent IO therapy. Citation Format: Richard D. Wilkinson, David I. Johnston, Eileen E. Parkes, Nuala McCabe, Richard D. Kennedy. Exploring the effect of chemotherapies on STING-dependent cytokine release [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3787.
Cryoballoon Versus Open Irrigated Radiofrequency Ablation in Patients With Paroxysmal Atrial Fibrillation
Authors: ArminLuik, AndreaRadzewitz, MeinhardKieser, MarleneWalter, PeterBramlage, PatrickHörmann, KerstinSchmidt, NicolasHorn, MariaBrinkmeier-Theofanopoulou, KevinKunzmann, TobiasRiexinger, GerhardSchymik, MatthiasMerkel, ClausSchmitt
Journal: Circulation (2015)

Background—There is a lack of data on the comparative efficacy and procedural safety of open irrigated radiofrequency (RF) and cryoballoon catheter (CB) ablation for pulmonary vein isolation in patients with paroxysmal atrial fibrillation. Methods and Results—In a prospective, noninferiority study, 315 patients were randomly assigned to RF (n=159) or CB (n=156) ablation. The primary end point was freedom from atrial arrhythmia with absence of persistent complications. Patients were largely comparable between groups with more vascular disease in the RF group (8.2% versus 2.6% for CB; P=0.028). The primary end point at 12 months was achieved by 70.7% with RF and 73.6% with CB (multiple procedure success), including 31 redo procedures in each group (19.5% of RF versus 19.9% of CB; P=0.933). For the intention-to-treat population, noninferiority of CB was revealed for the predefined inferiority margin (risk difference, 0.029; 95% confidence interval, −0.074 to 0.132; P<0.001). Rates at 6 months were 63.1% and ...
Regional Differences in the Recovery Course of Tachycardia-Induced Changes of Atrial Electrophysiological Properties
Authors: Shih-HuangLee, Fang-YueLin, Wen-ChungYu, Jun-JackCheng, PeiliangKuan, Chi-RenHung, Mau-SongChang, Shih-AnnChen
Journal: Circulation (1999)

Background—Regional differences in recovery of tachycardia-induced changes of atrial electrophysiological properties have not been well studied. Methods and Results—In the control group (5 dogs), atrial effective refractory period (AERP) and inducibility of atrial fibrillation (AF) were assessed before and every 4 hours for 48 hours after complete atrioventricular junction (AVJ) ablation with 8-week VVI pacing. In experimental group 1 (15 dogs), AERP and inducibility of AF were assessed before and after complete AVJ ablation with 8-week rapid right atrial (RA) pacing (780 bpm) and VVI pacing. In experimental group 2 (7 dogs), AERP and inducibility of AF were assessed before and after 8-week rapid left atrial (LA) pacing and VVI pacing. AERP and inducibility and duration of AF were obtained from 7 epicardial sites. In the control group, atrial electrophysiological properties obtained immediately and during 48-hour measurements after pacing did not show any change. In the 2 experimental groups, recovery of ...
Abstract 20158: Consequences of Co-isolation of Brain and Heart on the Function of Isolated Cardiac Mitochondria in a Swine Model of Cardiopulmonary Resuscitation
Authors: Timothy R Matsuura, Jason A Bartos, Adamantios Tsangaris, Kadambari Chandra Shekar, Matthew D Olson, Jennifer N Rees, Scott H McKnite, Demetris Yannopoulos
Journal: Circulation (2015)

Introduction: Functional testing of isolated mitochondria is a powerful in vitro tool for determining mitochondrial health following an ischemic stress. Successful preservation of intact mitochondria requires an efficient harvest technique under cold conditions. As heart and brain mitochondria are vital to the success of cardiopulmonary resuscitation (CPR), we sought to determine the consequence of co-isolation of these organs on cardiac mitochondrial function in a porcine model of cardiac arrest. Methods: After 15 min of ventricular fibrillation, 36 animals were randomized to active compression decompression + impedance threshold device (ACD-ITD) CPR (Control), or ACD-ITD CPR + ischemic postconditioning (IPC) and further randomized to heart-only (Control n=9, IPC n=11) or heart + brain mitochondrial isolation (Control n=8, IPC n=8). IPC consisted of 3 cycles of 20 sec compression / 20 sec pause for the first 2 min of CPR. Cardiac and brain mitochondria were isolated via differential centrifugation 4 min after initiation of CPR. To minimize warm ischemia, brain biopsies were performed while animals were supine with uninterrupted chest compressions. Heart biopsies were subsequently performed via intercostal incision. Respiratory control index (RCI) and calcium retention capacity (CRC) were measured for complex I and II substrates. Results: Due to technique, heart isolation was delayed by 100 s in heart + brain vs. heart-only animals. In animals with heart-only isolation, IPC increased complex I and II RCI and complex I CRC compared to Controls. In animals with heart + brain isolation, cardiac complex I and II RCI and complex I CRC decreased within the IPC group but not within the Control group. There were no differences in brain mitochondrial function between IPC and Controls. Conclusion: Mitochondrial isolation from multiple organs must consider warm ischemia that may worsen mitochondrial performance. Communication between the brain and heart during biopsy appears to be mediated by a mechanism antagonistic to the beneficial effects of IPC, as isolation of heart and brain resulted in deleterious cardiac mitochondrial performance in IPC but not in Controls. Further investigation is warranted to refine multi-organ mitochondrial isolation.
Abstract 12780: Impact of Atrial Fibrillation on Exercise Intolerance in Patients With Preserved Left Ventricular Ejection Fraction
Authors: ToshihikoGoto, MarinaIshida, ShoheiKikuchi, KazuakiWakami, KentoMori, HidekatsuFukuta, NobuyukiOhte
Journal: Circulation (2016)

Introduction: When atrial fibrillation (AF) develops, there is loss of the atrial kick, with consequent decrease of cardiac output. Therefore, AF is recognized as an exacerbating factor for heart failure in patients with heart disease. However, the relationship between permanent AF and exercise intolerance in this population has been incompletely understood. Accordingly, we examined whether the presence of AF exacerbates exercise tolerance in patients with preserved left ventricular ejection fraction (LVEF). Methods: We studied 402 patients (age 68.0±9.6 years; male 67.5%) with 370 in sinus rhythm (SR) and with 32 in permanent AF. All patients had preserved LVEF (>50%) and were 40 years old or more. Patients underwent cardio-pulmonary exercise testing (CPX) including an analysis for oxygen uptake at peak exercise (peak VO2). Before CPX, comprehensive Doppler echocardiography was carried out. Early diastolic transmitral velocity (E) and mitral annular velocity during early diastole (e’) were measured. Resu...
Semiconducting Photosensitizer‐Incorporated Copolymers as Near‐Infrared Afterglow Nanoagents for Tumor Imaging
Authors: Dong Cui, Chen Xie, Jingchao Li, Yan Lyu, Kanyi Pu
Journal: Advanced Healthcare Materials (2018)

The fact that cancer metastasis is the main cause of death for most cancer patients necessitates the development of imaging tools for sensitive detection of metastases. Although optical imaging has high temporospatial resolution, tissue autofluorescence compromises the sensitivity for in vivo imaging of cancer metastasis. Herein, the synthesis of a series of photosensitizer-incorporated poly(p-phenylenevinylene)-based semiconducting copolymers and their utility as near-infrared (NIR) afterglow imaging nanoagents that emit light after cessation of light irradiation are reported. As compared with nondoped nanoparticles, the nanoparticles derived from the photosensitizer-incorporated copolymers have red-shifted NIR luminescence and amplified afterglow signals, allowing the detection of tiny peritoneal metastatic tumors almost invisible to naked eye. Moreover, the intrinsic oxygen-sensitive nature of afterglow makes those nanoagents potentially useful for in vivo imaging of oxygen levels. Thus, this study introduces a generation of light-excitation-free background-minimized optical imaging agents for the sensitive detection of diseased tissues in vivo.
Relevant Ventricular Septal Defect Caused by Steam Pop During Ablation of Premature Ventricular Contraction
Authors: RobertSchönbauer, PhilippSommer, MartinMisfeld, BorislavDinov, LukasFiedler, YanHuo, ThomasGaspar, GerhardHindricks, ArashArya
Journal: Circulation (2013)
CYP2D6-SPECIFIC CD4+CD25+REGULATORY T-CELLS INHIBIT TH1 AND TH17, BUT PROMOTE TH2 CYTOKINE SECRETION IN PATIENTS WITH AUTOIMMUNE HEPATITIS TYPE 2
Authors: Maria Serena Longhi, Munther J. Hussain, Giorgina Mieli-Vergoni, Yun Ma, Diego Vergani
Journal: Hepatology (2008)
Composition of pertussis vaccine given to infants determines long-term T cell polarization
Authors: Stanley A. Plotkin
Journal: Journal of Clinical Investigation (2018)

The introduction of a whole-cell vaccine against Bordetella pertussis, the causative agent of whooping cough, dramatically reduced disease incidence. Unfortunately, the whole-cell formulation also induces severe reactions in some infants. Because of this, acellular vaccines have been developed, but they are used exclusively in high-income countries. However, the acellular vaccines do not provide long-term protection, and despite the use of routine boosters, the disease is on the rise. In this issue of the JCI, da Silva Antunes and colleagues demonstrate that the whole-cell vaccines promote long-term polarization toward Th1 and Th17 responses, while the acellular vaccines induce Th2 polarization. Moreover, this polarization is long term, as the response to acellular boosters is dependent on the initial vaccine given in infancy. The authors speculate that Tregs may be induced by initial acellular vaccine administration. The results of this study have important implications for the development of pertussis vaccination strategies that would induce Th1 and Th17 polarization.
Broad-Based Molecular Testing for Lung Cancer
Authors: Paul A. Bunn, Dara L. Aisner
Journal: JAMA (2018)

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