tbuckley/cabot-search huggingface dataset:
Abstract 4234: Machine learning-driven label-free cell sorting for cell therapy
Authors: Hiroshi Ochiai, Keiki Sugimoto
Journal: Cancer Research (2020)

Abstract Ghost cytometry (GC) is a recently realized approach for machine learning-driven analysis of image information without image production and enabled high throughput cell sorting through its integration with a microfluidic sorting technology. When a supervised machine learning is adopted in GC, a classifier model is first trained using a data set comprising of simultaneously measured imaging waveform signals and cell specific (ground truth) labels indicating cell types and functions. This trained model, in turn, is able to infer the cell specific label directly from the imaging waveforms at a speed of several orders of magnitude faster than the other methods, thus enabling subsequent cell sorting at high speed. Here, we investigate the applicability of label-free GC to manufacture and isolate the effective therapeutic cells.First, we tested classification of live T cells from dead cells to understand the potential of GC for monitoring the healthiness of live cells in cell manufacturing processes. A model for classifying the label-free information was trained using labels based on the positivity of annexin V and PI staining and applied to test data. Next, we assessed classification of T cells from live blood samples after hemolysis process. In this experiment, labels of a CD3 marker was used to construct a training data set to develop the T cell classifier. Finally, we applied the label-free GC to identify cells with low glycolytic activity because the cell metabolic status has a big impact on their therapeutic potency and persistency. Selection of the low glycolytic T cell may address current challenges on CAR-T cell therapy such as sustained tumor elimination. As a result, GC was found to classify not only live and dead cells but also apoptotic cells. Moreover, GC was able to discriminate CD3 positive T cells from PBMC with a good accuracy. These results indicate that our label-free GC can detect the healthy live cells without using any surface markers and could be beneficial for monitoring the quality of T cell products. Furthermore, the label-free GC may have a potential to classify the cells based on their phenotypic properties such as metabolic status. We would like to share our recent data at the meeting and discuss the potential of label-free GC for delivering sophisticated therapeutic cells, especially CAR-T cells, with good efficacy and persistency. Citation Format: Hiroshi Ochiai, Keiki Sugimoto. Machine learning-driven label-free cell sorting for cell therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4234.
Long Noncoding RNAs in Cholangiocarcinoma
Authors: Aude Merdrignac, Panagiotis Papoutsoglou, Cédric Coulouarn
Journal: Hepatology (2020)

1InsermUniv RennesNuMeCan (Nutrition Metabolisms and Cancer)UMR_S 1241CHU Rennes, F‐35000RennesFrance *ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: Cédric Coulouarn, Ph.D. Inserm UMR_S 1242, Chemistry, Oncogenesis, Stress Signaling, Centre de Lutte Contre le Cancer Eugène Marquis Rue de la Bataille Flandres Dunkerque, Bat D, F‐35042 Rennes, France E‐mail: [email protected] Tel.: +33‐2‐2323‐3881
Expression of heat-shock proteins (HSPs) in acute myeloid leukemia (AML)
Authors: Xavier G. Thomas, Lydia Campos, Christiane Mounier, Jerome Cornillon, Simone Piselli, Quoc-Hung Le, Annie Viallet, Denis Guyotat
Journal: Cancer Research (2004)

4431  Resistance to chemotherapy-induced apoptosis and a multidrug-resistance phenotype is the major problem in the treatment of AML. HSPs are responsible for chaperoning a vast array of client proteins that are involved in cell signalling, proliferation and survival. To identify prognostic factors alternative or additional to drug-resistance and apoptosis proteins, we studied the impact of the expression of HSPs (HSP27, HSP60, HSP70, HSP90, and HSP110) in newly diagnosed AML. 98 AML patients were studied before induction chemotherapy. HSP27 was expressed in 38 cases (39%), HSP60 in 25 cases (26%), HSP70 in 57 cases (58%), HSP90 in 40 cases (41%), and HSP110 in 29 cases (30%). There were significant correlations between the expression of the 5 HSPs, mostly between HSP90 and HSP110 (r=0.73). HSP expressions were correlated with that of differentiation antigens (CD34, CD14, CD15, CD33). A correlation was found between the expression of all HSPs and that of MRP (p
Abstract 2468: Phosphorylation of Thr55 mediates the tumor suppression activities of p53
Authors: Fan He, Lihong Chen, Jiandong Chen
Journal: Cancer Research (2020)

Abstract P53 is a transcription factor that plays a central role in the regulation of cell cycle, apoptosis and senescence. In unstressed cells, p53 is kept at low level under the strict control of its negative regulators. Upon DNA damage or oncogenic stress, p53 is activated via post-translational modifications. The phosphorylation of serine and threonine, such as Ser15 and Ser46, play important roles in p53 regulation. However, data for Thr55 (T55) phosphorylation is limited and functions of T55 phosphorylation remain elusive. We have previously defined an intramolecular interaction in p53 which modulates DNA binding. The observation of altered intramolecular interactions in T55A and T55D mutants leads to the hypothesis that T55 phosphorylation might affect p53 functions. We generate a T55 phospho-specific antibody to investigate the regulation through this site. The results show T55 phosphorylation is induced by DNA damage compounds. We induce the expression of wild type and T55A mutant p53 in p53 null H1299 cells via the transduction of doxycycline-inducible lentiviral gene expression plasmids. T55A mutant p53 exhibits significantly weaker inhibition of cell viability compared with wild type p53 containing cell in the existence of DNA damaging compounds. Consistently, T55A mutant p53 induces lower mRNA expression level of several important apoptosis related genes and higher MDM2 level in comparison with wild type p53. Overall, our results reveal that phosphorylation of Thr55 is induced by several DNA damaging compounds and alters the expression of p53 target genes, leading to an enhanced tumor suppression. Citation Format: Fan He, Lihong Chen, Jiandong Chen. Phosphorylation of Thr55 mediates the tumor suppression activities of p53 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2468.
Abstract 2361: Mendelian randomization study: The association between metabolic pathways and colorectal cancer risk
Authors: Su Yon Jung, Jeanette Papp, Eric Sobel, Zuo-Feng Zhang
Journal: Cancer Research (2020)

Abstract Purpose: The roles of obesity-related biomarkers and their molecular pathways in the development of postmenopausal colorectal cancer (CRC) have been inconclusive. We examined insulin resistance (IR) as a major hormonal pathway mediating the association between obesity and CRC risk in a Mendelian randomization (MR) framework. Methods: We performed MR analysis using individual-level data of 11,078 non-Hispanic white postmenopausal women from our earlier genome-wide association study. We identified four independent single-nucleotide polymorphisms associated with fasting glucose (FG), three with fasting insulin (FI), and six with homeostatic model assessment-IR (HOMA-IR), which were not associated with obesity. We estimated hazard ratios (HRs) for CRC by adjusting for potential confounding factors plus genetic principal components. Results: Overall, we observed no direct association between the combined 13 IR genetic instruments and CRC risk (HR = 0.96, 95% confidence interval [CI]: 0.78 - 1.17). In phenotypic analysis, genetically raised HOMA-IR exhibited its effects on the increased risk while FG and FI on the reduced risk for CRC, but with a lack of statistical power. Subgroup analyses by physical activity level and dietary fat intake with combined phenotypes showed that genetically determined IR was associated with reduced CRC risk in both physical activity-stratified (single contributor: MTRR rs722025; HR = 0.12, 95% CI: 0.02 - 0.62) and high-fat diet subgroups (main contributor: G6PC2 rs560887; HR = 0.59, 95% CI: 0.37 - 0.94). Conclusions: Complex evidence was observed for a potential causal association between IR and CRC risk, which may contribute to an additional value of intervention trials to lower IR and reduce CRC risk. Citation Format: Su Yon Jung, Jeanette Papp, Eric Sobel, Zuo-Feng Zhang. Mendelian randomization study: The association between metabolic pathways and colorectal cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2361.
Dietary Inflammatory and Insulinemic Potential and Risk of Type 2 Diabetes: Results From Three Prospective U.S. Cohort Studies
Authors: Dong Hoon Lee, Jun Li, Yanping Li, Gang Liu, Kana Wu, Shilpa Bhupathiraju, Eric B. Rimm, Kathryn M. Rexrode, JoAnn E. Manson, Walter C. Willett, Frank B. Hu, Fred K. Tabung, Edward L. Giovannucci
Journal: Diabetes Care (2020)

OBJECTIVE To examine whether proinflammatory and hyperinsulinemic diets are associated with increased risk of type 2 diabetes. RESEARCH DESIGN AND METHODS We prospectively followed 74,767 women from the Nurses’ Health Study (1984–2016), 90,786 women from the Nurses’ Health Study II (1989–2017), and 39,442 men from the Health Professionals Follow-up Study (1986–2016). Using repeated measures of food-frequency questionnaires, we calculated empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores, which are food-based indices that characterize dietary inflammatory or insulinemic potential based on circulating biomarkers of inflammation or C-peptide. Diagnoses of type 2 diabetes were confirmed by validated supplementary questionnaires. RESULTS We documented 19,666 incident type 2 diabetes cases over 4.9 million person-years of follow-up. In the pooled multivariable-adjusted analyses, individuals in the highest EDIP or EDIH quintile had 3.11 times (95% CI 2.96–3.27) and 3.40 times (95% CI 3.23–3.58) higher type 2 diabetes risk, respectively, compared with those in the lowest quintile. Additional adjustment for BMI attenuated the associations (hazard ratio 1.95 [95% CI 1.85–2.05] for EDIP and hazard ratio 1.87 [95% CI 1.78–1.98] for EDIH), suggesting adiposity partly mediates the observed associations. Moreover, individuals in both highest EDIP and EDIH quintiles had 2.34 times higher type 2 diabetes risk (95% CI 2.17–2.52), compared with those in both lowest quintiles, after adjustment for BMI. CONCLUSIONS Higher dietary inflammatory and insulinemic potential were associated with increased type 2 diabetes incidence. Findings suggest that inflammation and hyperinsulinemia are potential mechanisms linking dietary patterns and type 2 diabetes development.
Abstract 11527: Nonsteroidal Anti-inflammatory Drugs Produce Dose-dependent Inhibition of Endothelial Cell Migration
Authors: Kelley Chen, Linda M Graham
Journal: Circulation (2019)

Introduction: Endothelial cell (EC) migration is vital for healing after percutaneous coronary interventions. Activation of canonical transient receptor potential 6 channel by flufenamic acid (FFA)...
Long Non-Coding RNA Derived from lncRNA–mRNA Co-Expression Networks Modulates the Locust Phase Change
Authors: Ting Li, Bing Chen, Pengcheng Yang, Depin Wang, Baozhen Du, Le Kang
Journal: Genomics Proteomics & Bioinformatics (2020)

Long non-coding RNAs (lncRNAs) regulate various biological processes ranging from gene expression to animal behavior. Although protein-coding genes, microRNAs, and neuropeptides play important roles in the regulation of phenotypic plasticity in migratory locust, empirical studies on the function of lncRNAs in this process remain limited. Here, we applied high-throughput RNA-seq to compare the expression patterns of lncRNAs and mRNAs in the time course of locust phase change. We found that lncRNAs responded more rapidly at the early stages of phase transition. Functional annotations demonstrated that early changed lncRNAs employed different pathways in isolation and crowding phases to cope with changes in the population density. Two overlapping hub lncRNA loci in the crowding and isolation networks were screened for functional verification. One of them, LNC1010057, was validated as a potential regulator of locust phase change. This work offers insights into the molecular mechanism underlying locust phase change and expands the scope of lncRNA functions in animal behavior.
Trends in Obesity Prevalence by Race and Hispanic Origin—1999-2000 to 2017-2018
Authors: Cynthia L. Ogden, Cheryl D. Fryar, Crescent B. Martin, David S. Freedman, Margaret D. Carroll, Qiuping Gu, Craig M. Hales
Journal: JAMA (2020)

Cynthia L. Ogden, PhD; Margaret D. Carroll, MSPH; Hannah G. Lawman, PhD; Cheryl D. Fryar, MSPH; Deanna Kruszon-Moran, MS; Brian K. Kit, MD, MPH; Katherine M. Flegal, PhD
Long-lasting SARS-CoV-2-specific T cell memories
Authors: Cansu Cimen Bozkus
Journal: Nature reviews. Immunology (2020)

Inhaled nanobodies against COVID-19Nanobodies (Nbs) are naturally occurring single-domain antibody fragments from camelid heavy-chain antibodies.They have unique biophysical properties, including small size and thermostability, that allow aerosolized administration.In this preprint, Gai et al. describe Nb phage display libraries from camels immunized with the SARS-CoV-2 spike receptorbinding domain (RBD).Out of 381 Nbs identified, 7 blocked the interaction between the virus entry receptor ACE2 and 8 RBD variants.Nb11-59, a candidate with the highest neutralizing activity, was further selected to validate its interaction with the RBD by structure prediction analysis.Production of Nb11-59 in a yeast expression system followed by its nebulization showed potential for rapid and high-quality manufacturing.
Abstract LB-381: Mitigating on-target off-tumor cytotoxicity of EpCAM CAR-T by affinity tuning
Authors: Huan Yang, Janusz Puc, Yanping Yang, Jaclyn E. McCloskey, Yogindra Vedvyas, Hongtao Li, Irene M. Min, Moonsoo M. Jin, Eric v. Hofe
Journal: Cancer Research (2020)

Abstract Chimeric antigen receptor (CAR)-T cell therapy has shown robust anti-cancer responses in hematologic malignancies. However, application of this therapeutic approach to solid tumors has been hindered by multiple challenges, one of which is on-target/off-tumor cytotoxicity to normal tissues. Tumor-specific antigens exclusively present on tumor cells are rare. Most CAR-T cells are designed to target tumor associated antigens (TAAs) expressed in high levels on tumor cells. Yet, normal tissues express these antigens as well, albeit at much lower densities.To mitigate the on-target/off-tumor cytotoxicity, we developed a strategy for fine tuning the affinity of CARs to selectively target tumor cells. Epithelial cell adhesion molecule (EpCAM) is highly expressed in epithelial cells and overexpressed in tumor cells in a variety of epithelial carcinomas. High-affinity (nM range) EpCAM-targeting CAR-T cells kill both normal human epithelial cells and EpCAM-high tumor cells in vitro. To develop CAR-T cells specific to EpCAM-high cancers, we identified low-affinity scFv variants by rational design of amino acid substitutions. The affinities of these scFvs were measured by Surface Plasmon Resonance (SPR). CAR-T cells equipped with low-affinity scFvs showed antigen-dependent activation, proliferation and Th1-like cytokine secretion when co-cultured with target cells having varied levels of EpCAM. Importantly, low-affinity CAR-T cells still lysed EpCAM-high tumor cells but spared normal human epithelial cells in vitro. Treatment of MKN28 xenograft mice with low-affinity CAR-T cells resulted in tumor regression and prolonged survival. Moreover, transcriptomic profiling of CAR-T cells revealed significant differences in gene expression levels between high- and low- affinity CARs, particularly as they relate to the functional state of these CAR-T cells, and their resistance to exhaustion. Our results show that rational design of scFv can aid in the identification of CARs that are minimally reactive toward normal tissues while effectively eliminating tumors. Furthermore, affinity-tuned CARs demonstrate better overall fitness and antitumor activity in vivo. This affinity fine-tuning approach shows promise as a general strategy for identifying a therapeutic window for CAR-T cells targeting novel TAAs that may have been overlooked because of basal expression levels in normal tissues. Citation Format: Huan Yang, Janusz Puc, Yanping Yang, Jaclyn E. McCloskey, Yogindra Vedvyas, Hongtao Li, Irene M. Min, Moonsoo M. Jin, Eric v. Hofe. Mitigating on-target off-tumor cytotoxicity of EpCAM CAR-T by affinity tuning [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-381.
P255 Non-ischemic myocardial injury in heart failure is significantly associated with a higher symptomatic burden and higher circulating levels of sST2, inflammation mediators and natriuretic peptides
Authors: Josip Anđelo Borovac, Duška Glavaš, Zora Sušilović Grabovac, Anteo Bradarić, Daniela Šupe Domić, Darko Duplančić, Joško Božić
Journal: European Journal of Heart Failure (2020)
Comparison Between Ticagrelor and Clopidogrel in Elderly Patients With an Acute Coronary Syndrome
Authors: Karolina Szummer, Maria E. Montez-Rath, Joakim Alfredsson, David Erlinge, Bertil Lindahl, Robin Hofmann, Annica Ravn-Fischer, Per Svensson, Tomas Jernberg
Journal: Circulation (2020)

Background: The comparative efficacy and safety of ticagrelor versus clopidogrel in older patients with myocardial infarction (MI) has received limited study. Methods: We performed an observational analysis of all patients ≥80 years (n=14 005) who were discharged alive with aspirin combined with either clopidogrel (60.2%) or ticagrelor (39.8%) after a MI between 2010 and 2017 registered in the national registry SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies). Inverse probability treatment weighting was used in Cox regression models to adjust for differences in demographics, in-hospital therapies, and medications. The primary ischemic outcome (death, MI, or stroke), and bleeding were obtained from national registries at 1 year. A sensitivity analysis in &lt;80-year-old patients was performed. Results: In patients ≥80 years, the incidence of the primary ischemic outcome (hazard ratio [HR], 0.97 [95% CI, 0.88–1.06]) was similar for ticagrelor- and clopidogrel-treated patients. Ticagrelor was associated with a 17% and 48% higher risk of death (HR, 1.17 [95% CI, 1.03–1.32]) and bleeding (HR, 1.48 [95% CI, 1.25–1.76]), but a lower risk of MI (HR, 0.80 [95% CI, 0.70–0.92]) and stroke (HR, 0.72 [95% CI, 0.56–0.93]). In &lt;80-year-old patients, the incidence of the primary ischemic outcome was 17% (HR, 0.83 [95% CI, 0.77–0.89]) lower with ticagrelor. Ticagrelor was associated with 15% (HR, 0.85 [95% CI, 0.76–0.96]) lower risk of death, 32% higher risk of bleeding (HR, 1.32 [95% CI, 1.18–1.47]), but lower risk of MI (HR, 0.82 [95% CI, 0.75–0.91]) and stroke (HR, 0.82 [95% CI, 0.69–0.98]). Conclusions: Ticagrelor use among elderly patients with MI was associated with higher risk of bleeding and death compared with clopidogrel. A randomized study of ticagrelor versus clopidogrel in the elderly is needed.
OP0132 Myositis and pregnancy
Authors: CA Silva, DA Isenberg
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Polymyositis and dermatomyositis are the most common form of idiopathic inflammatory myopathy, overall the female to male ratio is 2–3: 1. The age at presentation is most often between 40 and 60 years. Pregnancies in these patients are uncommon, and the overall maternal and foetal risks are not well defined in patients with myositis. <h3>Objectives</h3> We assessed the prevalence and outcome of pregnancy in 37 patients with dermatomyositis and polymyositis. <h3>Methods</h3> 54 patients with myositis have been treated between 1976 and 2000 at the Bloomsbury Rheumatology Unit, University College/Middlesex Hospital. A prospective record of all such patients had been kept by one of us (DAI). All patients meet the Bohan and Peter Criteria for DM and PM. The presence of another autoimmune disease was noted as appropriate. Patients were reviewed on a regular basis in a specialist outpatient clinic, and for all patients basic demographic data, age at onset, treatment, number of pregnancies, activity of the disease during pregnancy were noted. For the purposes of this study all of the available 37 patients were examined by one of us (CS): 28 females and 9 males. <h3>Results</h3> The female patients medium age was 44 years, with age at onset ranging from 16 to 64. 16 have Dermatomyositis/Polymyositis (7- PM/9- DM) and 12 have myositis as part of an overlap syndrome (SLE (7 patients), 2 patients with RA, 2 with SS, and 2 with Scl). Only 3 of our patients have been pregnant after the onset of the disease. One, with a poor control of her disease, had an abortion during the first trimester, and was also on treatment with MTX. The other two had the disease under control and 2 normal pregnancies with good foetal outcome was achieved. Both suspended immunosupressants during pregnancy and were able to decrease steroid dosage, without increasing disease activity. <h3>Conclusion</h3> Pregnancy in myositis patients is a rare event. Pregnancies occuring in myositis patients with the disease under clinical remission can result in good foetal outcome. The activity of the disease remains stable. These results are consistent with the literature from recent years, and are probable due to better control of disease activity.
Safety and immunogenicity of a novel hexavalent group B streptococcus conjugate vaccine in healthy, non-pregnant adults: a phase 1/2, randomised, placebo-controlled, observer-blinded, dose-escalation trial
Authors: Judith Absalon, Nathan Segall, Stan L Block, Kimberly J Center, Ingrid L Scully, Peter C Giardina, James Peterson, Wendy J Watson, William C Gruber, Kathrin U Jansen, Yahong Peng, Samantha Munson, Danka Pavliakova, Daniel A Scott, Annaliesa S Anderson
Journal: The Lancet Infectious Diseases (2020)
Hypoxia‐induced factor‐1α induces NLRP3 expression by M1 macrophages in noneosinophilic chronic rhinosinusitis with nasal polyps
Authors: Bing Zhong, Jintao Du, Feng Liu, Yafeng Liu, Shixi Liu, Jie Zhang, Ping Lin, Jiao Zhou, Jing Liu, Hsiao Hui Ong, Kai Sen Tan, Deyun Wang, Luo Ba
Journal: Allergy (2020)

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