tbuckley/cabot-search huggingface dataset:
Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference
Authors: Paul J. Hop, René Luijk, Lucia Daxinger, Maarten van Iterson, Koen F. Dekkers, Rick Jansen, Bastiaan T. Heijmans, Peter A. C. ’t Hoen, Joyce van Meurs, Rick Jansen, Lude Franke, Dorret I. Boomsma, René Pool, Jenny van Dongen, Jouke J. Hottenga, Marleen M. J. van Greevenbroek, Coen D. A. Stehouwer, Carla J. H. van der Kallen, Casper G. Schalkwijk, Cisca Wijmenga, Sasha Zhernakova, Ettje F. Tigchelaar, P. Eline Slagboom, Marian Beekman, Joris Deelen, Diana van Heemst, Jan H. Veldink, Leonard H. van den Berg, Cornelia M. van Duijn, Aaron Isaacs, André G. Uitterlinden, P. Mila Jhamai, Michael Verbiest, H. Eka D. Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Hailiang Mei, Maarten van Iterson, Dasha V. Zhernakova, Peter van ’t Hof, Patrick Deelen, Peter A. C. ’t Hoen, Martijn Vermaat, René Luijk, Marc Jan Bonder, Freerk van Dijk, Wibowo Arindrarto, Szymon M. Kielbasa, Erik. W. van Zwet, Peter-Bram ’t Hoen, Joyce B. J. van Meurs, Peter A. C. ’t Hoen, M. Arfan Ikram, Marleen M. J. van Greevenbroek, Dorret I. Boomsma, P. Eline Slagboom, Jan H. Veldink, Erik W. van Zwet, Bastiaan T. Heijmans
Journal: Genome biology (2020)

Abstract Background DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data. Results By employing genetic instruments as causal anchors, we establish directed associations between gene expression and distant DNA methylation levels, while ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. The identified genes are enriched for transcription factors, of which many consistently increased or decreased DNA methylation levels at multiple CpG sites. In addition, we show that a substantial number of transcription factors affected DNA methylation at their experimentally determined binding sites. We also observe genes encoding proteins with heterogenous functions that have widespread effects on DNA methylation, e.g., NFKBIE , CDCA7(L) , and NLRC5 , and for several examples, we suggest plausible mechanisms underlying their effect on DNA methylation. Conclusion We report hundreds of genes that affect DNA methylation and provide key insights in the principles underlying epigenetic regulation.
Fluorescence background quenching as a means to increase Signal to Background ratio - a proof of concept during Nerve Imaging
Authors: Tessa Buckle, Steffen van der Wal, Danny M. van Willigen, Germaine Aalderink, Gijs H. KleinJan, Fijs W.B. van Leeuwen
Journal: Theranostics (2020)

Introduction: Adequate signal to background ratios are critical for the implementation of fluorescence-guided surgery technologies.While local tracer administrations help to reduce the chance of systemic side effects, reduced spatial migration and non-specific tracer diffusion can impair the discrimination between the tissue of interest and the background.To combat background signals associated with local tracer administration, we explored a pretargeting concept aimed at quenching non-specific fluorescence signals.The efficacy of this concept was evaluated in an in vivo neuronal tracing set-up.Methods: Neuronal tracing was achieved using a wheat germ agglutinin (WGA) lectin .functionalized with an azide-containing Cy5 dye (N3-Cy5-WGA).A Cy7 quencher dye (Cy7-DBCO) was subsequently used to yield Cy7-Cy5-WGA, a compound wherein the Cy5 emission is quenched by Förster resonance energy transfer to Cy7.The photophysical properties of N3-Cy5-WGA and Cy7-Cy5-WGA were evaluated together with deactivation kinetics in situ, in vitro (Schwannoma cell culture), ex vivo (muscle tissue from mice; used for dose optimization), and in vivo (nervus ischiadicus in THY-1 YFP mice).Results: In situ, conjugation of Cy7-DBCO to N3-Cy5-WGA resulted in >90% reduction of the Cy5 fluorescence signal intensity at 30 minutes after addition of the quencher.In cells, pretargeting with the N3-Cy5-WGA lectin yielded membranous staining, which could efficiently be deactivated by Cy7-DBCO over the course of 30 minutes (91% Cy5 signal decrease).In ex vivo muscle tissue, administration of Cy7-DBCO at the site where N3-Cy5-WGA was injected induced 80-90% quenching of the Cy5-related signal after 10-20 minutes, while the Cy7-related signal remained stable over time.In vivo, Cy7-DBCO effectively quenched the non-specific background signal up to 73% within 5 minutes, resulting in a 50% increase in the signal-to-background ratio between the nerve and injection site. Conclusion:The presented pretargeted fluorescence-quenching technology allowed fast and effective reduction of the background signal at the injection site, while preserving in vivo nerve visualization.While this proof-of-principle study was focused on imaging of nerves using a fluorescent WGA-lectin, the same concept could in the future also apply to applications such as sentinel node imaging.
Abstract 5493: Mathematical modeling of antibody nanoconjugates transport quantifies the impact of the tumor microenvironment on drug penetration
Authors: Cristina Vaghi, Anne Rodallec, Guillaume Sicard, Florian Correard, Raphaelle Fanciullino, Joseph Ciccolini, Clair Poignard, Sebastien Benzekry
Journal: Cancer Research (2020)

Abstract One of the major challenges in breast cancer treatment is the high toxicity associated with cytotoxic agents. To overcome this issue, we developed nanoparticles conjugated with cancer cell specific antibodies (trastuzumab) to improve drug delivery to the tumor, while sparing healthy tissues. These antibody nano-conjugates (ANCs) consist in docetaxel-encapsulated liposomes engrafted with trastuzumab on the surface. Intra-tumor penetration properties of these ANCs are not fully understood and could be improved. To this end, mathematical modeling can provide quantitative tools to obtain a description of the ANCs transport inside a tumor. Few models in literature characterize the nanoparticle penetration in tumors. We derived a multi-scale model to obtain a description of the fluid flow and nanoparticle transport in the tumor interstitium and vessels. Moreover, there is a lack of studies that integrate spatial data to theoretical models. Here, we aim at filling this gap. Experimental data - carried on human MDA-MB-231 xenografts - included ex-vivo microscopy images of tumor sections obtained from different regions of the tumor (central and peripheral) using fluorescence imaging. This data allowed to recover the tumor microstucture. Our multi-scale model consisted of two Darcy equations for the fluid flow and two convection-diffusion equations governing the ANCs penetration, including the porosity of the medium. Eventually, our model was calibrated with the ex-vivo imaging data. Simulations confirmed that the tumor microsctructure influences the macroscale flow dynamics and ANC delivery in the tumor interstitium. The model also provides quantitative predictions of the impact of the tumor microenvironment (e.g., heterogeneity, vessel leakage and interstitium permeability) on the accumulation and penetration of ANCs. This methodology could be further applied to personalize the dose of injected nanoparticles according to a patient's specific tumor histology. Citation Format: Cristina Vaghi, Anne Rodallec, Guillaume Sicard, Florian Correard, Raphaelle Fanciullino, Joseph Ciccolini, Clair Poignard, Sebastien Benzekry. Mathematical modeling of antibody nanoconjugates transport quantifies the impact of the tumor microenvironment on drug penetration [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 5493.
Development of paediatric non-stage prognosticator guidelines for population-based cancer registries and updates to the 2014 Toronto Paediatric Cancer Stage Guidelines
Authors: Sumit Gupta, Joanne Aitken, Ute Bartels, Nickhill Bhakta, Mihaela Bucurenci, James D Brierley, Beatriz De Camargo, Eric Chokunonga, Jessica Clymer, Dana Coza, Chris Fraser, Soad Fuentes-Alabi, Gemma Gatta, Thomas Gross, Zsuzsanna Jakab, Betsy Kohler, Tezer Kutluk, Florencia Moreno, Kayo Nakata, Sari Nur, D M Parkin, Lynne Penberthy, Jason Pole, Jenny N Poynter, Kathy Pritchard-Jones, Oscar Ramirez, Lorna Renner, Eva Steliarova-Foucher, Michael Sullivan, Rajaraman Swaminathan, Liesbet Van Eycken, Tushar Vora, A L Frazier
Journal: The Lancet Oncology (2020)
COVID-19 and mRNA Vaccines—First Large Test for a New Approach
Authors: Jennifer Abbasi
Journal: JAMA (2020)

Rebecca L. Winslow, MRCGP; Iain D. Milligan, MRCP; Merryn Voysey, MBiostat; Kerstin Luhn, PhD; Georgi Shukarev, MD; Macaya Douoguih, MD; Matthew D. Snape, MD
Characteristics of potential organ donors generated in an intensive care unit (medical icu) in a second level hospital during an eight-year period (2005-2012)
Authors: Cristobal Galbán Rodríguez, Enrique Alemparte Pardavila, José Luis Martínez Melgar, Ana María Ortega Montes, María Teresa Sánchez De Dios, Antonio Pais Almozara, José Ignacio Cenoz Osinaga
Journal: Intensive Care Medicine (2013)
Serum free testosterone and asthma, asthma hospitalisations and lung function in British adults
Authors: Yueh-Ying Han, Qi Yan, Ge Yang, Wei Chen, Erick Forno, Juan Carlos Celedon
Journal: Thorax (2020)

Objective We examined the relation between serum-free testosterone and asthma, wheeze, asthma hospitalisations and lung function in older adults. Design Cross-sectional study. Setting UK. Participants 256 419 adults aged 40 to 69 years, recruited from 2006 to 2010. Main outcome measures Multivariable logistic or linear regression was used for the analysis of free testosterone and physician-diagnosed asthma, current wheeze, asthma hospitalisations and lung function measures, which was adjusted for serum estradiol, smoking status and other covariates. Results Free testosterone levels above the lowest quartile (Q1) were significantly associated with lower odds of asthma in both women (adjusted OR (aOR) for Q4 (the highest quartile) versus Q1=0.67, 95% CI=0.64 to 0.71) and men (aOR for Q4 versus Q1=0.87, 95% CI=0.82 to 0.91). Among subjects with asthma, free testosterone levels above Q1 were significantly associated with lower odds of current wheeze in women (aOR range=0.78 to 0.87), and free testosterone levels in Q4 were associated with lower odds of current wheeze in men (aOR for Q4 versus Q1=0.86, 95% CI=0.77 to 0.95). Among women with asthma, free testosterone levels in Q4 were also associated with lower odds of ≥1 asthma hospitalisation. Among men, free testosterone was positively associated with FEV 1 and FVC. Among women, free testosterone was negatively and weakly associated with FVC. Conclusion In a large study of British adults, elevated free testosterone levels are associated with lower odds of asthma and current wheeze in women and men, lower odds of asthma hospitalisations in women, and higher FEV 1 and FVC in men. Dissemination to participants, and related patient and public communities The results of the study will be linked to the UK Biobank website.
Comparison of clinical practice guidelines for the management of chronic hepatitis B: When to start, when to change, and when to stop
Authors: Hyung Joon Yim, Ji Hoon Kim, Jun Yong Park, Eileen L. Yoon, Hana Park, Jung Hyun Kwon, Dong Hyun Sinn, Sae Hwan Lee, Jeong-Hoon Lee, Hyun Woong Lee
Journal: Clinical and Molecular Hepatology (2020)

Clinical practice guidelines are important for guiding the management of specific diseases by medical practitioners, trainees, and nurses. In some cases, the guidelines are utilized as a reference for health policymakers in controlling diseases with a large public impact. With this in mind, practice guidelines for the management of chronic hepatitis B (CHB) have been developed in the United States, Europe, and Asian-Pacific regions to suggest the best-fit recommendations for each social and medical circumstance. Recently, the Korean Association for the Study of the Liver published a revised version of its clinical practice guidelines for the management of CHB. The guidelines included updated information based on newly available antiviral agents, the most recent opinion on the initiation and cessation of treatment, and updates for the management of drug resistance, partial virological response, and side effects. Additionally, CHB management in specific situations was comprehensively revised. This review compares the similarities and differences among the various practice guidelines to identify unmet needs and improve future recommendations.
Abstract 4410: Automatic detection of consensus gene clusters across multiple single-cell datasets
Authors: Qianqian Song, Jing Su, Lance D. Miller, Wei Zhang
Journal: Cancer Research (2020)

Abstract Identifying co-expressed gene clusters can provide evidence for cellular activities. Thus, co-expression clustering will be a routine step in single-cell RNA-seq data analysis. We show that commonly used clustering methods for bulk-seq data are not suitable for single-cell data, and produce results that substantially disagree in the biological expectations of co-expressed genes. Herein, we present scLM, a tailored method for single-cell data, to extract co-expressed gene clusters matching the biological expectations and outperform widely used methods. Additionally, scLM can simultaneously cluster multiple single-cell datasets, i.e. consensus clustering, enabling users to leverage the large quantity of public data for novel comparative analysis. ScLM takes raw count data as input and preserves biological variations without being influenced by batch effects from multiple datasets. Results from both simulation data and real experimental data demonstrate that scLM outperforms the existing methods with considerably improved accuracy. To illustrate the biological insights of scLM, we apply it to our in-house and public experimental scRNA-Seq datasets. ScLM identifies novel functional gene modules and refines cell states, which facilitates mechanism discovery and understanding of complex biosystems such as cancers. Citation Format: Qianqian Song, Jing Su, Lance D. Miller, Wei Zhang. Automatic detection of consensus gene clusters across multiple single-cell datasets [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 4410.
Abstract 2038: Overall survival of glioblastoma patients treated by standard therapy in comparison to standard therapy plus tumor treating fields
Authors: Aaron Rulseh, Adam Derner, Jan Sroubek, Jan Klener, Josef Vymazal
Journal: Cancer Research (2020)

Abstract Introduction: Glioblastoma multiforme (GBM) is the most common malignant primary intracranial tumor and traditionally has a median survival of only 10 to 14 months, with only 3 to 5% of patients surviving more than three years. Recurrence is nearly universal, and further decreases the median survival to only 5 to 7 months with optimal therapy. Tumor treating fields (TTFields; Optune, Novocure, Haifa, Israel) therapy is a novel treatment technique that has recently shown significant prolonged survival in GBM patients. This therapy is approved for the treatment of newly diagnosed and recurrent GBM and is based on the principle that low intensity, intermediate frequency alternating electric fields (100 to 300 kHz) have an anti-mitotic effect in specific cell types. The applied fields disrupt the mitotic spindle, microtubule assembly and the segregation of intracellular organelles during cell division, leading to apoptosis or mitotic arrest. We aimed to compare overall survival between patients treated with standard therapy and standard therapy plus TTFields at our institution. Materials and Methods: A total of 34 patients (22 male, 15 female) diagnosed with GBM and treated by standard therapy plus TTFields (STDTh-TTF) at our institution were included. Standard therapy (STDTh) consisted of surgical resection, followed by combined radiotherapy and chemotherapy (Temozolomide); in 2 cases biopsy was performed in place of resection. The date of resection or biopsy was considered the entry date and was used in calculating survival, and ranged from June 2015 to July 2019. A matching control group treated by STDTh alone at our institution was assembled from our database, based primarily on date of resection or biopsy, and secondarily by age (1 subject underwent biopsy in place of resection). When assembling the control group, the investigators were blinded to survival outcome. Results: Significantly greater overall survival was observed for the group treated by TTFields in addition to standard therapy (p = 0.005; Hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.11-0.69). The groups were identical with respect to sex, and no differences with respect to age (p=0.12; STDTh-TTF mean 50.54 years, SD 10.3; STDTh mean 54.39 years, SD 9.3) or inclusion date (p=0.3) were detected. Conclusions: Our initial results appear promising with respect to overall survival in patients undergoing TTFields treatment in addition to standard therapy. Citation Format: Aaron Rulseh, Adam Derner, Jan Sroubek, Jan Klener, Josef Vymazal. Overall survival of glioblastoma patients treated by standard therapy in comparison to standard therapy plus tumor treating fields [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 2038.
Abstract 3721: Relationship between insulin resistance and chemosensitivity of high grade bone sarcoma
Authors: Pascaline Boudou-Rouquette, Ithar Gataa, Sixtine De Percin, Camille Tlemsani, David Biau, Valerie Dumaine, Virginie Audard, Frédérique Larousserie, Philippe Anract, Anne Jouinot, François Goldwasser
Journal: Cancer Research (2020)

Abstract Background: Neoadjuvant chemotherapy with intercalated surgery is the standard of care for resectable high-grade bone sarcoma (BS) but identification of biomarkers for chemosensitivity prediction is still needed. Insulin-like Growth Factor (IGF) pathway was first linked with sarcoma biology approximately 30 years ago (El-Brady OM, 1990). Methods: We recruited 138 pts with newly diagnosed primary localized or metastatic BS. We measured fasting blood glucose and insulin, body mass index (BMI). The HOMA-IR (Homeostasis Model Assessment) score ((Glucose (mmol/l) x Insulin) / 22.5), which has been proven to reliably detect insulin resistance IR was calculated, and patients with HOMA-IR &amp;gt; 2.6 were considered as IR. We collected characteristics usually associated with insulin resistance: age, obesity, diabetes, dyslipidemia and hypertension. Results: Out of 138 pts, 50 (36%) were insulin resistant: HOMA-IR &amp;gt;2.6. Thirty-two IR patients (64%) had no cardiovascular risk factor. In univariate analysis, IR was associated with obesity (BMI &amp;gt; 30 kg/m2)(22% vs 3%, p=0.0015), but not with age (median 36,8 vs 41 years, p=0.19). IR was more prevalent in Ewing sarcoma (14/29; 48%) and chondrosarcoma (7/16; 44%) followed by osteosarcoma (25/67; 37%) and other rare bone sarcomas (4/26; 15.3%), but not significantly (p=0.097). After neoadjuvant chemotherapy and surgery of Ewing tumor and osteosarcoma, pathologic tumor necrosis was higher in IR pts (88.9 vs 75%, p= 0.028). Conclusion: Our results suggest that metabolic profile may help to discriminate best candidates for neoadjuvant chemotherapy in high-grade bone sarcomas. Further studies are needed to confirm and explain these results. Citation Format: Pascaline Boudou-Rouquette, Ithar Gataa, Sixtine De Percin, Camille Tlemsani, David Biau, Valerie Dumaine, Virginie Audard, Frédérique Larousserie, Philippe Anract, Anne Jouinot, François Goldwasser. Relationship between insulin resistance and chemosensitivity of high grade bone sarcoma [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 3721.
In Search of “Hepatic Factor”: Lack of Evidence for ALK1 Ligands BMP9 and BMP10
Authors: Teresa L. Capasso, Sara M. Trucco, Morgan Hindes, Tristin Schwartze, Jamie L. Bloch, Jacqueline Kreutzer, Stephen C. Cook, Cynthia S. Hinck, Davide Treggiari, Brian Feingold, Andrew P. Hinck, Beth L. Roman
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Abstract  In children with single ventricle physiology, the Glenn procedure is performed to redirect venous return from the superior vena cava directly to the pulmonary arteries and route venous return from the inferior vena cava exclusively to the systemic circulation. Although this surgery successfully palliates the hemodynamic stress experienced by the single ventricle, patients frequently develop pulmonary arteriovenous malformations (PAVMs). Interestingly, PAVMs may regress upon rerouting of hepatic venous effluent to the pulmonary vasculature, suggesting the presence of a circulating “hepatic factor” that is required to prevent PAVMs. Here, we test the hypothesis that hepatic factor is bone morphogenetic protein 9 (BMP9) and/or BMP10. These circulating ligands are produced by the liver and activate endothelial endoglin (ENG)/ALK1 signaling, and mutations in ENG and ALK1 cause hereditary hemorrhagic telangiectasia, a genetic disease associated with AVM development. However, we found no within-subject variation in BMP9, BMP10, or BMP9/10 plasma concentrations when sampled from five cardiovascular sites, failing to support the idea that the Glenn would limit access of these ligands to the lung vasculature. Unexpectedly, however, we found a significant decrease in all three ligand concentrations in Glenn cases versus controls. Our findings suggest that BMP9/BMP10/ENG/ALK1 signaling may be decreased in the Glenn vasculature but fail to implicate these ligands as hepatic factor.