tbuckley/cabot-search huggingface dataset:
Safety and immunogenicity of the epicutaneous reactivation of pertussis toxin immunity in healthy adults: a phase I, randomized, double-blind, placebo-controlled trial
Authors: O. Chatzis, G. Blanchard-Rohner, L. Mondoulet, B. Pelletier, A. De Gea-Hominal, M. Roux, A. Huttner, P.L. Hervé, M. Rohr, A. Matthey, G. Gutknecht, B. Lemaître, C. Hayem, H.T. Pham, W. Wijagkanalan, P.H. Lambert, P.H. Benhamou, C.A. Siegrist
Journal: Clinical Microbiology and Infection (2020)

Protection induced by acellular vaccines can be short, requiring novel immunization strategies. Objectives of this study were to evaluate safety and capacity of a recombinant pertussis toxin (PTgen) -coated Viaskin® epicutaneous patch to recall memory responses in healthy adults.This double-blind, placebo-controlled randomized trial (Phase I) assessed the safety and immunogenicity of PTgen administered on days 0 and 14 to healthy adults using Viaskin® patches applied directly or after epidermal laser-based skin preparation. Patch administration was followed by Boostrix®dTpa on day 42. Antibodies were assessed at days 0, 14, 28, 42 and 70.Among 102 volunteers enrolled, 80 received Viaskin-PT (Viaskin-PT 25 μg (n = 25), Viaskin-PT 50 μg (n = 25), laser + Viaskin-PT 25 μg (n = 5), laser + Viaskin-PT 50 μg (n = 25)), Viaskin-placebo (n = 10) or laser + Viaskin-placebo (n = 2). Incidence of adverse events was similar across groups (any local event: 21/25 (84.0%), 24/25 (96.0%), 4/5 (80.0%), 24/25 (96.0%), 8/10 (80.0%), 10/12 (83.0%), respectively). Direct application induced no detectable response. On day 42, PT-IgG geometric mean concentrations were significantly higher following laser + Viaskin-PT 25 μg and 50 μg (139.87 (95% CI 87.30-224.10) and 121.76 (95% CI 95.04-156.00), respectively), than laser + Viaskin-placebo (59.49, 95% CI 39.37-89.90). Seroresponse rates were higher following laser + Viaskin-PT 25 μg (4/5 (80.0%), 95% CI 28.4-99.5) and 50 μg (22/25 (88.0%), 95% CI 68.8-97.5) than laser + Viaskin-placebo (0/12 (0.0%), 95% CI 0.0-26.5).Viaskin-PT applied after laser-based epidermal skin preparation showed encouraging safety and immunogenicity results: anti-PT booster responses were not inferior to those elicited by Boostrix®dTpa. This study is registered at ClinicalTrials.gov (NCT03035370) and was funded by DBV Technologies.
Abstract 1475: Blockade of IL17-GCSF-Bv8 inflammation axis ameliorate resistant to anti-angiogenic therapy for colon cancer
Authors: Yoshiro Itatani, Takamasa Yamamoto, Napoleone Ferrara
Journal: Cancer Research (2020)

Abstract Anti-angiogenic therapy in combination with chemotherapy is one of the standard strategies for metastatic/unresectable colon cancers. Therefore, resistance to anti-angiogenic therapy causes a critical problem for the treatment of colon cancer patients. While some resistant mechanisms of anti-angiogenic therapy were proposed, it is not yet completely unveiled. The aim of this study was to investigate the resistant mechanism against anti-angiogenic therapy using spontaneous colon cancer mouse models. We established a mouse model of anti-VEGF resistant colon cancer. Genetically-engineered Apc/Smad4 knockout mice developed several intestinal tumors that are sensitive to anti-VEGF neutralizing antibody. When Apc/Smad4 mice were treated with dextran sulfate sodium (DSS) (DSS-Apc/Smad4 mice), they developed colon tumors that were resistant to anti-VEGF antibody. Sera from DSS-Apc/Smad4 mice showed significant upregulation of granulocyte-colony stimulating factor (GCSF) compared to water-drinking Apc/Smad4 mice. Colon tumors from DSS-Apc/Smad4 mice also showed GCSF upregulation. It also showed upregulation of IL17, one of inflammatory cytokines upstream of GCSF, and Bv8, one of angiogenic factors downstream of GCSF, suggesting that IL17-GCSF-Bv8 inflammation axis contributes to obtaining anti-VEGF resistant. Immunostaining of the tumors from DSS-Apc/Smad4 mice revealed significant accumulation of neutrophils in the tumors. Neutrophils from tumor-bearing mice showed upregulation of Bv8 expression when stimulated with GCSF. Immunostaining confirmed that neutrophils in the tumors were positive for Bv8. When DSS-Apc/Smad4 mice were treated with either anti-IL17, anti-GCSF, or anti-BV8 neutralizing antibody in combination with anti-VEGF antibody, colonic tumor formation was significantly suppressed. We also performed ELISA analysis using human serum samples from subcohort of AVF2107 trial in which metastatic colon cancer patients were treated with chemotherapy (IFL with or without bevacizumab). Higher Bv8 serum levels by ELISA were significantly correlated with poor overall survival in human colon cancer patients. Collectively, inflammatory neutrophils in the tumor microenvironment of colon cancer provide anti-VEGF resistant through IL17-GCSF-Bv8 axis, and blockade of this pathway ameliorate resistance to anti-angiogenic therapy of colon cancer mouse models. Citation Format: Yoshiro Itatani, Takamasa Yamamoto, Napoleone Ferrara. Blockade of IL17-GCSF-Bv8 inflammation axis ameliorate resistant to anti-angiogenic therapy for colon cancer [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 1475.
The big one
Authors: Melissa Romano
Journal: British Journal of Sports Medicine (2020)

I have had concussions before, but this was different. In 2012, I was playing first base in a recreational softball league. A throw came to me for a double play, but I did not get my glove up, it tipped off my glove and hit me between the eyes. I did not lose consciousness, but was feeling out of it and foggy immediately. I played the rest of the inning despite my symptoms. I did not go to the hospital that night. The next morning, I drove into work (I am not sure how I drove in that day) flooded with symptoms: headache, dizziness, fogginess, to name a few. A coworker talked to me and it felt like she was screaming in my ear. I did not realise sensitivity to sound was a symptom of concussion. My bosses sent me home; I stopped at the pharmacy on the way. When I mentioned my symptoms, the pharmacist said, ‘Go to the ER right now’. So, 12 hours after being hit, I finally went to the Emergency Room (ER), got a CT and MRI, and was told I had a concussion. I was prescribed pain medication, and told to go home, rest and follow-up with my primary care physician (PCP). My recovery took 6 years.

The common thread of the team I eventually worked with was whether the professionals had experience …
Abstract 6116: Role of secretory factors from obese-derived omentum in supporting ovarian cancer progression
Authors: Jennifer Waters, Mikella Robinson, Samuel F. Gilbert, Logan J. Alexander, Carrie D. House
Journal: Cancer Research (2020)

Abstract Ovarian cancer is the most lethal gynecological malignancy in the United States, with a known predilection for metastasizing to the omentum, a sheet of fatty peritoneal tissue that encloses the abdomen. This finding coincides with some evidence that ovarian cancer is more aggressive in the obese setting with worse overall survival. While it has been shown that ovarian cancer cells invade towards adipocytes in vitro, the mechanism by which they support formation of secondary tumors is not well understood. We hypothesize that soluble factors enriched in the obese setting are activating signaling pathways in tumor cells to drive migration and proliferation. To evaluate this hypothesis we co-cultured primary human omental adipocytes derived from obese female donors with ovarian cancer cell lines and profiled secretory factors (cytokines and adipokines) responsible for increasing tumor initiation in vivo and clonogenicity, proliferation, and drug resistance in vitro. Secretion of cytokines IL-6, IL-8, and CCL2 by adipocytes is enhanced when co-cultured with ovarian cancer cells. A subcutaneous tumor model showed that low dilutions of ovarian cancer cells require adipocytes for engraftment and tumor formation. A transplantation assay showed that ovarian cancer cells require the presence of adipocytes for sustained tumor-initiation capacity. Studies are underway to investigate adipocyte-secreted factors in this process. Our findings highlight the role of adipocytes in the ovarian tumor microenvironment and uncover signaling factors that may enhance ovarian cancer progression. Understanding these processes will enable the design of more effective therapies for treating ovarian cancer. Citation Format: Jennifer Waters, Mikella Robinson, Samuel F. Gilbert, Logan J. Alexander, Carrie D. House. Role of secretory factors from obese-derived omentum in supporting ovarian cancer progression [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 6116.
ASTRAL-Pro: Quartet-Based Species-Tree Inference despite Paralogy
Authors: Chao Zhang, Celine Scornavacca, Erin K Molloy, Siavash Mirarab
Journal: Molecular Biology and Evolution (2020)

Phylogenetic inference from genome-wide data (phylogenomics) has revolutionized the study of evolution because it enables accounting for discordance among evolutionary histories across the genome. To this end, summary methods have been developed to allow accurate and scalable inference of species trees from gene trees. However, most of these methods, including the widely used ASTRAL, can only handle single-copy gene trees and do not attempt to model gene duplication and gene loss. As a result, most phylogenomic studies have focused on single-copy genes and have discarded large parts of the data. Here, we first propose a measure of quartet similarity between single-copy and multicopy trees that accounts for orthology and paralogy. We then introduce a method called ASTRAL-Pro (ASTRAL for PaRalogs and Orthologs) to find the species tree that optimizes our quartet similarity measure using dynamic programing. By studying its performance on an extensive collection of simulated data sets and on real data sets, we show that ASTRAL-Pro is more accurate than alternative methods.
Abstract 6018: The perfused 3DKUBE™ rare tumor assay models in vivo drug response
Authors: Melissa Millard, Kathryn M. Appleton, Ashley Elrod, Nicholas W. Bateman, Tamara Abulez, Kelly Conrads, Brian Hood, Thomas P. Conrads, Lillia M. Holmes, Teresa M. DesRochers
Journal: Cancer Research (2020)

Abstract Models that accurately reflect patient drug response are essential for the clinical design of personalized treatment plans and necessary for preclinical drug development. The advancement of predictive models for rare tumor types is impeded in part, by the relative scarcity of fresh tumor tissue available for study. To address the problem of tissue availability we have developed a label-free, combined functional and chemical selection method for the isolation of rare tumor cancer stem cells (CSC) and circulating tumor cells (CTC) from primary patient tissue and blood. Enriched cells were expanded as 3D microtumors under optimized conditions, validated as CSC through in vivo tumorigenesis studies, and characterized by correlative genomic, proteomic/phosphoproteomic, and phenomic analysis. We found isolation and expansion by this method yielded a source of primary cells suitable for live, cell-based predictive drug screening in multiple rare tumor derived models of neuroendocrine and mesenchymal origin, including locally or regionally advanced and metastatic SCLC, recurrent Merkel Cell Carcinoma, recurrent osteosarcoma and dermatofibrosarcoma protuberans. The 3DKUBE™ rare tumor assay was performed using validated CSCs cultured as perfused 3D microtumors (pMTs). Drug studies using the perfused, 3DKUBE™ rare tumor assay modeled individual patient response better than CSC-based or 3D static microtumor-based drug screens and thus demonstrate the effectiveness of this platform for predictive modeling of individual patient drug response. Taken together, this system provides a means of performing ex vivo drug response experiments on very small tissue samples, including core biopsies, with relevant results for patients. Citation Format: Melissa Millard, Kathryn M. Appleton, Ashley Elrod, Nicholas W. Bateman, Tamara Abulez, Kelly Conrads, Brian Hood, Thomas P. Conrads, Lillia M. Holmes, Teresa M. DesRochers. The perfused 3DKUBE™ rare tumor assay models in vivo drug response [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 6018.
Abstract 4603: Detection of pancreatic cancer using rapid dielectrophoresis based recovery of tumor derived extra cellular vesicles and exosomes from plasma
Authors: Augusta Modestino, Jesus Bueno Alvarez, Michael Heller, Stuart Ibsen
Journal: Cancer Research (2020)

Abstract Tumor derived extracellular vesicles, including exosomes, carry cancer related proteins on their outer surfaces making them a valuable source of tumor biomarkers in blood. However, these vesicles are difficult to recover from plasma and this prevents them from being widely used for clinical diagnostic tests. Here we present a technique that uses high conductance dielectrophoresis to rapidly recover these vesicles from plasma allowing for immunofluorescence detection of cancer related biomarkers. We demonstrate this technique can be used to detect biomarkers that successfully distinguish patients with pancreatic cancer from those with benign pancreatic disease, such as pancreatitis, as well as healthy individuals. What makes dielectrophoresis different from other vesicle recovery techniques is that it takes advantage of the large contrast in the dielectric properties between the vesicles and the surrounding plasma. The dielectrophoretic force preferentially draws vesicles to an electrode array at the bottom of a microfluidic chip where they are held in place allowing a fluidic wash to remove the bulk plasma. The vesicles are concentrated at the electrode edge thereby increasing the signal to noise ratio of the fluorescent immunostaining signal and placing the particles in known locations allowing for automated detection and quantification of biomarker levels. This technique takes 30 min to complete, requires 30-50 µl of plasma, and can be highly automated to reduce labor effort making it a promising technology for future translation into the clinical laboratory setting and enabling the use of extracellular vesicles and exosomes for diagnostic applications. Citation Format: Augusta Modestino, Jesus Bueno Alvarez, Michael Heller, Stuart Ibsen. Detection of pancreatic cancer using rapid dielectrophoresis based recovery of tumor derived extra cellular vesicles and exosomes from plasma [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 4603.
Abstract LB-187: Enhanced mapping of N6-methyladenosine (m6A) RNA modification sites with m6A-eCLIP
Authors: Ines Rabano, Alexander A. Shishkin, Kylie Shen, Heather M. Foster, Peter Chu, Eric L. Van Nostrand, Gene W. Yeo
Journal: Cancer Research (2020)

Abstract N6-methyladenosine (m6A) is the most prevalent epitranscriptomic RNA modification found in eukaryotes and has been shown to regulate many stages of RNA biology including splicing, secondary/tertiary structure, localization, stability, and translation. Adenosine modifications are actively added, recognized, and removed by a series of “writer”, “reader”, and “eraser” proteins, making m6A a dynamic and reversible system for regulating RNAs. Further, there are now clear links between m6A writer, reader, and eraser proteins as well as m6A state of specific mRNAs to cancer pathogenesis, indicating that both global and specific dysregulation of m6A can have targeted effects that lead to disease. Thus, there is a need for methods to robustly profile m6A-modification states in both cell lines as well as tissues, and in normal as well as diseased or modified states. Advancements in high-throughput sequencing have led to the development of methods to map m6A transcriptome-wide, but there remains a need for improved methods that are scalable across conditions and treatments and with low abundance samples, such as blood or patient tissue. To address this need, we adapted enhanced crosslinking and immunoprecipitation (eCLIP) to create an optimized protocol for profiling m6A modification sites with 20-50-fold less starting RNA material (m6A-eCLIP). Using m6A-eCLIP, we recover traditional m6A motif enrichment and positioning enrichment at stop codons, validating the accuracy of the approach. Further, the improved handling and efficiency enabled us to profile m6A status across cell types and tissues, showing that m6A-eCLIP can be a robust method that is widely applicable for epitranscriptomic profiling across a range of conditions. Citation Format: Ines Rabano, Alexander A. Shishkin, Kylie Shen, Heather M. Foster, Peter Chu, Eric L. Van Nostrand, Gene W. Yeo. Enhanced mapping of N6-methyladenosine (m6A) RNA modification sites with m6A-eCLIP [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-187.
Abstract 931: Assessment of tumor mutational burden using a multiplex amplicon-based NGS target enrichment approach
Authors: Chenyu LI
Journal: Cancer Research (2020)

Abstract Tumor mutational burden (TMB) is gaining significant importance in cancer therapeutics with its correlation to patient response to checkpoint inhibitor-base immunotherapy. A whole exome sequencing approach is traditionally used to assess TMB, but this approach is expensive and time consuming, requiring high sample inputs and complex workflows. Alternatively, a targeted enrichment strategy using multiplexed PCR can provide better coverage of regions of interest and reduce costs. But increasing the multiplexity of PCR, as required for tumor profiling, can lead to problems with non-specific interactions, poor uniformity, and high bias. In this study, we present a multiplex PCR-based strategy for targeting hundreds of genes for tumor profiling applications and assessment of TMB. Paragon Genomics designed a 500-gene TMB panel which uses about 27,000 pairs of primers for target enrichment via multiplex PCR. The amplicons were designed to target short segments of about 113 bp on average to allow for target amplification from challenging fragmented samples such as FFPE DNA and cfDNA. The 27,000 pairs of PCR primers cover a total of 1.6 Mb (1.2 Mb of coding sequence). Paragon Genomics' CleanPlex® technology enables a streamlined library preparation workflow which includes a multiplex PCR step with the targeted primers, a subsequent cleanup step to remove by-products, and a final PCR step to add sequencer flow cell adapters and sample indexes. The 500-gene TMB panel exhibits on-target rates of ~96% and uniformity at 0.2X mean of ~94%. Little to no GC bias or amplicon length bias is observed despite the highly multiplexed nature of this panel. At an average read depth of 3000 paired-end reads, 97% of the expected mutations with allele frequencies ≥ 5% were detected. Lastly, Paragon Genomics utilized an internally developed variant-calling algorithm to calculate the TMB values from sequenced libraries prepared from tumor cell line DNA. The advanced design of this panel along with the CleanPlex technology enables the rapid interrogation of these genes and of the TMB value in a robust assay. Citation Format: Chenyu LI. Assessment of tumor mutational burden using a multiplex amplicon-based NGS target enrichment approach [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 931.
Corrigendum to: “Portopulmonary hypertension in the current era of pulmonary hypertension management” [J Hepatol (2020);73:130–139]
Authors: Laurent Savale, Manuel Guimas, Nathan Ebstein, Marie Fertin, Mitja Jevnikar, Sébastien Renard, Delphine Horeau-Langlard, Cécile Tromeur, Céline Chabanne, Grégoire Prevot, Ari Chaouat, Pamela Moceri, Élise Artaud-Macari, Bruno Degano, Romain Tresorier, Clément Boissin, Hélène Bouvaist, Anne-Claire Simon, Marianne Riou, Nicolas Favrolt, Sylvain Palat, Delphine Bourlier, Pascal Magro, Vincent Cottin, Emmanuel Bergot, Nicolas Lamblin, Xavier Jaïs, Audrey Coilly, François Durand, Claire Francoz, Filomena Conti, Philippe Hervé, Gérald Simonneau, David Montani, Jean-Charles Duclos-Vallée, Didier Samuel, Marc Humbert, Pascal De Groote, Olivier Sitbon
Journal: Journal of Hepatology (2020)
Abstract LB-246: Venice: A new algorithm for finding marker genes of single-cell populations in tumor microenvironment
Authors: Son Pham, Hy Vuong, Thao Truong
Journal: Cancer Research (2020)

Abstract Most widely used tools for finding marker genes insingle-cell data(SeuratT/NegBinom/Poisson, CellRanger, EdgeR, limmatrend) rely on a conventional definition of differentially expressed genes from bulk RNA-seq: genes with different means of expression values . However, in single-cell data (e.g., cell populations in tumor microenvironments), a cell population can be a mixture of many cell types/cell states, hence the mean expression of genes cannot represent the whole population. In addition, these tools assume that the gene expression of a population belongs to a specific family of distribution. This assumption is often violated in single-cell data. In this work, we define marker genes of a cell population as genes that can be used to distinguish cells in the population from cells in other populations. Besides log-fold change, we devise anew metric to classify genes into up-regulated, down-regulated, and transitional states. In a benchmark for finding up-regulated and down-regulated genes, our tool outperforms all compared methods, including Seurat, ROTS, scDD, edgeR, MAST, limma, normal t-test, Wilcoxonand Kolmogorov-Smirnov test. Our method is much faster than all compared methods, therefore, it enables interactive analysis for large single-cell data sets in BioTuring Browser (https://bioturing.com/bbrowser). Citation Format: Son Pham, Hy Vuong, Thao Truong. Venice: A new algorithm for finding marker genes of single-cell populations in tumor microenvironment [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-246.