tbuckley/cabot-search huggingface dataset:
Abstract IA24: Interrogating therapy response and resistance in engineered preclinical models
Authors: Lukas E. Dow
Journal: Cancer Research (2020)

Abstract The past decade has produced a vast amount of clinical sequencing data that have defined the genetic landscape of human cancers. We know with greater detail than ever the number and type of mutation in any given gene, yet we have a limited understanding of how this mutational heterogeneity impacts cancer initiation, progression, or therapeutic response. Thus, despite the enormous resources invested in genome sequencing, the vast amount of information gathered is uninformative as we simply do not know how most cancer-associated mutations dictate tumor behavior. Even extremely well-studied genes such as KRAS and APC harbor an array of mutational variants that may have significant prognostic and therapeutic relevance but remain scarcely characterized. Further complicating the challenge is the number of mutational combinations that impact cancer behavior. To meet this challenge, we develop and exploit new genetic technologies to engineer organoid and animal model systems that faithfully represent the mutational events in human cancer. We use these tools to determine how specific mutational variants in major oncogenic pathways shape cancer progression and influence cancer cell vulnerabilities and response to therapy. I will describe our efforts to understand the contribution of recurrent alterations in APC and KRAS, as well as our ongoing work to prospectively define mechanism of response and resistance to new WNT-targeted therapies now entering clinical trials. Citation Format: Lukas E. Dow. Interrogating therapy response and resistance in engineered preclinical models [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA24.
Abstract IA25: Detection of somatic mutations and HPV in saliva of patients with head and neck squamous cell carcinoma
Authors: Nishant Agrawal
Journal: Clinical Cancer Research (2020)

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy in the world and is associated with significant morbidity and mortality. HNSCC develops in the oral cavity, pharynx, and larynx and is associated with tobacco exposure, alcohol abuse, and infection with oncogenic viruses. Despite numerous diagnostic and therapeutic advances, HNSCC often presents with advanced disease and the long-term survival for patients with HPV-negative SCC has remained ~55%. Conventional analysis of tissue through cytopathology or histopathology is the mainstay of diagnosis. There are no useful biomarkers for disease diagnosis or surveillance. The genetic landscape of HNSCC has demonstrated that these tumors are largely driven by tumor-suppressor mutations. The broad mutation spectrum detected in HNSCC by these sequencing studies not only sheds light on its molecular pathogenesis, but also serves as a molecular signature that is exquisitely specific to the individual tumor. Therefore, methods that use these molecular signatures and biomarkers and aid in improved screening/early detection, prognostication, monitoring, and surveillance are paramount for improving outcomes. We will explore tumor DNA (somatic mutations and HPV DNA) in saliva and plasma for screening, monitoring, and surveillance and outline resulting implications for personalized medicine. In HNSCC, analysis of tumor DNA has the potential to enhance tumor profiling, aid in determining patient prognosis, and guide treatment decisions. Citation Format: Nishant Agrawal. Detection of somatic mutations and HPV in saliva of patients with head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr IA25.
AB1032 CONTRIBUTION OF BONE BIOPSY DURING REVELATORY BONE METASTASES
Authors: S. Jriri, M. Ben Majdouba, S. Ben Jemaa, A. Feki, R. Akrout, M. Ezzeddine, M. H. Kallel, H. Fourati, S. Baklouti
Journal: Annals of the Rheumatic Diseases (2020)

Background: Bone metastases (BM) are tumor cells that originate in a primary malignant tumor and are localized remotely in bone tissue. They more or less faithfully reproduce the morphological and biological characteristics of the primary tumor. Histological analysisis essential to confirm the diagnosis of BM and to identify the primary tumor if possible and sometimes to help in the selection of treatment. Objectives: The aim of this work is to study the contribution of bone biopsy during revealing BM in diagnostic strategy and therapeutic decision. Methods: We retrospectively studied the files of 105 patients hospitalized in a Rheumatology department of for BM revealing from January 2000 until December 2015. For each patient we collected epidemioclinical and anatomopathological data to arrive at the diagnosis of primary neoplasm and histological type. Results: The patients were divided into 86 men (81.9%) and 19 women (18.1%) with a sex ratio (M / F) of 4.52. The average age of our patients was 64.91 ± 13.29 years. Pain was the most frequent reason for consultation found in 97.1%. This pain was either of bone site (61.9%) or of radicular topography (41.9%). Bone swelling or a pathological fracture revealed BM in 4.8% and 8.6% of the cases, respectively. The onset of neurological damage was noted in 13.3% of the cases. Histologically, the bone biopsy performed in 64 patients made it possible to specify the histological type (carcinoma, adenocarcinoma) in 64% of the cases and to lead to primary cancer in 57.8%. A non-radio-guided percutaneous bone biopsy was performed in 44 patients (68.75%) including 41 osteo-medullary biopsy in iliac crest (BOM) and 3 in the sternum, a bone biopsy directed under scanner in 16 cases (25%) and a surgical bone biopsy in 4 cases. The BOM was positive in 21 cases (51.2%) showing a poorly or moderately differentiated adenocarcinoma or carcinoma. It allowed referral to a primitive in 20 cases: a prostatic origin in 11 cases, a pulmonary origin in 5 cases, a digestive origin in 2 cases, a mammary origin in one case and a neuroblastoma in one case. Conclusion: Thanks to improved sampling and immunohistochemistry techniques, the precise histological type and location of the primary tumor could be identified, there by improving the quality of care for patients with increased life expectancy. Disclosure of Interests: None declared
NADPH oxidase subunit NOXO1 is a target for emphysema treatment in COPD
Authors: Michael Seimetz, Natascha Sommer, Mariola Bednorz, Oleg Pak, Christine Veith, Stefan Hadzic, Marija Gredic, Nirmal Parajuli, Baktybek Kojonazarov, Simone Kraut, Jochen Wilhelm, Fenja Knoepp, Ingrid Henneke, Alexandra Pichl, Zeki I. Kanbagli, Susan Scheibe, Athanasios Fysikopoulos, Cheng-Yu Wu, Walter Klepetko, Peter Jaksch, Christina Eichstaedt, Ekkehard Grünig, Katrin Hinderhofer, Miklós Geiszt, Niklas Müller, Flavia Rezende, Giulia Buchmann, Ilka Wittig, Matthias Hecker, Andreas Hecker, Winfried Padberg, Peter Dorfmüller, Stefan Gattenlöhner, Claus F. Vogelmeier, Andreas Günther, Srikanth Karnati, Eveline Baumgart-Vogt, Ralph T. Schermuly, Hossein A. Ghofrani, Werner Seeger, Katrin Schröder, Friedrich Grimminger, Ralf P. Brandes, Norbert Weissmann
Journal: Nature Metabolism (2020)
Abstract IA04: Stem cells: Coping with stress and cancer
Authors: Elaine Fuchs
Journal: Cancer Research (2020)

Abstract Adult tissue stem cells have the ability to self-renew long term and differentiate into one or more tissues. Many stem cells are used sparingly to replenish cells during normal homeostasis. However, even stem cells that are quiescent must be able to respond quickly to injury in order to fuel rapid tissue regeneration. How stem cells balance self-renewal and differentiation is of fundamental importance to our understanding of normal tissue maintenance and wound repair. The regulatory circuitry governing this normal balancing act must be intricately regulated in normal homeostasis and then transiently altered to cope with injury responses. Increasing evidence suggests that the mechanism goes awry in inflammation and becomes hijacked in cancers. Skin epithelium is an excellent model system to understand how stem cells remain quiescent during times of minimal wear and tear, how these cells become mobilized during the cyclical bouts of hair growth and wound repair, and how the normal process of stem cell activation goes awry in cancer and inflammation. We have identified and characterized at a molecular level the skin’s stem cells and shown that they reside in distinct niches that impart to the stem cells their behavior both in task and in the molecular properties they display. We use high-throughput genetic and genomic approaches to dissect at a molecular level how stem cell interactions with their niches differ in homeostasis, wound repair, and inflammation, and how heterogeneity in the tumor microenvironment can confer on stem cells resistance to chemotherapy and immunotherapy. Our global objective is to apply our knowledge of the basic science of epithelial stem cells to unfold new avenues for therapeutics. Citation Format: Elaine Fuchs. Stem cells: Coping with stress and cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA04.
Management of primary hepatic malignancies during the COVID-19 pandemic: recommendations for risk mitigation from a multidisciplinary perspective
Authors: Aisling Barry, Smith Apisarnthanarax, Grainne M O'Kane, Gonzalo Sapisochin, Robert Beecroft, Riad Salem, Sang Min Yoon, Young-Suk Lim, John Bridgewater, Brian Davidson, Marta Scorsetti, Luigi Solbiati, Adam Diehl, Pablo Munoz Schuffenegger, Jonathan G Sham, David Cavallucci, Zita Galvin, Laura A Dawson, Maria A Hawkins
Journal: The Lancet. Gastroenterology & hepatology (2020)
Factors Predicting Survival In Patients With `Non-High-Risk' Acute Variceal Bleeding Receiving Nsbb And/Or Ebl To Prevent Re-Bleeding
Authors: Mattias Mandorfer, Virginia Hernandez-Gea, Bogdan Procopet, Alvaro Giraldez, Lucio Amitrano, Candid Villanueva, Dominique Thabut, Luis Ibanez Samaniego, Gilberto Silva-Junior, Javier Martinez, Joan Genesca, Christophe Bureau, Jonel Trebicka, Elba Llop Herrera, Wim Laleman, Jose Maria Palazon Azorin, Jose Castellote Alonso, Lise Lotte Gluud, Carlos Noronha Ferreira, Nuria Canete, Manuel Rodriguez, Arnulf Ferlitsch, Jose Luis Mundi, Henning Gronbaek, Manuel Nicolas Hernandez Guerra, Roman Sassatelli, Alessandra Dell'Era, Marco Senzolo, Juan Gonzalez Abraldes, Manuel Romero-Gomez, Alexander Zipprich, Meritxell Casas, Helena Masnou, Massimo Primignani, Aleksander Krag, Frederik Nevens, Jose Luis Calleja, Christian Jansen, Maria Vega Catalina, Agustin Albillos, Marika Rudler, Edilmar Alvarado Tapias, Maria Anna Guardascione, Marcel Tantau, Remy Schwarzer, Thomas Reiberger, Stig Borbjerg Laursen, Marta Lopez-Gomez, Alba Cachero, Alberto Ferranese, Cristina Ripoll, Vincenzo La Mura, Jaime Bosch, Juan Carlos Garcia-Pagan
Journal: Hepatology (2019)
T cell engagement of cross-presenting microglia protects the brain from a nasal virus infection
Authors: E. Ashley Moseman, Alexa C. Blanchard, Debasis Nayak, Dorian B. McGavern
Journal: Science Immunology (2020)

Microglia protect the brain from an intranasal VSV infection by cross-presenting neuronal antigen to antiviral CD8 + T cells.
Givosiran — Running RNA Interference to Fight Porphyria Attacks
Authors: Gloria Gonzalez-Aseguinolaza
Journal: New England Journal of Medicine (2020)

The porphyrias are a group of rare and ultra-rare devastating disorders of heme biosynthesis. The majority of these disorders are inherited, and patients present with disabling symptoms that have a profound effect on their quality of life. The subtypes of acute hepatic porphyria — including acute intermittent porphyria (the most common subtype), hereditary coproporphyria, variegate porphyria, and delta-aminolevulinic acid (ALA) dehydratase–deficiency porphyria — are characterized by the occurrence of severe neurovisceral attacks. The genetic deficit that causes acute hepatic porphyria reduces heme availability under conditions of increased heme demands, which leads to activation of the heme-synthesis pathway and up-regulation of . . .
SAT0191 PLASMA PROTEOMICS IDENTIFIES A PROTEIN SIGNATURE ASSOCIATED WITH RESPONSE TO RITUXIMAB IN PATIENTS WITH SLE
Authors: J. Reynolds, J. Prattley, M. Lunt, I. N. Bruce
Journal: Annals of the Rheumatic Diseases (2020)

Background: Rituximab (RTX) is B cell-depleting biological therapy used in the treatment of systemic lupus erythematosus (SLE). Response rates are typically around 50% and there are currently no robust biomarkers to identify which patients are more likely to respond. Objectives: To determine whether proteomic analysis of baseline plasma samples could identify novel biomarkers of response to RTX in patients with active SLE. Methods: Patients with SLE (≥ 4 ACR criteria) receiving RTX for active disease (BILAG A or 2 BILAG B scores) from the UK-based BILAG-BR register were included. Improvement at 12 months was defined as a reduction to ≤ 1 BILAG B score with no increase in either SLEDAI score or steroid dose. Proteomic analysis was performed on baseline plasma samples using sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS). Data were aligned and normalised to give relative protein abundance. A Lasso penalised logistic regression, with an outcome of improvement at 12 months, was used to perform the variable selection procedure using the R package ‘glmnet’. The penalty metric was set at the value which minimised deviance in a 10-fold cross-validation procedure. Confounding variables of sex, age, ethnicity, oral steroid dose, and SLEDAI score had no penalty applied and were thus forcibly retained in the model. Protein-protein interaction networks were visualised using STRING v11.0. Results: 70 patients of whom 63/70 (90%) were female with a median (IQR) age of 41 (32, 51) years and disease duration of 11 (6, 20) years at baseline were included. Patients had active disease with a median SLEDAI score of 10 (6, 16). All patients received RTX according to NHS England guidelines. Of 829 proteins, 815 were detected in at least 1 patient. We identified 9 proteins which were associated with clinical improvement at 12 months. A literature search identified that these proteins have relevance to T cell function, complement activation and lupus nephritis. Gender had the greatest weight in the model followed by Serpin Family A Member 10 (SERPINA10) and complement factor B (CFB). Protein interaction networks linked SERPINA10 to CFB by C3 complement (figure). Conclusion: Plasma proteome analysis has identified a protein signature associated with response to RTX in SLE. These findings will be validated in independent cohorts and may offer the ability to predict response to RTX in lupus patients. Protein Interaction Network of the 9 proteins from the multivariable model (with one additional level added). Cyan/magenta lines shown known interactions. Other colours show predicted interactions. Disclosure of Interests: : John Reynolds: None declared, Jennifer Prattley: None declared, Mark Lunt: None declared, Ian N. Bruce Grant/research support from: Genzyme Sanofi, GSK, and UCB, Consultant of: Eli Lilly, AstraZeneca, UCB, Iltoo, and Merck Serono, Speakers bureau: UCB
Transcriptional regulation of androgen receptor gene expression in prostate cancer
Authors: Liying Zhang
Journal: Cancer Research (2004)

970  Prostate cancer (CaP) cells are typically androgen dependent and androgen ablation is the standard systemic therapy for this disease. Virtually all CaP patients treated with androgen ablation eventually develop resistance to therapy, an ominous clinical state for which no consistently effective therapy exists. The mechanisms and biochemical pathways that contribute to the development of androgen independent prostate cancer (AIPC) are not well understood. Abnormal activation of androgen receptor (AR) has been proposed as one important mechanism. We have performed DNA microarray analysis of 11 noncancerous prostatic tissues and 86 CaP specimens in different clinical states. Therapy resistance has associated with a marked increase in AR transcripts without gene amplification, which suggests that upregulation of AR transcript is a critical event. Based on a correlation with AR transcript level, several transcription factors (NF-κB, Ets-2, AP-1) were identified as potential regulators of AR expression and signaling during progression to hormone therapy resistance. Transient transfection data indicated that NF-κB, Ets-2 could upregulate the AR expression in LNCaP cells. Gel mobility shift assay indicated that NF-κB p65 and p50 subunits specifically bind to the consensus NF-κB binding sites within the human AR promoter. Our data suggest that the transcriptional activation of AR gene represents a novel mechanism involved in the development of AIPC. The identification and characterization of these transcriptional regulators may provide therapeutic opportunities for this disease.
Abstract 11880: Association Between the Presence and Extent of Coronary Artery Disease and Atrial Fibrillation: Insights From the Life-heart Study
Authors: Jelena Kornej, Sylvia Henger, Ralph Burkhardt, Holger Thiele, Joachim Thiery, Markus Scholz
Journal: Circulation (2019)

Introduction: Coronary artery disease (CAD) is a significant risk factor for atrial fibrillation (AF). Several experimental studies demonstrated that right atrial ischemia induced by right coronary...
Abstract 12165: Association of Right Ventricular Dysfunction by Echocardiographic Parameters With Short Term Adverse Outcomes After Left Sided Valvular Surgery
Authors: Arooge Towheed, Ebrahim Sabbagh, Salem A Assiri, Mohammed A Chowdhury, George V Moukarbel, Thomas Schwann, Mark Bonnell, Christopher Cooper, Samer Khouri
Journal: Circulation (2018)

Background: The prognostic value of echocardiographic indices of right ventricular dysfunction(RVD) in left sided valve surgery has not been well described. The main objective of this study is to e...
Distinct neutralizing antibody correlates of protection among related Zika virus vaccines identify a role for antibody quality
Authors: Sonia Maciejewski, Tracy J. Ruckwardt, Kaitlyn M. Morabito, Bryant M. Foreman, Katherine E. Burgomaster, David N. Gordon, Rebecca S. Pelc, Christina R. DeMaso, Sung-Youl Ko, Brian E. Fisher, Eun Sung Yang, Deepika Nair, Kathryn E. Foulds, John Paul Todd, Wing-Pui Kong, Vicky Roy, Maya Aleshnick, Scott D. Speer, Nigel Bourne, Alan D. Barrett, Martha C. Nason, Mario Roederer, Martin R. Gaudinski, Grace L. Chen, Kimberly A. Dowd, Julie E. Ledgerwood, Galit Alter, John R. Mascola, Barney S. Graham, Theodore C. Pierson
Journal: Science Translational Medicine (2020)

The emergence of Zika virus (ZIKV) in the Americas stimulated the development of multiple ZIKV vaccine candidates. We previously developed two related DNA vaccine candidates encoding ZIKV structural proteins that were immunogenic in animal models and humans. We sought to identify neutralizing antibody (NAb) properties induced by each vaccine that correlated with protection in nonhuman primates (NHPs). Despite eliciting equivalent NAb titers in NHPs, these vaccines were not equally protective. The transfer of equivalent titers of vaccine-elicited NAb into AG129 mice also revealed nonequivalent protection, indicating qualitative differences among antibodies (Abs) elicited by these vaccines. Both vaccines elicited Abs with similar binding titers against envelope protein monomers and those incorporated into virus-like particles, as well as a comparable capacity to orchestrate phagocytosis. Functional analysis of vaccine-elicited NAbs from NHPs and humans revealed a capacity to neutralize the structurally mature form of the ZIKV virion that varied in magnitude among vaccine candidates. Conversely, sensitivity to the virion maturation state was not a characteristic of NAbs induced by natural or experimental infection. Passive transfer experiments in mice revealed that neutralization of mature ZIKV virions more accurately predicts protection from ZIKV infection. These findings demonstrate that NAb correlates of protection may differ among vaccine antigens when assayed using standard neutralization platforms and suggest that measurements of Ab quality, including the capacity to neutralize mature virions, will be critical for defining correlates of ZIKV vaccine-induced immunity.
Initial results of the phase 1 portion of an ongoing phase 1/2 study of RP1 as a single agent and in combination with nivolumab in patients with solid tumors
Authors: M Middleton, J Sacco, J Merchan, A Thomassen, B Curti, A VanderWalde, A Olsson-Brown, F Aroldi, N Fotiadis, S Baum, H Kaufman, K Harrington
Journal: Journal for ImmunoTherapy of Cancer (2019)
Abstract IA26: Liquid biopsy in precision pathology: Plasma and beyond!
Authors: George J. Netto
Journal: Clinical Cancer Research (2020)

Abstract Launched in 2006, The Cancer Genome Atlas project (TCGA) aimed at systematically exploring the entire spectrum of genomic changes involved in human cancer. This year, the colossal effort culminated with the analysis of 11,000 cases across 33 tumor types. The comprehensive multiparametric (i.e., genomic, transcriptomic, epigenomic, and proteomic) analysis has yielded staggering datasets characterizing the molecular underpinning of human cancer types. This resulted in robust molecular classifications for common malignancies. A shared functional categorization of molecular alterations across tumor types has emerged, which offers a multitude of druggable targets. As the list of actionable genetic alterations in solid and hematologic malignancies continue to grow, molecular diagnostic applications are rapidly penetrating the daily practice of the pathologist in an unparalleled pace. “Precision pathology” is now an integral part of the practice of “precision oncology.” Despite initial response, patients receiving targeted therapy will develop resistance due to clonal evolution and the acquired survival advantage of nonresponsive tumor clones. As a result, treated patients are increasingly subjected to longitudinal surveillance for clonal evolution in search of new targets. The need for repeated tumor sampling for surveillance is driving the search for dynamic noninvasive tumor sampling methods. Non-tissue-based sampling methods (liquid biopsy) offer easy repeated access to tumor material in cancer patient body fluids for genomic analysis. Compared to traditional tissue biopsies, liquid biopsies also offer the advantage of “global” analysis of the often heterogeneous tumor genomic landscape both within primary and metastatic sites. The promise of liquid biopsy assays has fueled billions of dollars of investment from major biotechnology players. The current seminar will discuss the principles of liquid biopsy technology. Challenges facing the applications of plasma and urine-based liquid biopsy techniques in precision pathology will be highlighted. Citation Format: George J. Netto. Liquid biopsy in precision pathology: Plasma and beyond! [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr IA26.