tbuckley/cabot-search huggingface dataset:
Copy-Number Alteration Burden Differentially Impacts Immune Profiles and Molecular Features of Hepatocellular Carcinoma
Authors: Laia Bassaganyas, Roser Pinyol, Roger Esteban-Fabró, Laura Torrens, Sara Torrecilla, Catherine E. Willoughby, Sebastià Franch-Expósito, Maria Vila-Casadesús, Itziar Salaverria, Robert Montal, Vincenzo Mazzaferro, Jordi Camps, Daniela Sia, Josep M. Llovet
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Chromosomal instability is a hallmark of cancer that results in broad and focal copy-number alterations (CNAs), two events associated with distinct molecular, immunologic, and clinical features. In hepatocellular carcinoma (HCC), the role of CNAs has not been thoroughly assessed. Thus, we dissected the impact of CNA burdens on HCC molecular and immune features. Experimental Design: We analyzed SNP array data from 452 paired tumor/adjacent resected HCCs and 25 dysplastic nodules. For each sample, broad and focal CNA burdens were quantified using CNApp, and the resulting broad scores (BS) and focal scores (FS) were correlated with transcriptomic, mutational, and methylation profiles, tumor immune composition, and clinicopathologic data. Results: HCCs with low broad CNA burdens (defined as BS ≤ 4; 17%) presented high inflammation, active infiltrate signaling, high cytolytic activity, and enrichment of the “HCC immune class” and gene signatures related to antigen presentation. Conversely, tumors with chromosomal instability (high broad CNA loads, BS ≥ 11; 40%), displayed immune-excluded traits and were linked to proliferation, TP53 dysfunction, and DNA repair. Candidate determinants of the low cytotoxicity and immune exclusion features of high-BS tumors included alterations in antigen-presenting machinery (i.e., HLA), widespread hypomethylation, and decreased rates of observed/expected neoantigenic mutations. High FSs were independent of tumor immune features, but were related to proliferation, TP53 dysfunction, and progenitor cell traits. Conclusions: HCCs with high chromosomal instability exhibit features of immune exclusion, whereas tumors displaying low burdens of broad CNAs present an immune active profile. These CNA scores can be tested to predict response to immunotherapies.
Abstract 5567: <i>In vivo</i> administration of the STING agonist, JNJ-67544412, leads to complete regression of established murine subcutaneous tumors
Authors: Melissa Smith, Diana Chin, Szeman Chan, Sally Mahady, Liam Campion, Caitlin Morgan, Shefali Patel, Gerald Chu, Anna Hughes, Gilles Bignan, Pete Connolly, Stuart Emanuel, Kathryn Packman, Leopoldo L. Luistro
Journal: Cancer Research (2020)

Abstract STING (Stimulator of Interferon Genes) is an important mediator of innate and adaptive immunity that responds to invading cytosolic bacterial and viral pathogens, and double stranded DNA from transformed cells. Activation of the cGAS-STING pathway leads to pleiotropic cytokine (IFN-α, IFN-β, TNF-α, IL-6) production, maturation and activation of macrophages, and MHC class II expressing dendritic cells (DCs) with generation of CD8+ T cells. JNJ-67544412 (JNJ-4412) is a cyclic dinucleotide (CDN) developed as a STING agonist. JNJ-4412 binds both mouse and human STING and is more potent binding all the major human STING alleles than most other STING CDN agonists. JNJ-4412 phosphorylate STING and IRF3 and induces high levels of IFNβ and other cytokines in M1 and M2 macrophages, dendritic cells, and monocytes. In syngeneic mouse tumor studies, JNJ-4412 was dosed intratumorally (i.t.) on a q3d x 3 or qweekly schedule resulting in significant tumor regression, complete cures and long-lasting antitumor immunity. Body weight loss (&amp;lt;20%) was observed but was transient and recoverable and could be mitigated by utilizing a qweekly schedule with no loss of activity. Proinflammatory cytokines such as IFN-α, IFN-β, IP-10, TNF-α, IL-6 and MCP-1 were detected in tumor and plasma after dosing. Combination studies with anti-PD-1 resulted in enhanced dose-dependent efficacy in treated tumors. In bilateral tumor studies, JNJ-4412 inhibited growth of contralateral un-injected tumors. Pharmacodynamic (PD) and mechanism of action (MOA) studies revealed increased number of CD8+ T cells in the treated tumors; increased apoptosis (cleaved caspase 3); loss of vascularization; decreased tumor cell proliferation and pronounced hemorrhagic necrosis in tumors. Rechallenge of cured mice demonstrated long-lasting antitumor immunity. Thus, in vivo administration of JNJ-4412 potently activates the STING pathway resulting in inflammatory cytokine induction, activation of dendritic cells, proliferation of CD8+ T cells, increased apoptosis and curative antitumor efficacy with immunologic memory. Citation Format: Melissa Smith, Diana Chin, Szeman Chan, Sally Mahady, Liam Campion, Caitlin Morgan, Shefali Patel, Gerald Chu, Anna Hughes, Gilles Bignan, Pete Connolly, Stuart Emanuel, Kathryn Packman, Leopoldo L. Luistro. In vivo administration of the STING agonist, JNJ-67544412, leads to complete regression of established murine subcutaneous tumors [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 5567.
Accuracy and usefulness in assessing proficiency of the observational clinical human reliability assessment checklist of the open inguinal hernia repair procedure: A cross-sectional study
Authors: T. Nazari, M.P. Simons, J.J.G. van Merriënboer, T. Wiggers
Journal: International Journal of Surgery (2020)

The Observational Clinical Human Reliability Assessment (OCHRA) can be used to score errors during surgical procedures. To construct an OCHRA-checklist, steps, substeps, and hazards of a surgical procedure need to be defined. A step-by-step framework was developed to segment surgical procedures into steps, substeps, and hazards. The first aim of this study was to investigate if the step-by-step framework could be used to construct an accurate Lichtenstein open inguinal hernia repair (LOIHR) stepwise description. The second aim was to investigate if the OCHRA-checklist based on this stepwise description was accurate and useful for surgical training and assessment.Ten expert surgeons rated statements regarding the accuracy of the LOIHR stepwise description, the accuracy, and the usefulness of the LOIHR OCHRA-checklist (eight, seven, and six statements, respectively) using a 5-point Likert scale. One-sample Wilcoxon signed-rank test was used to compare the outcomes to the neutral value of 3.The accuracy of the stepwise description and the accuracy and usefulness of the OCHRA-checklist were rated statistically significantly higher than the neutral value of 3 (median 4.75 [5.00-4.00] with p = .009, median 5.00 [5.00-4.00] with p = .012, median 4.00 [5.00-4.00] with p = .047, respectively). The experts rated the OCHRA-checklist to be useful for the training (5.00 [5.00-4.00], p = .009), and assessment (4.50 [5.00-4.00], p = .010) of surgical residents.This preliminary study showed that the stepwise LOIHR description constructed using the step-by-step framework was found to be accurate. The LOIHR OCHRA-checklist developed using the stepwise description was also accurate, and particularly useful for the training and assessment of proficiency of surgical residents.
THU0178 Clinical significance of rapid radiographic progression in rheumatoid arthritis
Authors: JB Wong, CJ Wong, JM Hazes, PL Van Riel, FC Breedveld, DM Van der Heidje, BG Feagan
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> New treatments for rheumatoid arthritis have established radiographic stabilisation of joint disease as an achievable therapeutic goal, but the amount of radiologic progression that is clinically significant remains uncertain. OMERACT has defined significant radiographic progression by the smallest detectable difference (SDD) based on random measurement error calculated from between observer variation in pairwise radiographic scoring and interpretation. <h3>Objectives</h3> To examine the clinical significance of SDD-defined radiographic progression. <h3>Methods</h3> We combined 2 Dutch cohorts of early rheumatoid arthritis patients from Nijmegen and Leiden. Using an SDD of 15 for the modified Sharp score, 279 patients had year 2 or 3 radiographs (mean age 50.5 year, 76.7% women, 71.7% RF+, 60.1% HLA DR4+) and were divided into 2 groups based on their annual radiographic progression rate: rapid (&gt;7.5) vs non-rapid (&lt;7.5) radiographic progressors. Exploratory statistical analyses were performed using the Chi-square and Wilcoxon rank sum tests. <h3>Results</h3> In this cohort, 199 of the 279 patients (71%) were ?rapid progressors? after 2 – 3 years of RA. At that time, fast progressors tended to be HLA DR4+ (p = 0.11) but had higher ESR, Ritchie articular index, HAQ and Disease Activity Scores (DAS) (all p &lt; 0.02), and were more likely to be older and RF+ (all p &lt; 0.0001). After 5 – 6 years of RA, fast progressors had higher median modified Sharp scores (102 vs 8, p &lt; 0.0001), HAQ scores (0.50 vs 0.23, p &lt; 0.003), and DAS (2.80 vs 2.02, p = 0.003). After 12 years of RA, fast progressors had higher median HAQ (0.88 vs 0.26, p = 0.013) and DAS (2.88 vs 2.35, p = 0.11). <h3>Conclusion</h3> Although SDD-based radiographic progression is defined as a statistically significant worsening beyond random measurement error, such radiologic progression of joint disease appears to identify rheumatoid arthritis patients who are significantly more likely to experience clinically progressive disease. Identifying and targeting the use of new biologic therapies toward this group of radio logically rapidly progressive rheumatoid arthritis patients is likely to yield the most favourable cost-effectiveness ratios because in the absence of these new treatments, these patients are at higher risk of developing progressive disability.
Randomized Phase III Trial of Dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin, or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients with Muscle-invasive Bladder Cancer. Analysis of the GETUG/AFU V05 VESPER Trial Secondary Endpoints: Chemotherapy Toxicity and Pathological Responses
Authors: Christian Pfister, Gwenaelle Gravis, Aude Fléchon, Michel Soulié, Laurent Guy, Brigitte Laguerre, Nicolas Mottet, Florence Joly, Yves Allory, Valentin Harter, Stéphane Culine
Journal: European Urology (2020)
Abstract 996: Reversing tumor induced immune suppression: Role of the secretory autophagy pathway
Authors: Marissa Ashton Howard
Journal: Cancer Research (2020)

Abstract The goal is to reverse cancer immune evasion at the level of the sentinel lymph node. Reduced expansion of CD8+Tcells and other innate immune effector cells in the cancer draining SLN is associated with progression and resistance to checkpoint inhibitors. Cancer derived extracellular vesicles (EVs) that are PD-L1 positive suppress immune recognition at the level of the SNL. Experimental goal: To remodel the SNL to overcome cancer EV-associated immune suppression and induce immune rejection of the tumor. We developed three methodologies for this project a) Collection of draining lymph fluid to characterize extracellular vesicles (EVs) shed by 4T1 syngeneic breast tumors growing in the mammary fat pad. b) Chromatographic separation and characterization of the repertoire of EVs shed by tumors into the tumor microenvironment interstitial space using western blotting, mass spectrometry, and electron microscopy. c) Nanoparticle delivery of purified classes of EVs to the tumor draining SNL in combination with cytokine chemoattractants for innate immune cells. Results: Murine and human breast cancer cell lines shed classic exosomes and autophagosomes. The latter are shed extracellularly by the activation of the secretory autophagy pathway. The classic exosomes(exosome marker positive) contained PD-L1. In contrast the LC3 I/II P62 positive double membrane extracellular autophagosomes contained mitochondrial components (mitophagy). SLN immune cell populations could be massively remodeled by introducing hydrogel nanoparticles that affinity release chemoattractants locally in the subcapsular sinus. Nanoparticles could also be used to deliver concentrated packages of EVs of different classes to the SLN. Introduction of the autophagosome containing EV population to the SLN augmented tumor growth, angiogenesis, and metastasis, even when cytokine induction was used to remodel the SLN. In marked contrast, introduction of the PD-L1 positive exosomes to the SLN in combination with nanoparticle release of T-cell and dendritic cell chemoattractants, induced immune rejection of the syngeneic breast cancer, reducing tumor growth and blocking metastasis. The findings demonstrate that different classes of EVs have opposite effects on cancer immune evasion at the level of the SLN and that immune suppression can be reversed by SLN remodeling to augment dendritic and CD8 T cells. Citation Format: Marissa Ashton Howard. Reversing tumor induced immune suppression: Role of the secretory autophagy pathway [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 996.
Abstract 2471: Role of FOXO transcription factor dynamics in determining cell fates following EGFR inhibition
Authors: Julie M. Huynh, Kayenat S. Aryeh, Lisa Shanks, Andrew L. Paek
Journal: Cancer Research (2020)

Abstract Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first line treatment for patients with advanced non-small cell lung cancer (NSCLC) who have specific hyperactive mutations in EGFR. Though patients have seen improvements in survival after EGFR TKI treatment, resistance commonly develops as not all NSCLC cells die following treatment. Indeed, EGFR inhibitor treatment induces both cell-cycle arrest (allowing for cell survival) and death in cancer cells. The FOXO family of transcription factors have been implicated in both death and arrest responses following EGFR inhibition. This is consistent with FOXOs function in regulating both arrest and apoptotic genes programs. However, it is unknown how the FOXO network ‘decides' between these two oppositional programs to enact following treatment with EGFR inhibitors. Protein dynamics, meaning how the levels or location of a protein changes over time, is a mechanism cells use to encode information about cellular fates. The p53 transcription system is an established example of a dynamically regulated system–it responds to multiple inputs and is capable of enacting multiple outputs (gamma radiation causes oscillations of p53 levels that result in cellular arrest while UV causes a sustained increase of p53 levels that result in cellular death). FOXO's network is similar to the p53 system (multiple input, multiple output), making it a good candidate for dynamic regulation. We have tagged Foxo3a with a fluorescent marker (Venus) at its endogenous locus in PC9 NSCLC cells using CRISPR/Cas9 to determine whether FOXO dynamics dictate cell fate following EGFR TKI treatment. Using live cell microscopy on this line, we have acquired FOXO nuclear cytoplasmic shuttling dynamics as well as cell fate (death/arrest) in single cells. Using time-series analyses we are trying to determine if there are dynamic patterns associated with each fate following EGFR inhibition. Through our studies, we hope to gain a better understanding of this non-genetic mechanism cells use to determine their fate. Our long-term goal is to identify dynamic patterns that push cancer cells to more terminal fates following treatment. Citation Format: Julie M. Huynh, Kayenat S. Aryeh, Lisa Shanks, Andrew L. Paek. Role of FOXO transcription factor dynamics in determining cell fates following EGFR inhibition [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 2471.
Abstract 6530: Old target, but new approach: Targeting cancer-associated MUC1 with ADC and Car-T
Authors: Jin G Jung, Min-Seok Kim, Hwa-Chul Jung, Hoil Choi, Kyung-Duk Moon
Journal: Cancer Research (2020)

Abstract Purpose: The characteristics of aberrant overexpression and distinct features of cancer-associated (CA)-MUC1 has been often considered as a promising target in most of the solid cancers. MUC1 is composed of α and β subunits to form a full length of MUC1, and α subunit is released and circulated into the blood in cancer, which is used as biomarkers such as CA 15-3 and CA 27-29. As those α subunit-targeting strategies were failed in the numerous clinical trials due to, at least in part, the diminished α subunit of MUC1 in cancer, we have developed a humanized Ab, PAb001 targeting the residual β subunit of MUC1, called as an onco-tethered (OT)-MUC1. To prove the concept of this strategy, an antibody-drug conjugate (ADC) and chimeric antigen receptor (CAR) T cells were applied to assess its efficacies. Methods: We produced a monoclonal antibody (mAb) against OT-MUC1 from mouse and sequentially generated its derivative humanized antibody, PAb001. Then, the target product profiles (TPP) were determined by SPR, ELISA, FACS, immunohistochemical analysis, pilot tissue cross-reactivity, and pharmacokinetics (PK) analysis. Then, to evaluate anti-cancer efficacies, we either conjugated PAb001 with Monomethyl auristatin E (MMAE) or generated the second-generation CAR T cells and then sequentially tested in vitro and in vivo cancer models. Results: Based on the TPP criteria, PAb001 antibody was chosen over a hundred of candidate antibodies tested. Next, it was conjugated with MMAE, treated and measured its cytotoxicity in ovarian and breast cancer cell lines, including triple-negative breast cancers (TNBC). As a result, PAb001-ADC selectively inhibited the growth of cancer cell lines, depending on the expression level of MUC1. Also, it showed 80-100 % tumor growth inhibition rates (TGI) in the cell lines- and patient-derived xenograft models. Lastly, OT-MUC1 Car-T cells showed significant and selective growth inhibition of cancer cells. Conclusion: Taken together, the preclinical studies of PAb001-ADC and Car-T indicate the high therapeutic potentials targeting OT-MUC1 in cancer, which further provided the rationale for clinical development. Citation Format: Jin G Jung, Min-Seok Kim, Hwa-Chul Jung, Hoil Choi, Kyung-Duk Moon. Old target, but new approach: Targeting cancer-associated MUC1 with ADC and Car-T [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 6530.
Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Dinesh Khanna, Celia J F Lin, Daniel E Furst, Jonathan Goldin, Grace Kim, Masataka Kuwana, Yannick Allanore, Marco Matucci-Cerinic, Oliver Distler, Yoshihito Shima, Jacob M van Laar, Helen Spotswood, Bridget Wagner, Jeffrey Siegel, Angelika Jahreis, Christopher P Denton, Eleonora Lucero, Bernardo Pons-Estel, Mariano Rivero, Guillermo Tate, Vanessa Smith, Ellen De Langhe, Rasho Rashkov, Anastas Batalov, Ivan Goranov, Rumen Stoilov, James Dunne, Sindhu R. Johnson, Janet E. Pope, Dušanka Martinović Kaliterna, Mette Mogensen, Anne Braae Olesen, Yannick Allanore, Joerg Christoph Henes, Ulf Müller-Ladner, Gabriela Riemekasten, Alla Skapenko, Panayiotis Vlachoyiannopoulos, Emese Kiss, Tünde Minier, Lorenzo Beretta, Elisa Gremese, Marco Matucci-Cerinic, Gabriele Valentini, Yoshihide Asano, Tatsuya Atsumi, Hironobu Ihn, Tomonori Ishii, Osamu Ishikawa, Masataka Kuwana, Yoshihito Shima, Hiroki Takahashi, Kazuhiko Takehara, Yoshiya Tanaka, Yoshioki Yamasaki, Loreta Bukauskiene, Irena Butrimiene, Gabriel Medrano Ramirez, Cesar Ramos-Remus, Tatiana Sofia Rodriguez Reyna, Jeska de Vries-Bouwstra, Jacob M. van Laar, Bogdan Batko, Slawomir Jeka, Eugeniusz Kucharz, Maria Majdan, Marzena Olesinska, Zaneta Smolenska, Jose Alves, Maria Santos, Carmen Marina Mihai, Simona Rednic, Ivan Castellvi Barranco, Francisco Javier Lopez Longo, Carmen Simeon Aznar, Patricia Carreira, Oliver Distler, Ulrich A. Walker, Emma Derrett-Smith, Bridget Griffiths, Neil McKay, Christopher P. Denton, Jacob Aelion, Michael Borofsky, Roy Fleischmann, Joseph Z. Forstot, Daniel E. Furst, Suzanne Kafaja, M. Faisal Khan, Dinesh Khanna, Michael D. Kohen, Richard W. Martin, Fabian Mendoza-Ballesteros, Alireza Nami, Shirley Pang, Grissel Rios, Robert Simms, Keith Michael Sullivan, Virginia D. Steen
Journal: The Lancet Respiratory Medicine (2020)
Evolution of the COVID-19 vaccine development landscape
Authors: Tung Thanh Le, Jakob P. Cramer, Robert Chen, Stephen Mayhew
Journal: Nature Reviews Drug Discovery (2020)

The COVID-19 vaccine R&D landscape has developed at unprecedented scale and speed since our initial analysis in April identified 115 candidates in the pipeline (Nat.Rev. Drug Discov.19, 305-306; 2020).In this updated overview, we focus on candidates in clinical trials and provide some initial perspectives on their clinical development.
Abstract IA21: Integrating head and neck cancer immunotherapy into locally advanced treatment
Authors: Robert Ferris
Journal: Clinical Cancer Research (2020)

Abstract Recognition that the immune system plays an important role in the development and progression of cancer has permitted a renaissance in the testing of agents designed to stimulate antitumor immunity. Recent FDA approvals have validated that cancer immunotherapy is now established as a standard-of-care agent in many tumor types, primarily in the recurrent/metastatic (R/M) setting. For those with previously untreated, locally advanced disease, the future portends an exciting and rational approach to integrating this new type of therapy into conventional cancer treatment. We will present recent trials and biomarkers of targeted immunotherapy and correlation with response. Human papillomavirus associated (HPV+) oropharyngeal cancer (OPC) is an emerging entity with improved prognosis and distinct staging system from traditional HPV-negative HNSCC. The lecture will address how PD-1-based immunotherapy may represent deintensification without decreased survival for stage I patients at low or intermediate risk, or as an “add-on” strategy for intensification in conjunction with postoperative adjuvant radiation (RT) or chemoradiation (CRT). In addition, neoadjuvant approaches provide dynamic insight into immunosuppression and responses, and guide rational immunotherapeutic combinations for targeting immune checkpoint receptors and inflammatory agonists, including the development of predictive biomarkers to facilitate efficient patient selection. Indeed, a major deficiency of targeted immunotherapies is the lack of dynamic biomarkers to monitor alterations in the tumor microenvironment. Neoadjuvant “window of opportunity” trials present a useful method to obtain predictive biomarkers for patients receiving novel immunotherapeutic agents modulating tumor-infiltrating lymphocytes. Citation Format: Robert Ferris. Integrating head and neck cancer immunotherapy into locally advanced treatment [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr IA21.