tbuckley/cabot-search huggingface dataset:
The Changing Landscape of Therapeutic Cancer Vaccines—Novel Platforms and Neoantigen Identification
Authors: Jessica Jou, Kevin J. Harrington, Mai-Britt Zocca, Eva Ehrnrooth, Ezra E.W. Cohen
Journal: Clinical Cancer Research (2020)

Therapeutic cancer vaccines, an exciting development in cancer immunotherapy, share the goal of creating and amplifying tumor-specific T-cell responses, but significant obstacles still remain to their success. Here, we briefly outline the principles underlying cancer vaccine therapy with a focus on novel vaccine platforms and antigens, underscoring the renewed optimism. Numerous strategies have been investigated to overcome immunosuppressive mechanisms of the tumor microenvironment (TME) and counteract tumor escape, including improving antigen selection, refining delivery platforms, and use of combination therapies. Several new cancer vaccine platforms and antigen targets are under development. In an effort to amplify tumor-specific T-cell responses, a heterologous prime-boost antigen delivery strategy is increasingly used for virus-based vaccines. Viruses have also been engineered to express targeted antigens and immunomodulatory molecules simultaneously, to favorably modify the TME. Nanoparticle systems have shown promise as delivery vectors for cancer vaccines in preclinical research. T-win is another platform targeting both tumor cells and the TME, using peptide-based vaccines that engage and activate T cells to target immunoregulatory molecules expressed on immunosuppressive and malignant cells. With the availability of next-generation sequencing, algorithms for neoantigen selection are emerging, and several bioinformatic platforms are available to select therapeutically relevant neoantigen targets for developing personalized therapies. However, more research is needed before the use of neoepitope prediction and personalized immunotherapy becomes commonplace. Taken together, the field of therapeutic cancer vaccines is fast evolving, with the promise of potential synergy with existing immunotherapies for long-term cancer treatment.
Abstract PO-031: Innate immune genes distinguish the immune microenvironment of early onset colorectal cancer
Authors: Ivy H. Gardner, Ragavan Siddarthan, Katherine Watson, Elizabeth Dewey, Rebecca Ruhl, Xiangnan Guan, Zheng Xia, Liana V. Tsikitis, Sudarshan Anand
Journal: Cancer Research (2020)

Abstract Despite a decrease in the incidence of colorectal cancer (CRC) over the last 40 years, the incidence of CRC in people under 50 years old is increasing around the globe. Early onset (≤50 years old) and late onset (≥65 years old) CRC appear to have differences in their clinicopathological and genetic features, but it is unclear if there are differences in the tumor microenvironment. We hypothesized that the immune microenvironment of early onset CRC is distinct from late onset CRC and promotes tumor progression. We used Nanostring immune profiling to analyze mRNA expression of immune genes in FFPE surgical specimens from patients with early (N=40) and late onset (N=39) CRC. We found three genes, SAA1, C7, and CFD, have increased expression in early onset colorectal cancer and distinct immune signatures based on the tumor location. After adjusting for clinicopathological features, increased expression of CFD and SAA1 were associated with worse progression free survival and increased expression of C7 was associated with worse overall survival. Our data demonstrate that the immune microenvironment in early onset CRC is unique, location dependent, and associated with worse outcomes. We propose that age specific immune signatures in the colorectal immune microenvironment can be used as biomarkers for prognosis as well as the development of targeted immune modulatory agents. Citation Format: Ivy H. Gardner, Ragavan Siddarthan, Katherine Watson, Elizabeth Dewey, Rebecca Ruhl, Xiangnan Guan, Zheng Xia, Liana V. Tsikitis, Sudarshan Anand. Innate immune genes distinguish the immune microenvironment of early onset colorectal cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-031.
A Large London District General Hospital Highlights CLL and Bame As Risk Factors for Severe Disease Amongst Haematology-Oncology Patients
Authors: Isabel Farmer, Samah Babiker, Jumoke Stella Okikiolu, Matthew Steel, Chandima Wanniarachchi, Shona Littlewood, Yishi Tan, Kameta Imaeva, Ana Duran, Evdoxia Douvali, Murugaiyan Thanigaikumar, Sunil Gupta, Tullie Yeghen, Sabia Rashid, Naheed Mir, Satyajit Sahu, Sarah Oram
Journal: Blood (2020)
Phase I Study of Ixazomib with Conventional Chemotherapy in the Treatment of Acute Myeloid Leukemia in Older Adults
Authors: Philip C. Amrein, Eyal C. Attar, Geoffrey Fell, Traci M. Blonquist, Andrew M. Brunner, Gabriela S. Hobbs, Hanno R. Hock, Steven L. McAfee, Rupa Narayan, Jenna A. Moran, Meghan Bergeron, Julia E. Foster, Christina Bertoli, Kristin McGregor, Molly Macrae, Meghan Burke, Tanya T. Behnan, Tina T. Som, Aura Y. Ramos, Megan K. Vartanian, Jennifer Lombardi Story, Donna S. Neuberg, Amir T. Fathi
Journal: Blood (2020)
A Phase 1, First-in-Human Study of Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D (GPRC5D) x CD3 Bispecific Antibody, in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)
Authors: Ajai Chari, Jesus G. Berdeja, Albert Oriol, Niels W. C. J. van de Donk, Paula Rodriguez, Elham Askari, Maria-Victoria Mateos, Monique C. Minnema, Raluca Verona, Suzette Girgis, Thomas Prior, Brandi W. Hilder, Jeffery Russell, Jenna D. Goldberg, Amrita Krishnan
Journal: Blood (2020)
Co-Expression of JAK2-V617F and Calr-del52 In Vivo Enhances Myeloproliferative Phenotype in Mice and Does Not Influence Competitive Fitness of Hematopoietic Stem Cells
Authors: Andrea Majoros, Harini Nivarthi, Ruochen Jia, Roland Jäger, Sarada Achyutuni, Christina M. Schueller, Robert Kralovics
Journal: Blood (2020)
Effects of oncogenic NRAS suppression on gene expression in human melanoma cell lines.
Authors: Malihe Eskandarpour, Fei Haung, Karen A. Revees, Edwin Clark, Johan Hansson
Journal: Cancer Research (2006)

5020  NRAS codon 61 mutations are among the most common oncogenic alterations in cutaneous melanoma. Oncogenic N-Ras is thought to constitutively activate a series of signal transduction pathways crucial for the control of growth signals, cell survival and invasion of melanoma cells. As somatic mutations leading to the expression of oncogenic N-Ras are known to arise early in melanoma development and be maintained throughout melanoma progression, oncogenic NRAS represents an attractive therapeutic target. We previously showed that suppression of oncogenic Q61R human melanoma cell lines, 224 and BL, which harbor this mutation resulted decreased levels of phosphorylated ERK and apoptosis. We used the Affymetrix H-133 A chips to further study the effects of suppressing oncogenic mutant Q61R NRAS on intracellular signaling in these cell lines. Some genes were identified that changed their expression by suppressing oncogenic Q61R NRAS. Thirty-one probe sets (30 unique genes) were significantly regulate by NRAS Mut-siRNA in both cell lines. These results were further validated by western blot and immunofluorescence staining. Genes with altered expression are involved in regulation of apoptosis and cell proliferation, and may identify molecular targets for the development of novel treatment strategies.
Zella 201: A Biomarker-Guided Phase II Study of Alvocidib Followed By Cytarabine and Mitoxantrone in MCL-1 Dependent Acute Myeloid Leukemia (AML): Results of Newly Diagnosed High-Risk Exploratory Arm
Authors: Joshua F. Zeidner, Daniel J. Lee, Gil Fine, Eunice S. Wang, Vijaya R. Bhatt, Andrew Dalovisio, Pau Montesinos, Kathryn S. Kolibaba, Stephen P. Anthony, David J. Bearss, B. Douglas Smith
Journal: Blood (2020)
A Patient with Fever and Dyspnea
Authors: Wilfredo R. Matias, Anand Vaidya, Manfred Brigl, Lisa M. Bebell
Journal: New England Journal of Medicine (2020)

A Patient with Fever and Dyspnea This interactive case features a 60-year-old woman who presented with a 5-day history of fevers and chills early in the Covid-19 pandemic. In the 3 days before pres...
A Simple, Safe and Effective Approach for Personalized Precision <i>Ex Vivo</i> Gene Therapy Based on Autoinfusion of Gene-Modified Leucoconcentrate (GML) <i>Prepared</i> from Routine Unit of Patient's Peripheral Blood
Authors: Rustem I. Islamov, Michail E. Sokolov, Zufar Z Safiullov, Maria A Davleeva, Ravil R Garifulin, Farid V. Bashirov, Ilnur I. Salafutdinov, Albert A Rizvanov, Olga V Zubkova, Maxim M Smarov, Denis Yu Logunov, Boris S Naroditskyi, Ramil G Turaev
Journal: Blood (2020)
Longitudinal Genomic Characterization Using Cell-Free DNA in Patients with Idiopathic Aplastic Anemia
Authors: Georgina L Ryland, Lucy C Fox, Xiangting Chen, Satwica Yerneni, Jeffrey Szer, Ashish Bajel, Robin J Filshie, Sue Morgan, Sarah-Jane Dawson, Piers Blombery
Journal: Blood (2020)
Hepcidin Mimetic (PTG-300) Reverses Iron Deficiency While Controlling Hematocrit in Polycythemia Vera Patients
Authors: Yelena Ginzburg, Marina Kremyanskaya, Andrew T. Kuykendall, Abdulraheem Yacoub, Jay Yang, Suneel K Gupta, Frank Valone, Sarita Khanna, Ronald Hoffman, Srdan Verstovsek
Journal: Blood (2020)
Incidence of Multiple vs First Cutaneous Squamous Cell Carcinoma on a Nationwide Scale and Estimation of Future Incidences of Cutaneous Squamous Cell Carcinoma
Authors: Selin Tokez, Loes Hollestein, Marieke Louwman, Tamar Nijsten, Marlies Wakkee
Journal: JAMA Dermatology (2020)

Until now, most studies on cutaneous squamous cell carcinoma (cSCC) incidence rates concerned only the first cSCC per patient. Given the increase in incidence rates and the frequent occurrence of subsequent cSCCs per patient, population-based data on the incidence rates of both first and multiple cSCCs are needed.To calculate annual age-standardized incidence rates for histopathologically confirmed first and multiple cSCCs per patient and to estimate future cSCC incidence rates up to 2027.A nationwide population-based epidemiologic cohort study used cancer registry data on 145 618 patients with a first histopathologically confirmed cSCC diagnosed between January 1, 1989, and December 31, 2017, from the Netherlands Cancer Registry and all patients with multiple cSCCs diagnosed in 2017.Age-standardized incidence rates for cSCC-standardized to the European Standard Population 2013 and United States Standard Population 2000-were calculated per sex, age group, body site, and disease stage. A regression model with positive slope was fitted to estimate cSCC incidence rates up to 2027.A total of 145 618 patients in the Dutch population (84 572 male patients [58.1%]; mean [SD] age, 74.5 [11.5] years) received a diagnosis of a first cSCC between 1989 and 2017. Based on incident data, European Standardized Rates (ESRs) increased substantially, with the highest increase found among female patients from 2002 to 2017, at 8.2% (95% CI, 7.6%-8.8%) per year. The ESRs for first cSCC per patient in 2017 were 107.6 per 100 000 person-years (PY) for male patients, an increase from 40.0 per 100 000 PY in 1989, and 68.7 per 100 000 PY for female patients, an increase from 13.9 per 100 000 PY in 1989, which corresponds with a US Standardized Rate of 71.4 per 100 000 PY in 2017 for men and 46.4 per 100 000 PY in 2017 for women. Considering multiple cSCCs per patient, ESRs increased by 58.4% for men (from 107.6 per 100 000 PY to 170.4 per 100 000 PY) and 34.8% for women (from 68.7 per 100 000 PY to 92.6 per 100 000 PY). Estimation of ESRs for the next decade show a further increase of 23.0% for male patients (ESR up to 132.4 per 100 000 PY [95% prediction interval, 125.8-139.0 per 100 000 PY]) and 29.4% for female patients (ESR up to 88.9 per 100 000 PY [95% prediction interval, 84.3-93.5 per 100 000 PY]).This nationwide epidemiologic cohort study suggests that incidence rates of cSCC keep increasing, especially among female patients, and that the occurrence of multiple cSCCs per patient significantly adds to the current and future burden on dermatologic health care. Revision of skin cancer policies are needed to halt this increasing trend.
Polatuzumab Vedotin Plus Venetoclax with Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Primary Efficacy Analysis of a Phase Ib/II Study
Authors: Giuseppe Gritti, Paula Marlton, Tycel J. Phillips, Christopher Arthur, Rajat Bannerji, Paolo Corradini, Anna Johnston, John F. Seymour, Sam Yuen, Jamie Hirata, Lisa Musick, Sourish Saha, Brandon Croft, Christopher Flowers
Journal: Blood (2020)
The Accuracy of Physical Examination to Diagnose Anemia Among Patients 5 Years of Age or Older: A Systematic Review of the Literature
Authors: Neha Vyas, Oluwatoyosi Onwuemene, Stephanie Hendren, Charu Monga, Tushar Sehgal, Arulselvi Subramanian, Vishal Vashistha
Journal: Blood (2020)
Deep Learning for Distinguishing Morphological Features of Acute Promyelocytic Leukemia
Authors: John-William Sidhom, Ingharan J Siddarthan, Bo-Shiun Lai, Adam Luo, Bryan Hambley, Jennifer Bynum, Amy S. Duffield, Michael B. Streiff, Alison R. Moliterno, Philip H. Imus, Christian B. Gocke, Lukasz P. Gondek, Amy E. DeZern, Alexander S Baras, Thomas S. Kickler, Mark Levis, Eugene Shenderov
Journal: Blood (2020)
Opposing regulatory functions of the TIM3 (HAVCR2) signalosome in primary effector T cells as revealed by quantitative interactomics
Authors: Yunhao Zhai, Javier Celis-Gutierrez, Guillaume Voisinne, Daiki Mori, Laura Girard, Odile Burlet-Schiltz, Anne Gonzalez de Peredo, Romain Roncagalli, Bernard Malissen
Journal: Cellular and Molecular Immunology (2020)

Deciphering how T-cell antigen receptor signals are modulated by coinhibitors is a fundamental goal in immunology and of considerable clinical interest because blocking coinhibitory signals via therapeutic antibodies have become a standard cancer immunotherapeutic strategy. Most of the attention devoted to T-cell immunoglobulin and mucin domain-3 (TIM3; also known as HAVCR2 or CD366) molecules stems from their expression on exhausted T cells in settings of chronic viral infection and tumors. Moreover, T cells expressing high levels of both PD-1 and TIM3 coinhibitors appear more dysfunctional than those expressing PD-1 alone. Combination therapies intending to block both PD-1 and TIM3 are thus actively being explored in the cancer treatment setting. Upon interaction with Galectin-9 (GAL-9) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1), the tyrosines found in the TIM3 cytoplasmic tail are phosphorylated.1 Because these conserved tyrosines do not form a recognizable inhibitory signaling motif, the mechanism by which TIM3 transmits inhibitory signals has not been elucidated. Paradoxically, TIM3 also has costimulatory activity in T cells.2,3 Published biochemical studies attempting to unveil the mode of action of TIM3 have relied on approaches addressing one candidate effector at a time with limited quantitative insight, and most used transformed cells. Using mice expressing an affinity Twin-Strep-tag (OST) at the TIM3-protein C-terminus (TIM3OST mice) (Figs. 1a and S1a) and affinity purification coupled with mass spectrometry (AP-MS), we herein defined the composition and dynamics of the signaling protein complex (signalosome) used by TIM3 in primary effector T cells. These results provide a more complete model of TIM3 signaling and explain its paradoxical coinhibitory and costimulatory functions
Biomimetic codelivery overcomes osimertinib-resistant NSCLC and brain metastasis via macrophage-mediated innate immunity
Authors: Pengfei Zhao, Jiaxin Zhang, Aihua Wu, Meng Zhang, Yuge Zhao, Yisi Tang, Bing Wang, Tianxiang Chen, Feng Li, Qiang Zhao, Yongzhuo Huang
Journal: Journal of Controlled Release (2020)
Abstract 418: Caveolar Disruption of L-type Calcium Channel and Ryanodine Receptor Facilitates Atrial Ectopy and Arrhythmogenesis in Heart Failure Mice
Authors: Di Lang, Lucas ratajczyk, Leonid Tyan, Daniel Turner, Francisco Alvarado, Timothy J Kamp, Alexey Glukhov
Journal: Circulation Research (2020)

Atrial fibrillation (AF) often occurs during heart failure (HF). Ectopic foci that trigger AF, are linked to discrete atrial regions that experience the highest remodeling and clinically used for AF ablation; however, mechanisms of their arrhythmogenic propensity remain elusive. We employed in vivo ECG telemetry, in vitro optical mapping and confocal imaging of Ca 2+ transients (CaT) from myocytes isolated from the right atrial appendage (RAA) and inter-caval region (ICR) of wild type (WT, n=10), caveolin-3 knockout (KO, n=6) and 8-weeks post-myocardial infarction HF (n=8) mice. HF and KO mice showed an increased susceptibility to pacing-induced AF and enhanced ectopy originated exclusively from ICR. Optical mapping in isolated atria showed prolongation of CaT rise up time (CaT-RT) in HF ICR, which suggested a remodeled coupling between L-type Ca 2+ channels (LTCCs) and ryanodine receptors (RyRs) in this specific region. In WT mice, RAA consists of structured myocytes with a prominent transverse-axial tubular system (TATS) while ICR myocytes don’t have TATS. In RAA, CaT-RT depends on LTCCs in TATS triggering RyR, while in ICR, all the LTCCs are localized in surface caveolae where they can activate subsarcolemmal RyRs and lead to a slow diffusion of Ca 2+ inside the cell interior. Downregulation of caveolae was observed specifically in HF ICR. To mimic this, we used cav3-KO mice. Triggered activities were observed in myocytes isolated from HF and KO ICR, which presumably underlie the ectopic activities in tissue level. These myocytes presented significantly unsynchronized sarcoplasmic reticulum (SR) Ca 2+ releases (synchronization index: 10.8±0.9 in WT vs 38.3±4.1 in HF vs 21.5±2.1 in KO, p &lt;0.01 for HF and KO vs WT respectively) especially at the subsarcolemmal space that prolongs CaT-RT (62.2±4.1 ms in WT vs 122.5±12.8 ms in KO, p &lt;0.01). In addition, failing ICR myocytes showed a higher occurrence and size of spontaneous Ca 2+ sparks which were linked to CaMKII activity and associated phosphorylation of RyR. Our findings demonstrate that in HF, caveolar disruption creates “hot spots” for arrhythmogenic ectopic activity emanated from discrete vulnerable regions of the right atrium which are associated with desynchronized SR Ca 2+ release and elevated fibrosis.
Abstract MP102: Skeletal Muscle Alpha Actin Acetylation Enhances Myosin Binding and Increases Calcium Sensitivity <i>in vitro</i>
Authors: Samantha S Romanick, Allison Matsumura, Travis Stewart, Kianna Boc, Jonathan Baker, Bradley S Ferguson
Journal: Circulation Research (2020)

Actin and myosin are key proteins for muscle contraction/relaxation, while tropomyosin regulates actin-myosin interactions in the presence or absence of calcium. Mutations or dysregulation of any of these proteins results in cardiomyopathy. We previously showed that skeletal muscle alpha actin (ACTA1) was significantly deacetylated on lysine residues, K52, K317, and K328 in remodeled left ventricular tissue of obese mice. Computational modeling suggests that the positively charged lysine residues K328 and K317 of ACTA1 can interact electrostatically with the negatively charged glutamic acid residue E181 of tropomyosin and E286 of myosin. As acetylation is predicted to neutralize the positively charged lysine, ACTA1 acetylation would be postulated to decrease actin-myosin or actin-tropomyosin electrostatic interactions. To test this hypothesis, we used an in vitro actin motility assay to determine myosin sliding velocity, calcium sensitivity, and attachment/detachment kinetics of acetylated/deacetylated ACTA1. In addition, an actin binding protein spin-down assay was used to determine actin-myosin binding affinity using skeletal and cardiac myosin. In these assays, ACTA1 was chemically acetylated with acetic anhydride. In vitro actin motility analysis showed a significant decrease in sliding velocity with acetylated ACTA1 and skeletal myosin (1.709±0.210 μm/s) compared with deacetylated ACTA1 (4.427±0.275 μm/s). A similar significant decrease was also noted with cardiac myosin. Further analysis showed a significant increase in calcium sensitivity with ACTA1 acetylation (3.197x10-7 Kd compared to deacetylated ACTA1 1.191x10-6 Kd) and a loss of tropomyosin regulation with increasing ACTA1 acetylation. Lastly, ACTA1 acetylation enhanced actin binding affinity to cardiac and skeletal myosin. Investigation of attachment/detachment kinetics are currently underway. These data suggest that ACTA1 acetylation disrupts tropomyosin’s ability to inhibit myosin binding in the absence of calcium and further regulates actin-myosin interactions. Lastly, these data highlight acetylation as an additional post-translational modification outside of phosphorylation in the regulation of muscle contraction.
Novel Resistance Mechanisms Including L1196Q, P1094H, and R1248_D1249 Insertion in Three Patients With NSCLC After ALK Tyrosine Kinase Inhibitor Treatment
Authors: Hiromi Furuta, Mitsugu Araki, Katsuhiro Masago, Yukari Sagae, Shiro Fujita, Katsutoshi Seto, Junichi Shimizu, Yoshitsugu Horio, Eiichi Sasaki, Waki Hosoda, Ryohei Katayama, Yasushi Okuno, Toyoaki Hida
Journal: Journal of Thoracic Oncology (2020)
IMPact of the COVID-19 epidemic on the moRTAlity of kidney transplant recipients and candidates in a French Nationwide registry sTudy (IMPORTANT)
Authors: Olivier Thaunat, Camille Legeai, Dany Anglicheau, Lionel Couzi, Gilles Blancho, Marc Hazzan, Myriam Pastural, Emilie Savoye, Florian Bayer, Emmanuel Morelon, Yann Le Meur, Olivier Bastien, Sophie Caillard, Olivier Thaunat, Emmanuel Morelon, Charlene Levi, Fanny Buron, Alice Koenig, Thomas Barba, Sophie Caillard, Bruno Moulin, Samira Fafi-Kremer, Marc Hazzan, Anglicheau Dany, Alexandre Hertig, Jérôme Tourret, Benoit Barrou, Lionel Couzi, Pierre Merville, Anna Kaminski, Valérie Moal, Tristan Legris, Pierre-François Westeel, Maïté Jaureguy, Luc Frimat, Didier Ducloux, Jamal Bamoulid, Dominique Bertrand, Michel Tsimaratos, Florentine Garaix-Gilardo, Jérôme Dumortier, Sacha Mussot, Antoine Roux, Laurent Sebbag, Yannick Le Meur, Gilles Blancho, Christophe Masset, Nassim Kamar, Hélène Francois, Eric Rondeau, Nicolas Bouvier, Christiane Mousson, Matthias Buchler, Philippe Gatault, Jean-François Augusto, Agnès Duveau, Cécile Vigneau, Marie-Christine Morin, Jonathan Chemouny, Leonard Golbin, Philippe Grimbert, Marie Matignon, Antoine Durrbach, Clarisse Greze, Renaud Snanoudj, Charlotte Colosio, Betoul Schvartz, Paolo Malvezzi, Christophe Mariat, Antoine Thierry, Moglie Le Quintrec, Antoine Sicard, Jean Philippe Rerolle, Anne-Élisabeth Heng, Cyril Garrouste, Henri Vacher Coponat, Éric Epailly, Olivier Brugiere, Sébastien Dharancy, Éphrem Salame, Faouzi Saliba
Journal: Kidney International (2020)