tbuckley/cabot-search huggingface dataset:
216 Multiplex base editing of NK cell to enhance cancer immunotherapy
Authors: Minjing Wang, Mitchell Kluesner, Patricia Claudio Vázquez, Beau Webber, Branden Moriarity
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Natural killer (NK) cells have many unique features that have gained attention in cancer immunotherapy. NK cells can kill in antigen independent and dependent fashion, can be used as an allogeneic product, and perform antibody-dependent cell-mediated cytotoxicity (ADCC). However, NK cell function is regulated by many activating and inhibitory receptors, which cancer cells take advantage of to avoid being killed by NK cells. NK cells are also known for their technical and biological challenges which result in low editing efficiencies, compared to T cells and other immune cells. Methods Base editing (BE) is a CRISPR-Cas9 based genome editing technology that allows precise single base transitions. Previously, we reported a high efficiency method for multiplex engineering of T cells using BE and thus reasoned that applying similar concepts in NK cells may offer an opportunity to alter many genes simultaneously at higher efficiency through multiplex base editing. We thus selected a panel of genes bearing critical roles in NK cell function for immunotherapy, including inhibitory intracellular regulator AHR and CISH, inhibitory checkpoint receptor KLRG1, TIGIT, KLRC1, and PDCD1, and Fc receptor CD16A. CD16A is responsible for NK cell ADCC and is regulated via cleavage upon NK activation. Non-cleavable CD16A improves ADCC killing and can be achieved through single-base substitution with BE. Results Using the adenosine BE (ABE8e), we achieved multiplex editing (6 genes) rates up to 99% and 95% editing/knockout at DNA and protein levels, respectively. Notably, we assessed for reduction in editing efficiency when additional genes were targeted and found no significant reduction in editing efficiencies when targeting up to 6 genes simultaneously. Moreover, functional evaluation of non-cleavable CD16A NK cells revealed up to 35% increase of cytotoxicity against Raji cells. Conclusions We were able to achieve high multiplex editing efficiency in primary human NK cells using ABE8eand there was no significant decrease of editing efficiency as the number of gene of interest increases, up to 6 genes in total. Functional assay confirmed increased NK cell cytotoxicity against tumor cells. Our end goal is to achieve high efficiency multiplex editing in CAR-expressing NK cells to further improve NK cell activity and toxicity for cancer immunotherapy. Reference Webber B, Lonetree C, Kluesner M, et al . Highly efficient multiplex human T cell engineering without double-strand breaks usingCas9 base editors. Nat Commun 2019; 10 :5222.
Evaluation of the Main Regulators of Systemic Iron Homeostasis in Pyruvate Kinase Deficiency
Authors: Anna Zaninoni, Roberta Russo, Roberta Marra, Elisa Fermo, Immacolata Andolfo, Anna Paola Marcello, Dario Consonni, Barbara Eleni Rosato, Stefania Martone, Bruno Fattizzo, Wilma Barcellini, Achille Iolascon, Paola Bianchi
Journal: Blood (2021)
75 Comprehensive profiling of the tumor-immune microenvironment using an augmented transcriptome
Authors: Eric Levy, Pamela Milani, Fabio Navarro, Gabor Bartha, Charles Abbott, Jose Jacob, Rena McClory, Robin Li, John West, John Lyle, Sean Boyle, Richard Chen
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Comprehensive profiling of both the tumor and tumor microenvironment (TME) can help further our understanding of tumor progression and response to treatment. Many immune features can be extracted from transcriptomic data, including characterization of the immune infiltrate and profiling the diversity of immune receptors. To address this, we have developed multiple TME profiling features as part of the ImmunoID NeXT Platform®, an augmented, immuno-oncology-optimized exome/transcriptome platform designed to provide comprehensive information regarding the tumor and TME from a single FFPE tumor sample. These features including quantification of immune cell infiltration and profiling of the T-cell receptor (TCR) and B-cell receptor (BCR). Methods To develop our immune infiltrate quantification method, we profiled the transcriptomes of eight purified immune cell types using ImmunoID NeXT™ to develop platform-specific gene sets, and compared our transcriptome quantification to immune cell quantification with IHC. For TCR and BCR methods, we analyzed the reproducibility of clone results, and compared top clones to standalone TCR and BCR sequencing approaches. In addition, we characterized the immune content of over 800 tumor samples across 14 cancer types. Finally, we analyzed the immune features in a cohort of melanoma patients who underwent PD-1 blockade. Results We observe significant concordances between cell fractions by IHC and ImmunoID NeXT’s transcriptome-based scores in tumor FFPE samples for B cells, CD8+ T cells, and macrophages (R2&gt;0.82, R2&gt;0.75, and R2&gt;0.52, respectively). For TCR and BCR methods, abundances of clones shared between subsequent curls of a tumor FFPE sample have very high concordances (R2&gt;0.89, R2&gt;0.92, and R2&gt;0.76 for TRB, IgG, and IgA, respectively). Compared to the standalone approaches, we identify 100% of the top 500 TRB clones and 95% of the top 500 IgG clones, with highly concordant abundances (R2&gt;0.94 and R2&gt;0.82 for TRB and IgG, respectively) in a PBMC sample. We identify biologically-relevant immune signatures across tumor types by characterizing the immune features across over 800 tumor samples. Finally, in a melanoma cohort, TRB clonality and CD8+ T cell scores are significantly different in responders to checkpoint inhibition. Conclusions RNA sequencing can be used as a scalable approach to profile the immune composition in tumors. Such analysis can add to our understanding of the tumor-immune interaction, including studies of response to immunotherapy. We show that immune infiltrate quantification and TCR and BCR profiling – all part of the ImmunoID NeXT Platform – are able to accurately and effectively evaluate the composition and diversity of tumor-infiltrating immune cells.
Recipient HLA-B Leader Genotype, and Its Relationship to Total KIR Missing Ligand, Informs Relapse and Survival Following Haploidentical Transplantation Using Post-Transplant Cyclophosphamide
Authors: Scott R. Solomon, Michael T Aubrey, Xu Zhang, Katelin C Jackson, Christina L Roark, Brian M Freed, Lawrence E Morris, H. Kent Holland, Asad Bashey, Melhem Solh
Journal: Blood (2021)
Abstract PO-119: DFMO mediated improvement in survival of an orthotopic model of pancreatic cancer is associated with modulating immune suppression in the tumor microenvironment
Authors: Sai Preethi Nakkina, Sarah B. Gitto, Veethika Pandey, Jordan M. Beardsley, Michael W. Rohr, Jignesh G. Parikh, Otto Phanstiel, Deborah A. Altomare
Journal: Cancer Research (2021)

Abstract There remains an urgent need to target pancreatic tumor cells using innovative strategies. KRAS and MYC, are important oncogenes in pancreatic ductal adenocarcinoma (PDAC) which pose a challenge to successful treatment of PDAC. Our previous studies have shown that inhibition of ornithine decarboxylase 1 (ODC1) using difluoromethylornithine (DFMO) decreases MYC expression and tumorigenesis. GW5074 can modulate RAF1, a downstream effector of KRAS. Here we test the responsiveness of pancreatic tumor cells treated with DFMO alone and in combination with GW5074. We used an orthotopic animal model of pancreatic tumor using KRas-driven murine pancreatic cancer cells (PanO2) to test the effects of these compounds on tumor microenvironment and overall survival. Cellular and molecular changes in the tumor microenvironment were assessed using immunohistochemistry. The results showed an inhibition of pancreatic cancer cell viability in DFMO and DFMO+GW5074 treatment groups in vitro, with a significant decrease in tumor weight compared to control treatment group in vivo. However, in terms of overall survival, DFMO alone resulted in a dramatic increase in survival compared to control treatment group. Interestingly, GW5074 alone or DFMO in combination with GW5074 did not result in a detectable effect on survival. Further investigation of immune cells in the tumor microenvironment revealed that standalone DFMO treatment was associated with an increase in infiltration of macrophages, T cell costimulatory marker CD86 and T cell markers (CD3, CD4 and CD8) compared to control and GW5074 treated groups. Additionally, DFMO is associated with decreased MYC expression compared to control and GW5074 treated groups. In conclusion, DFMO decreased MYC expression and associated immune suppression in the PDAC microenvironment. In contrast standalone GW5074 treatment resulted in maintenance of MYC expression and worse survival. In conclusion, the present study highlights the success of DFMO in PDAC treatment in part through downregulation of MYC and a decrease in associated immune suppression. Citation Format: Sai Preethi Nakkina, Sarah B. Gitto, Veethika Pandey, Jordan M. Beardsley, Michael W. Rohr, Jignesh G. Parikh, Otto Phanstiel, Deborah A. Altomare. DFMO mediated improvement in survival of an orthotopic model of pancreatic cancer is associated with modulating immune suppression in the tumor microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-119.
Abstract 13704: Activatable Nanoprobe Reveals the Therapeutic Potential of Autophagy Modulation During Cardiotoxic Chemotherapy
Authors: Howard H Chen, Zehedina Khatun, Choukri Mekkaoui, Lin Meng, Robert M Blanton, Hushan Yuan, Saumya Das, Lee Josephson, David E Sosnovik
Journal: Circulation (2019)

Background: Cardiotoxicity due to chemotherapy remains a major problem. Recent evidence suggests that doxorubicin (Dox)-induced toxicity may be due to a reduction in cardiomyocyte (CM) autophagy. W...
Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology
Authors: Patrick A. Brown, Bijal Shah, Anjali Advani, Patricia Aoun, Michael W. Boyer, Patrick W. Burke, Daniel J. DeAngelo, Shira Dinner, Amir T. Fathi, Jordan Gauthier, Nitin Jain, Suzanne Kirby, Michaela Liedtke, Mark Litzow, Aaron Logan, Selina Luger, Lori J. Maness, Stephanie Massaro, Ryan J. Mattison, William May, Olalekan Oluwole, Jae Park, Amanda Przespolewski, Sravanti Rangaraju, Jeffrey E. Rubnitz, Geoffrey L. Uy, Madhuri Vusirikala, Matthew Wieduwilt, Beth Lynn, Ryan A. Berardi, Deborah A. Freedman-Cass, Mallory Campbell
Journal: Journal of the National Comprehensive Cancer Network (2021)

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.
The Omission of High-Dose Cytarabine during Consolidation Therapy of Ph-Positive ALL Patients Treated with Nilotinib and Low-Intensity Chemotherapy Results in an Increased Risk of Relapses Despite Non-Inferior Levels of Late <i>BCR-ABL1</i> MRD Response. First Results of the Randomized Graaph-2014 Study
Authors: Philippe Rousselot, Yves Chalandon, Sylvie Chevret, Jean-Michel Cayuela, Francoise Huguet, Patrice Chevallier, Carlos Graux, Anne Thiebaut-Bertrand, Sylvain Chantepie, Xavier Thomas, Laure Vincent, Celine Berthon, Norbert Vey, Emmanuel Raffoux, Martine Escoffre-Barbe, Isabelle Plantier, Jean Pierre Marolleau, Pascal Turlure, Florence Pasquier, Amine Belhabri, Gabrielle Roth Guepin, Olivier Spertini, Veronique Lheritier, Emmanuelle Clappier, Nicolas Boissel, Hervé Dombret
Journal: Blood (2021)
Disrupting Ectopic Super-Enhancers to Treat Multiple Myeloma
Authors: Seth Welsh, Daniel Riggs, Erin Meermeier, Chang-Xin Shi, Victoria Garbitt, Meaghen E Sharik, Megan Du, Kennedi Todd, Zachary Hammond, Sochilt Brown, Caleb K Stein, Paola Neri, Nizar J. Bahlis, Benjamin G Barwick, Larry H. Boise, W. Michael Kuehl, Marta Chesi, P. Leif Bergsagel
Journal: Blood (2021)
Abstract 14360: Clinical Significance of the Assessment of Valvular Calcification Using 18F-sodium Fluoride Positron Emission Tomography
Authors: Rie Aoyama, Masashi Kameyama, Joji Ishikawa, Kazumasa Harada
Journal: Circulation (2021)

Introduction: With an aging population, valvular heart disease (VHD) of a degenerative etiology has been increasing. Although calcification of valves and mitral annulus (MAC) increase in the elderl...
Abstract 9512: Involvement of Orai1 Ca <sup>2+</sup> Channel in the Pathogenesis of Pulmonary Arterial Hypertension. Orai1 as a New Potential Therapeutic Target?
Authors: Bastien Masson, Helene Le Ribeuz, Jessica Sabourin, Emily Woodhouse, Richard Foster, Yann Ruchon, Mary Dutheil, Angele Boet, Maria-Rosa Ghigna, Olaf Mercier, David J Beech, Jean-Pierre Benitah, marc bailey, Marc Humbert, David Montani, veronique capuano, Fabrice Antigny
Journal: Circulation (2021)

Introduction: Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by a progressive obstruction of distal pulmonary artery (PA) leading to right ventricular hypertrophy and failure. Exacerbated intracellular Ca 2+ signalling contributes to functional abnormalities in pulmonary arterial smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance, exacerbated migration and pulmonary artery contractility. The role of archetypal Store-Operated Ca 2+ entry (SOCE) Orai1 Ca 2+ channel in PAH pathogenesis is unclear. Methods: Using a combination of Ca 2+ imaging, molecular biology, in vitro , ex vivo and in vivo approaches, we decipher the role of Orai1 Ca 2+ channel in pulmonary artery remodelling in PAH. We also analyzed the consequence of in vivo pharmacological inhibition of Orai1 in experimental models of PH. Results: We demonstrated that SOCE is increased in human PASMCs (hPASMCs) from patients with idiopathic PAH (iPAH) associated with an increased expression of Orai1 at mRNA and protein levels. Moreover, in vitro in iPAH-hPASMCs the pharmacological inhibition of Orai1 (by two different inhibitors) or the knockdown of Orai1 by siRNA reduced the SOCE as well as aberrant proliferation, apoptosis resistance phenotype and exacerbated cell migration. In addition, Orai1 knockdown reduced the exacerbated calcineurin activity in iPAH-hPASMCs. Using myograph experiments on isolated human and rat PAs we showed that pharmacological inhibition of Orai1 channels reduced the capacity of PAs to constrict. In rat experimental PH induced by Monocrotaline (MCT)-exposure or by Chronic-Hypoxia (CH) we found an overexpression of Orai1. Finally, in vivo pharmacological inhibition of Orai1 by three different blockers (BTP2, JPIII and 5J4) reduced experimental-PH in these experimental PH-models. Conclusion: In human PAH and experimental PH, the expression of Orai1 is increased compared to controls. In vitro and in vivo inhibition of Orai1 normalize the PAH phenotype of cultured iPAH-hPASMCs and reduce experimental-PH (MCT and CH). These results provide proof of concept that Orai1 contributes to PAH pathogenesis and that pharmacological inhibition of Orai1 should be considered as a new therapeutic target in PAH.
Evaluation of Thalidomide Treatment of Patients With Chronic Erythema Multiforme
Authors: Camille Roux, Emilie Sbidian, Jean-David Bouaziz, Diane Kottler, Pascal Joly, Vincent Descamps, Catherine Prost, Mahtab Samimi, Julien Seneschal, Nicolas Dupin, Céline Girard, Muriel Paul, Laurence Le Cleach, Saskia Ingen-Housz-Oro
Journal: JAMA Dermatology (2021)

Erythema multiforme (EM) may become long term, with a recurrent or persistent course. First-line treatment for chronic EM is valaciclovir. There is no consensus for selection of second-line treatment of chronic EM.The aim of this study was to assess the effectiveness of treatment with thalidomide for patients with chronic EM.In this retrospective national multicenter cohort study, among 68 French hospital dermatology departments contacted by e-mail, 10 reported having eligible cases. All adults aged 18 years or older under dermatology care for chronic EM (including recurrent and persistent forms) who had received thalidomide between 2010 and 2018 were included. Analyses were conducted from June 24, 2019, to December 31, 2019.The primary outcome was the proportion of patients who did not experience an EM flare within 6 months of initiating thalidomide treatment for recurrent EM or with complete clearance at 6 months for persistent EM (complete remission).Overall, 35 patients with chronic EM (median [range] age, 33 [15-65] years; 20 [57%] female) experienced failure of at least 1 previous treatment prior to initiating treatment with thalidomide. After 6 months of continuous thalidomide treatment, 23 (66%) were in complete remission, 5 (14%) had stopped the treatment, and 7 (20%) experienced at least 1 flare. The median (IQR) initial dose followed by remission was 50 (50-100) mg/d. Main adverse effects were asthenia (16 [46%]) and neuropathy (14 [40%]). Twenty-five (71%) of patients stopped thalidomide treatment after a median (IQR) of 12 (8-20) months owing to lack of effect (7/25 [28%]), neuropathy or another adverse effect (14/25 [56%]), or long-term complete remission (4/25 [16%]). Low-dose thalidomide, less than 50 mg every other day was sufficient in 9 of 23 (39%) of responders and was associated with less neuropathy and longer treatment duration.In this cohort study, second-line therapy with thalidomide was associated with complete remission in two-thirds of the 35 patients with chronic EM. However, adverse events were a common cause of thalidomide withdrawal. In the long term, dose reduction when possible may allow for continuation by improving tolerance.
First-line Nivolumab plus Ipilimumab Versus Sunitinib in Patients Without Nephrectomy and With an Evaluable Primary Renal Tumor in the CheckMate 214 Trial
Authors: Laurence Albiges, Nizar M. Tannir, Mauricio Burotto, David McDermott, Elizabeth R. Plimack, Philippe Barthélémy, Camillo Porta, Thomas Powles, Frede Donskov, Saby George, Christian K. Kollmannsberger, Howard Gurney, Marc-Oliver Grimm, Yoshihiko Tomita, Daniel Castellano, Brian I. Rini, Toni K. Choueiri, David Leung, Shruti Shally Saggi, Chung-Wei Lee, M. Brent McHenry, Robert J. Motzer
Journal: European Urology (2021)
Day 14 Measurable Residual Disease As a Predictor of Post-Induction Response in Patients with Acute Myeloid Leukemia
Authors: Reyes María Martín-Rojas, Jon Badiola, Pablo Silva De Tena, Ana Pérez-Corral, Ignacio Gómez-Centurión, Gabriela Rodríguez-Macias, Mónica Ballesteros, Carolina Martínez-Laperche, Patricia Font Lopez, Isabel Pérez-Sánchez, Ismael Buño, Javier Anguita, Mi Kwon, Jose L. Diez-Martin
Journal: Blood (2021)
The Importance of Disease Burden after Induction and Prior to Transplantation in Patients with Acute Myeloid Leukaemia Receiving Allogeneic Transplantation
Authors: Claudia Nunez-Torron, Carlos Jimenez Chillon, Fernando Martin Moro, Alejandro Luna, Adolfo Saez, Kyra Velázquez-Kennedy, Juan Marquet Palomanes, Miguel Piris-Villaespesa, Valentín Garcia-Gutiérrez, Anabelle Chinea, Gemma Moreno Jiménez, Javier López Jiménez, Pilar Herrera
Journal: Blood (2021)
Impact of Collagen Triple Helix Structure on Melanoma Cell Invadopodia Formation and Matrix Degradation upon BRAF Inhibitor Treatment
Authors: Della S. Shin, Megan E. Schroeder, Kristi S. Anseth
Journal: Advanced Healthcare Materials (2021)

A collagen-rich tumor microenvironment (TME) is associated with worse outcomes in cancer patients and contributes to drug resistance in many cancer types. In melanoma, stiff and fibrillar collagen-abundant tissue is observed after failure of therapeutic treatments with BRAF inhibitors. Increased collagen in the TME can affect properties of the extracellular matrix (ECM), including stiffness, adhesiveness, and interaction of integrins with triple helix forming nanostructures. Decoupling these biochemical and biophysical properties of the ECM can lead to a better understanding of how each of these individual properties affect melanoma cancer behavior and drug efficacy. In addition, as drug treatment can induce cancer cell phenotypic switch, cancer cell responsiveness to the TME can be dynamically changed during therapeutic treatments. To investigate cancer cell phenotype changes and the role of the cancer TME, poly(ethylene glycol) (PEG) hydrogels functionalized with collagen mimetic peptides (CMPs) is utilized, or an interpenetrating network (IPN) of type І collagen within the PEG system to culture various melanoma cell lines in the presence or absence of Vemurafenib (PLX4032) drug treatment is prepared. Additionally, the potential of using CMP functionalized PEG hydrogels, which can provide better tunability is explored, to replace the existing invadopodia assay platform based on fluorescent gelatin.
Negative MRD at Day 100 after Allogenic Hematopoietic Stem Cell Transplant (HSCT): The Grail to Reach in Acute Myeloid Leukemia (AML)
Authors: Audrey DA Rocha, Alexis Caulier, Magalie Joris, Amandine Charbonnier, Mathieu Sage, Lavinia Merlusca, Lydia Montes, Nicolas Guillaume, Judith Desoutter, Marie-Noëlle Lacassagne, Marine Quint, Thomas Boyer, Véronique Harrivel, Nicolas Duployez, Alice Marceau, Jean-Pierre Marolleau, Delphine Lebon
Journal: Blood (2021)
Association of Race, Ethnicity, Age and Socioeconomic Status with Access to Virtual Visits within the Brigham &amp; Women's Hospital Division of Hematology during the COVID-19 Pandemic
Authors: Miriam Kwarteng-Siaw, Lauren E. Merz, Siyang Ren, Donna S. Neuberg, Maureen Achebe, Jorge A. Rodriguez, Arielle L. Langer
Journal: Blood (2021)