tbuckley/cabot-search huggingface dataset:
230 Preclinical efficacy of CLEC-1 antagonist as novel myeloid immune checkpoint therapy for oncology
Authors: Vanessa Gauttier, Marion Drouin, Sabrina Pengam, Javier Saenz, Bérangère Evrard, Stéphanie Neyton, caroline Mary, Géraldine Teppaz, Ariane Desselle, Virginie Thépénier, Emmanuelle Wilhelm, Nicolas Poirier, Elise Chiffoleau
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background C-type lectin receptors (CLRs) are powerful pattern recognition receptors shaping immune cell-mediated tissue damage by positively or negatively regulating myeloid cell functions and hence tumor elimination or evasion. We previously reported that the orphan CLR CLEC-1 expressed by dendritic cells (DCs) tempers T cell’s responses in vivo by limiting antigen cross-presentation by cDC1. Furthermore, we observed that CLEC-1 is highly expressed by myeloid cells purified from human tumor microenvironment, in particular tumor-associated macrophages. Methods Macrophages were generated from monocytes of healthy volunteers for phagocytosis assays. MC38 and Hepa 1.6 murine tumor cells were implanted in Clec1a KO or KI mice for immunotherapeutic treatment evaluation. Results Using newly developed anti-human CLEC-1 monoclonal antibodies (mAbs), we found that antagonist anti-CLEC-1 mAbs with the capacity to block CLEC-1/CLEC-1Ligand interaction, as opposed to non-antagonist CLEC-1 mAbs, increase the phagocytosis of CLEC-1Ligand-positive human tumor cells by human macrophages, in particular when opsonized by tumor-associated antigen mAbs (Rituximab, Cetuximab, Trastuzumab) or with anti-CD47 mAb (Magrolimab). In-vivo, CLEC-1 knock-out (KO) mice (n=19) display significant prolonged survival in monotherapy as compared to wild-type littermates (n=12) in an orthotopic hepatocellular carcinoma (HCC) model and anti-tumor memory responses was demonstrated by tumor rechallenge in cured mice. CLEC1 KO mice also illustrate significant eradication of MC38 colorectal tumors in combination with chemotherapy promoting CLEC-1Ligand expression by tumor cells (n=16 with Gemcitabine or n=11 with Cyclophosphamide). HCC tumor microenvironment analysis after 2 weeks of tumor implantation shows significantly higher number of CD8+ and memory CD8+ T cells with reduced PD1 expression in CLEC1 KO animals (n=16 versus n=12 for KO vs WT mice respectively). Finally, we recently generated human CLEC-1 knock-in mice expressing the extracellular human CLEC1 domain fused to the intracellular mouse CLEC1 tail and confirmed preclinical efficacy in vivo with anti-human CLEC1 antagonist mAb in monotherapy in the orthotopic HCC model. Conclusions These data illustrate that CLEC-1 inhibition represents a novel therapeutic target for immuno-oncology modifying T cell immune responses and tumor cell phagocytosis by macrophages.
Diagnostic Excellence Through the Lens of Patient-Centeredness
Authors: Donald M. Berwick
Journal: JAMA (2021)

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Functional pre-therapeutic evaluation by genome editing of variants of uncertain significance of essential tumor suppressor genes
Authors: Amandine Billaud, Louise-Marie Chevalier, Paule Augereau, Jean-Sebastien Frenel, Christophe Passot, Mario Campone, Alain Morel
Journal: Genome Medicine (2021)

Abstract Background Targeted therapies in oncology are promising but variants of uncertain significance (VUS) limit their use for clinical management and necessitate functional testing in vitro. Using BRCA1 and BRCA2 variants, which have consequences on PARP inhibitor sensitivity, and POLE variants, potential biomarkers of immunotherapy response, we developed a rapid functional assay based on CRISPR-Cas9 genome editing to determine the functional consequences of these variants having potentially direct implications on patients’ access to targeted therapies. Methods We first evaluated the functional impact of 26 BRCA1 and 7 BRCA2 variants by editing and comparing NGS results between the variant of interest and a silent control variant. Ten of these variants had already been classified as benign or pathogenic and were used as controls. Finally, we extended this method to the characterization of POLE VUS. Results For the 23 variants that were unclassified or for which conflicting interpretations had been reported, 15 were classified as functionally normal and 6 as functionally abnormal. Another two variants were found to have intermediate consequences, both with potential impacts on splicing. We then compared these scores to the patients’ responses to PARP inhibitors when possible. Finally, to prove the application of our method to the classification of variants from other tumor suppressor genes, we exemplified with three POLE VUS. Among them, two were classified with an intermediate functional impact and one was functionally abnormal. Eventually, four POLE variants previously classified in databases were also evaluated. However, we found evidence of a discordance with the classification, variant p.Leu424Val being found here functionally normal. Conclusions Our new rapid functional assay can be used to characterize the functional implication of BRCA1 and BRCA2 variants, giving patients whose variants were evaluated as functionally abnormal access to PARP inhibitor treatment. Retrospective analysis of patients’ responses to PARP inhibitors, where accessible, was consistent with our functional score evaluation and confirmed the accuracy of our protocol. This method could potentially be extended to the classification of VUS from all essential tumor suppressor genes and can be performed within a timeframe compatible with clinical applications, thereby having a direct theranostic impact.
Post-Covid-19 Hemostatic Characteristics of Convalescent Patients: The Bergamo Experience
Authors: Carmen Julia J Tartari, Giulia Milani, Francesco Salvetti, Marina Marchetti, Laura Russo, Alfonso Vignoli, Massimiliano Vitali, Francesca Schieppati, Giulia Ravasio, Laura Castellani, Eleonora Sanga, Debora Romeo, Anna Falanga
Journal: Blood (2021)
Elongator Complex Regulates MCL1 Dependency Via IRE1-XBP1 Axis of the ER Stress Response Pathway in Multiple Myeloma
Authors: Neeraj K Aryal, Anjana Sundarrajan, Scott Boiko, David Jenkins, Huayang Liu, Miika Ahdesmaki, Aurelie Bornot, Andrew Jarnuczak, Eric Miele, Ultan McDermott, Stephen Fawell, Lisa Drew, Larry H. Boise, Justin Cidado
Journal: Blood (2021)
Abstract 11954: Coronary Atherosclerotic and Inflammatory Changes for Varying Lengths of Myocardial Bridge
Authors: Tasuku Watanabe, Kensuke Nishimiya, Hideaki Ota, Satoshi Higuchi, Erika Yamamoto, Satoshi Takeuchi, Kento Fukui, Akira Suda, Shigeo Godo, Tomohiko Shindo, Kiyotaka Hao, Yoku Kikuchi, Jun Takahashi, Satoshi Yasuda
Journal: Circulation (2021)

Background: Myocardial bridge (MB) is a frequent cause of ischemia and nonobstructive coronary artery disease (INOCA). Coronary segments proximal to the MB likely develop atherosclerotic lesions due to altered endothelial shear stress (ESS) as a consequence of systolic compression beneath MB. We recently demonstrated that optical coherence tomography (OCT)-delineated adventitial vasa vasorum (AVV) formation as a marker for vascular inflammation are extensive at the segments proximal to the MB. This study was aimed to examine coronary atherosclerotic and inflammatory changes depending on varying MB length. Methods and Results: Amongst 165 INOCA patients who underwent both coronary computed tomography angiography (CCTA) and co-registered OCT, 31 subjects with CCTA-derived MB in the left anterior descending coronary arteries were enrolled ( Fig. A ). Biplane coronary angiography was merged with serial OCT cross-sections to be three-dimensionally volume-rendered for the ESS mapping ( Fig. B ). Using OCT, tissue type of each coronary segment was classified as intimal hyperplasia (IT), fibrous plaque (FP), fibroatheroma (FA), or fibrocalcific plaque (FC). The segment proximal to the MB was with the lowest ESS level, where OCT displayed the lesion with FA ( Fig. B ). Indeed, advanced lesions with FA and FC were more frequently noted at the sites 5-mm proximal to the MB when compared to the middle portions beneath MB ( Fig. C ). Notably, % intimal plus medial (I+M) area = [(I+M area/vessel area) х100] as a marker for atherosclerotic changes were correlated with the lengths of MB at the proximal segments ( Fig. D ). Lesions with FP, FA and FC showed longer MB lengths as compared with IT (One-way ANOVA. P&lt;0.05). Likewise, AVV formation was positively correlated with the length of MB ( Fig. E ). Conclusion: These results indicated that in addition to the ESS, varying MB lengths alter atherosclerotic and inflammatory coronary lesions proximal to the MB.
Daratumumab with Pomalidomide and Dexamethasone at First Relapse in Relapsed and/or Refractory Multiple Myeloma (RRMM) Patients
Authors: Nisha Joseph, Kathryn T. Maples, Kevin Hall, Vikas A Gupta, Larry H. Boise, Leonard T. Heffner, Madhav V Dhodapkar, Craig C. Hofmeister, Jonathan L. Kaufman, Sagar Lonial, Ajay K. Nooka
Journal: Blood (2021)
Homeostatic IL-13 in healthy skin directs dendritic cell differentiation to promote TH2 and inhibit TH17 cell polarization
Authors: Johannes U. Mayer, Kerry L. Hilligan, Jodie S. Chandler, David A. Eccles, Samuel I. Old, Rita G. Domingues, Jianping Yang, Greta R. Webb, Luis Munoz-Erazo, Evelyn J. Hyde, Kirsty A. Wakelin, Shiau-Choot Tang, Sally C. Chappell, Sventja von Daake, Frank Brombacher, Charles R. Mackay, Alan Sher, Roxane Tussiwand, Lisa M. Connor, David Gallego-Ortega, Dragana Jankovic, Graham Le Gros, Matthew R. Hepworth, Olivier Lamiable, Franca Ronchese
Journal: Nature Immunology (2021)
Prevalence and Risk Factors of Antibodies to Class I and II Human Leukocyte Antigens in Haploidentical Allograft Candidates: A Prospective Study on 3805 Subjects
Authors: Ning Ma, Lan-Ping Xu, Xiaohui Zhang, Yu Wang, Huan Chen, Wei Han, Yuqian Sun, Chenhua Yan, Fei-Fei Tang, Xiaodong Mo, Yan-Rong Liu, Kaiyan Liu, Xiao Jun Huang, Ying-Jun Chang
Journal: Blood (2021)
Endoscopic intraperitoneal subserosal dissection combined with endoscopic ultrasonography-assisted location of an extraluminally growing stromal tumor
Authors: Meng-Jiang He, Wei-Feng Chen, Xin-Yang Liu, Jie He, Jian-Wei Hu, Ping-Hong Zhou
Journal: Endoscopy (2021)

A 70-year-old gentleman was admitted with a suspected gastric submucosal tumor (SMT) detected by abdominal contrast computed tomography (CT) ([Fig. 1]) performed to investigate his complaints of dull pain in the abdomen. Preoperative endoscopic ultrasonography (EUS) helped to confirm and locate the lesion after repeated esophagogastroduodenoscopy revealed nothing ([Fig. 1]). Endoscopic intraperitoneal subserosal dissection technique was employed in this case. Details of the steps are shown in [Fig. 2] and [Video 1], including mucosal incision, submucosal tunneling, intraperitoneal subserosal dissection, removal of the lesion, and mucosal closure. The pathological diagnosis was gastrointestinal stromal tumor (GIST) (WHO, Digestive System Tumours, 5th edn.), prognostic group 1. Intravenous antibiotics were given for 1 day after operation. The gastric tube was removed on postoperative day (POD) 2, fluid diet was resumed on POD3, and on POD7 the patient was discharged.
Overactivation of the NLRP3 Inflammasome in Chronic Myelomonocytic Leukemia KRAS Mutated Patients Can be Detected By the Apoptosis-Associated Speck-like Protein (ASC) and Reverted By IL1β Inhibitors
Authors: Laura Hurtado-Navarro, Ernesto J Cuenca, Eva Soler, Andres Jerez, Helios Martínez-Banaclocha, Esperanza Such, Beatriz Bellosillo, Lurdes Zamora, Jesus Maria Hernández-Rivas, Javier Marco, Laura Martínez-Alarcón, María Dolores Linares-Latorre, Josefa Marco, Sara García Ávila, Paula Amat, Teresa González, Marta Martín Izquierdo, Montserrat Arnan Sangerman, Helena Pomares, Tzu Hua Chen-Liang, Maite Herranz, Gonzalo Carreño, Carlos Garcia-Palenciano, Raul Teruel Montoya, Pablo Pelegrin, Francisca Ferrer Marin
Journal: Blood (2021)
Small Molecule Inhibition of PDE6D-RAS Interaction Suppresses the Growth of Acute Lymphoblastic Leukemia Cell Lines
Authors: Sara Canovas Nunes, Haiming Xu, Serena De Vita, Andrew Anighoro, Francois Autelitano, Edward Beaumont, Pamela Klingbeil, Meaghan McGuinness, Beatrice Duvert, Chad E. Harris, Lu Yang, Sheela Pangeni Pokharel, Chun-Wei David Chen, Monika Ermann, David A. Williams
Journal: Blood (2021)
A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of Mitapivat in Patients with Sickle Cell Disease
Authors: Joanna Howard, Kevin H.M. Kuo, Abdulafeez Oluyadi, Hui Shao, Susan Morris, Ahmar U Zaidi, Eduard J. Van Beers, Swee Lay Thien
Journal: Blood (2021)
The Application of Decitabine in Combination with G-CSF, Low-Dose Cytarabine and Aclarubicin in AML-MRC: A Single Center Case Control Study
Authors: Hao Jiang, Jing Liu, Xiaohong Liu, Jinsong Jia, Lizhong Gong, Shengye Lu, Xiaojun Huang, Jing Wang, Xiaosu Zhao, Yueyun Lai, Hongxia Shi, Yingjun Chang, Guorui Ruan
Journal: Blood (2021)
Breast Implant-Associated Anaplastic Large Cell Lymphoma: A Cost Evaluation Study of Management and Surveillance, and Review of the Recent USA and UK Guidelines
Authors: Aia S Mehdi, Rachel O'Connell, Michael Potter, Chris Marshall, Liza Van Kerckhoven, Sunil Iyengar, Emma Nicholson, Dima El-Sharkawi, Marios Tasoulis, David Cunningham, Bhupinder Sharma
Journal: Blood (2021)
Abstract 9105: Eliminated Male Advantages in Cardiopulmonary Exercise Testing Performance after Fontan Operation Indicates a Central Mechanism of Decreased Exercise Performance in a Single Ventricle Physiology
Authors: Takeshi Tsuda, Daphney Kernizan, Gina D'Aloisio
Journal: Circulation (2021)

Background: Fontan patients have significantly diminished exercise performance compared with healthy peers. Sex differences in exercise performance after Fontan operation have not been well characterized. Methods: We retrospectively analyzed cardiopulmonary exercise testing (CPET) of Fontan and age-matched control adolescents. Data were analyzed via one-way analysis of variance (ANOVA) and are shown as mean ± standard deviation. Results: We studied 36 Fontan patients (male 18/female 18) and 65 age-matched controls (male 32/female 33). When compared between Fontan and controls, peak values of heart rate (HR), oxygen consumption (VO2), and work rate (WR), ventilator anaerobic threshold (VAT), and oxygen uptake efficiency slope (OUES) were significantly lower in Fontan than in controls in both sexes. In controls, significant sex differences were noted in peak values of VO2, oxygen pulse (OP), WR, VAT, heart rate dependency (αHR/αWR), OUES, and ventilatory efficiency (αVE/αVCO2) whereas no such sex differences were detected in Fontan patients (Table). Significant sex differences noted in correlations between weight and peak VO2 and between αHR/αWR and peak VO2 in controls were not appreciated in Fontan patients (Figure), suggesting that single ventricle physiology abolished some key male advantages in exercise performance under biventricular physiology including body mass (skeletal muscle mass) effects and stroke volume reserve. Conclusion: Disappearance of male advantages in CPET performance in Fontan patients indicates a limitation of systemic ventricular filling due to the absence of sub-pulmonary ventricle as a central determinant of low exercise performance.
Abstract 14238: A Real-World Comparison of Percutaneous Coronary Intervention vs Coronary Artery Bypass in Patients With Chronic Total Occlusion
Authors: Mahin Khan, Mian Tanveer Ud Din, Sohaib Roomi, Waqas Ullah, Salim S Virani, ihab hamzeh, Mirza Khalid, Yochai Birnbaum, Mahboob Alam
Journal: Circulation (2021)

Introduction: There is a paucity of data comparing percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with chronic total occlusion (CTO) of the coronary arteries. Methods: The National Inpatient Sample (NIS) database was queried to identify all CTO related hospitalizations from 2002-2018. Patients undergoing PCI were compared with those having CABG for CTO using Cochran-Mantel-Haenszel statistics to determine unadjusted odds ratios (OR). A propensity matched analysis (PSM) was used to determine adjusted OR for major in-hospital outcomes. Results: A total of 404,563 patients with CTO were included in the analysis. Of these, 20,841 (5.6%) patients underwent CABG whereas 383,722 (94.8%) underwent PCI. Patients in the PCI group had a higher percentage of chronic obstructive pulmonary disease, diabetes, coagulopathy, obesity and renal failure. On an unadjusted analysis, the primary outcome of in-hospital mortality was comparable between the two groups. The odds of stroke, acute kidney injury, sepsis, major bleeding and need for IABP were higher with CABG, whereas the odds of cardiopulmonary arrest and coronary artery dissection were higher with PCI. On a propensity adjusted analysis, PCI was associated with a higher mortality and comparable rate of major bleeding and sepsis compared to CABG (Table). CABG, however, had a higher hospitalization cost ($ 156113.03 vs. $ 103078.48, p=&lt;0.0001), and a mean length of stay (8.93 vs. 4.82 days, p=&lt;0.0001) as compared to PCI. Conclusions: Our findings show that CABG has a lower inpatient mortality for CTO as compared to PCI, however it is associated with increased risk of complications, higher cost and increased length of hospitalization, highlighting the need for randomized data on the subject.
Phase 1b/2 Study of Vipor (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide) in Relapsed/Refractory and Untreated Mantle Cell Lymphoma: Safety, Efficacy, and Molecular Analysis
Authors: Christopher Melani, Rahul Lakhotia, Stefania Pittaluga, Milos D. Miljkovic, James D. Phelan, Jagan R. Muppidi, Craig J. Thomas, Michele Ceribelli, Anna Marie Juanitez, Amynah Pradhan, Amy Hillsman, Seth M. Steinberg, Elaine S. Jaffe, Mark Roschewski, Louis M. Staudt, Wyndham H. Wilson
Journal: Blood (2021)
CD73 Inhibition Overcomes Immunosuppression and Triggers Autologous T-Cell Mediated Multiple Myeloma Cell Lysis in the Bone Marrow Milieu
Authors: Arghya Ray, Melissa R Junttila, Ting DU, Dena Sutimantanapi, Xi Chen, Bob Warne, Jae Chang, Brian Blank, Kejia Wu, Jared Moore, Chudi Ndubaku, Tatiana Zavorotinskaya, Omar Nadeem, Lori Friedman, Dharminder Chauhan, Kenneth C. Anderson
Journal: Blood (2021)
COP26 summit: leaders frustrated at watered down climate deal
Authors: Jacqui Wise
Journal: BMJ (2021)

The COP26 summit in Glasgow ended with a watered down climate deal with pledges that don’t go far enough to limit the global temperature rise to 1.5°C although there was agreement to meet next year to make further major carbon cuts to keep the goal alive.1

For the first time COP agreed a plan to reduce coal power, the worst fossil fuel for greenhouse gases. But after India and China objected the text was changed from a commitment to “phase out” coal to the much weaker “phasedown of unabated coal”—in other words coal burning which is carried out without some form of carbon capture and storage. The agreement does still call for “phase out” of inefficient subsidies for fossil fuels.

India’s climate minister Bhupender Yadav asked how developing countries could promise to phase out coal and fossil fuel subsidies when “they have still to deal with their development agendas and poverty eradication.”

The COP president Alok Sharma was on …
Maladaptive Autophagy in the Pathogenesis of Autoimmune Epithelitis in Sjögren's Syndrome
Authors: Serena Colafrancesco, Cristiana Barbati, Roberta Priori, Erisa Putro, Federico Giardina, Angelica Gattamelata, Benedetta Monosi, Tania Colasanti, Alessandra Ida Celia, Bruna Cerbelli, Carla Giordano, Susanna Scarpa, Massimo Fusconi, Giulio Cavalli, Onorina Berardicurti, Saviana Gandolfo, Saba Nayar, Francesca Barone, Roberto Giacomelli, Salvatore De Vita, Cristiano Alessandri, Fabrizio Conti
Journal: Arthritis & Rheumatology (2021)

Salivary gland epithelial cells (SGECs) are key cellular drivers in the pathogenesis of primary Sjögren's syndrome (SS); however, the mechanisms sustaining SGEC activation in primary SS remain unclear. We undertook this study to determine the role of autophagy in the survival and activation of SGECs in primary SS.Primary SGECs isolated from the minor SGs of patients with primary SS or sicca syndrome were evaluated by flow cytometry, immunoblotting, and immunofluorescence to assess autophagy (autophagic flux, light chain 3 IIB [LC3-IIB], p62, LC3-IIB+/lysosome-associated membrane protein 1 [LAMP-1] staining), apoptosis (annexin V/propidium iodide [PI], caspase 3), and activation (intercellular adhesion molecule, vascular cell adhesion molecule). Focus score and germinal center presence were assessed in the SGs from the same patients to assess correlation with histologic severity. Human SG (HSG) cells were stimulated in vitro with peripheral blood mononuclear cells (PBMCs) and serum from primary SS patients in the presence or absence of autophagy inhibitors to determine changes in autophagy and epithelial cell activation.SGECs from primary SS patients (n = 24) exhibited increased autophagy (autophagic flux [P = 0.001]; LC3-IIB [P = 0.02]; p62 [P = 0.064]; and as indicated by LC3-IIB/LAMP-1+ staining), increased expression of antiapoptotic molecules (Bcl-2 [P = 0.006]), and reduced apoptosis (annexin V/PI [P = 0.002]; caspase 3 [P = 0.057]), compared to samples from patients with sicca syndrome (n = 16). Autophagy correlated with histologic disease severity. In vitro experiments on HSG cells stimulated with serum and PBMCs from primary SS patients confirmed activation of autophagy and expression of adhesion molecules, which was reverted upon pharmacologic inhibition of autophagy.In primary SS SGECs, inflammation induces autophagy and prosurvival mechanisms, which promote SGEC activation and mirror histologic severity. These findings indicate that autophagy is a central contributor to the pathogenesis of primary SS and a new therapeutic target.
Blocking the Don't Eat Me Signal (CD47-SIRPα Axis) to Improve Antibody-Based Immunotherapy of Multiple Myeloma
Authors: Katja Klausz, Carina Lynn Gehlert, Ammelie Svea Boje, Marta Lustig, Steffen Krohn, Syeda Maliha Ahmed, Christian Kellner, Thomas Valerius, Lenka Besse, Andrej Besse, Christoph Driessen, Martin Gramatzki, Matthias Peipp
Journal: Blood (2021)