tbuckley/cabot-search huggingface dataset:
Modified Delphi Method Identifies Consensus Areas for Routine Minimal Residual Disease Testing in Multiple Myeloma
Authors: Karthik Ramasamy, Hervé Avet-Loiseau, Cecilie Hveding Blimark, Michel Delforge, Francesca Gay, Salomon Manier, Joaquin Martinez-Lopez, Maria-Victoria Mateos, Mohamad Mohty, Niels W.C.J. van de Donk, Katja Weisel
Journal: Blood (2021)
Outcome of Donor-Derived Tumor Associated Antigen-Specific T Cell Therapy in Patients with High-Risk or Relapsed Acute Leukemia Post Allogeneic BMT
Authors: Hannah Kinoshita, Kenneth R. Cooke, Melanie Grant, Maja Stanojevic, Conrad Russell Young Cruz, Michael Keller, Maria Fernanda Fortiz, Fahmida Hoq, Haili Lang, John Barrett, Hua Liang, Jay Tanna, Nan Zhang, Abeer Shibli, Anushree Datar, Kirsten M. Williams, Hema Dave, Jeffrey Dome, David Jacobsohn, Patrick Hanley, Richard J. Jones, Catherine M. Bollard
Journal: Blood (2021)
Myocardial infarction in the absence of obstructive coronary artery disease (MINOCA): A Challenge to Diagnose and Manage
Authors: Meera D Kondapaneni, Ahmad Jabri, Aisha Siraj, Saima Karim
Journal: Clinical Cardiology and Cardiovascular Interventions (2020)

Myocardial Infarction in the absence of obstructive coronary artery disease [MINOCA] is seen in 5-6% of the patients presenting with myocardial infarction. While patients with MINOCA can present with either ST segment elevation or non-ST segment elevation myocardial infarction, they are less likely to have ST segment deviation on electrocardiography and have less of cardiac biomarker elevation compared to their obstructive coronary artery disease counterparts. Patients with MINOCA are usually younger and with lower prevalence of traditional cardiovascular risk factors compared with patients presenting with obstructive coronary artery disease. A variety of atherosclerotic and non-atherosclerotic mechanisms can lead to MINOCA. A diagnosis of MINOCA can only be made in patients whose clinical presentation is attributed to an ischemic event after excluding obstructive coronary artery disease and alternate causes for troponin elevation. A systematic approach to diagnosing the underlying causes is warranted to optimally treat patients presenting with MINOCA.
Abstract 9083: Beta1-Adrenergic cAMP Signaling is Uncoupled after Acute Treatment of Anthrax Lethal Toxin in Cardiomyocytes in Normal Rats
Authors: Xiaoqiang Sun, Che Ping Cheng, Jing Cao, Zhe Chen, Xiaowei Zhang, Yixi Liu, Michael Callahan, Heng Cheng
Journal: Circulation (2021)

Background: Our recent in vivo study has shown that anthrax lethal toxin (LeTx) causes time-dependent progressive depression of left ventricular (LV) contractility and β-adrenergic reserve. However, the mechanisms are poorly understood. We tested the hypothesis that LeTx-induced altered cardiac subtypes of β-adrenergic receptor (AR) regulation may contribute to this effect. Methods: We examined acute exposure of LeTx caused alterations of myocyte β 1 - and β 3 -AR expression and myocyte basal contraction and relaxation and responses to isoproterenol (ISO), a β-AR agonist, and colforsin (COLF), a cAMP activator. Cardiomyocytes were isolated from eight adult normal rats incubated for 6 hours in study buffer without and with LeTx (10 nM PA and 1 nM LF). Result: Compared with controls, LeTx treatment caused no significant changes on basal myocyte contraction and relaxation. Myocyte β 1 -AR (0.47±0.04 vs 0.46±0.02) and β 3 -AR (0.21±0.02 vs 0.23±0.02) protein levels also remained relatively unchanged. In controls, superfusion with ISO (10 -8 M) caused about 46% increase in cell percent shortening (SA, 14.5 vs 10.0%) and 83% and 44% increases in peak velocity shortening (dL/dt max , 270.0 vs 147.7 μm/s) and relengthening (dR/dt max , 172.2 vs 119.6 μm/s), respectively. However, after LeTx treatment, myocyte positive inotropic functional response to β-AR stimulation was significantly decreased. In LeTx-treated myocytes, ISO produced significantly less increases in SA (25%, 9.9 vs 12.3%), dL/dt max (29%, 130.5 vs 183.6 μm/s) and dR/dt max (32.4%, 87.5 vs 115.8 μm/s). In contrast, superfusion of COLF (10 -6 M) caused similar increases in SA (43.1 vs 43.7%), dL/dt max (77.4 vs 83.2%) and dR/dt max (35.2 vs 30.8%). In addition, compared with normal controls, LeTx-treated myocyte contractile responses to zinterol (ZIN, 10 -5 M), a highly selective β 2 -AR agonist, and BRL-37,344 (BRL, 10 -8 M), a selective β 3 -AR agonist, were also unaffected. Conclusion: Acute treatment of LeTx causes cardiac myocyte β 1 -AR uncoupling from cAMP-mediated signaling and impairs myocyte β-adrenergic reserve. These results suggest that the early changes in cardiac subtypes of β-AR signal transduction system may mediate the connection between the acute and chronic cardiac action of LeTx.
Abstract 9091: Care Fragmentation and Health Outcomes Among African Americans: Jackson Heart Study
Authors: Vishal N Rao, Zhen Li, Bradley G Hammill, Robert J Mentz, Mario Sims, Emily C OBrien
Journal: Circulation (2021)

Introduction: African American (AA) adults experience high comorbidity burden, yet the association between care fragmentation and outcomes among AA is unknown. We aimed to characterize care fragmentation among AA Medicare beneficiaries in the Jackson Heart Study (JHS) and associated outcomes. Methods: We identified 2 cohorts of JHS participants enrolled in Medicare: 1) established cardiovascular disease (CVD), including coronary artery disease, stroke, and heart failure, and 2) complex medical needs, defined as a Charlson Comorbidity Index ≥ 3. Care fragmentation was defined as 1 - Bice-Boxerman index, which was estimated from all ambulatory visits in Medicare claims during 1 year before (pre-baseline) and 1 year after baseline exam. Cox proportional hazard was used to assess associations between pre-baseline exam care fragmentation and cumulative incident all-cause hospitalizations and mortality over 3 years. Results: Among eligible JHS participants, 148 had CVD and 94 had complex medical needs. Pre-baseline care fragmentation was ≥ 0.5 among 78% of Cohort 1 and 84% of Cohort 2. Age, sex, insurance status, and income were similar across care fragmentation quartiles in each cohort. Depression symptom scores were higher in the highest care fragmentation quartile compared to the lowest quartile in Cohort 1 (19.5 vs. 11.0; p=0.006), but not in Cohort 2 (16.0 vs. 16.0; p=0.05). Burden of care fragmentation was similar 1 year before and after baseline exam in each cohort ( Figure ). Pre-baseline care fragmentation was not associated with 3-year incident all-cause hospitalization and mortality in each cohort, even after adjustment for age, sex, Charlson score, and depressive symptoms. Conclusions: Care fragmentation was prevalent among AA Medicare beneficiaries with CVD or complex medical needs during 1 year before and after enrollment into JHS. There were no associations between care fragmentation and outcomes in either cohort, though the sample size was limited.
Challenges in the Histopathologic Diagnosis of Histiocytic Neoplasms
Authors: Karen L. Rech, Rong He
Journal: Journal of the National Comprehensive Cancer Network (2021)

Histiocytic neoplasms, including Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD), present a diagnostic challenge due to nonspecific fibroinflammatory infiltrates and a diverse clinical presentation. The pathologist can play a key role in classification of these disorders through multidisciplinary collaboration and correlation of pathologic features with clinical and radiologic findings. The histopathologic differential diagnosis is broad, requiring knowledge of the possible diagnoses at each specific anatomic site, and a careful assessment to exclude other inflammatory and neoplastic disorders. An immunohistochemistry panel including CD163, CD1a, langerin, S100, Factor XIIIa, OCT2, and BRAF V600E can provide definitive diagnosis in LCH and RDD, whereas ECD requires classic clinical features as well as confirmation of an activating MAPK pathway mutation by genetic studies.
IMMU-23. NEOANTIGEN-DIRECTED CELLULAR THERAPY IN A PRECLINICAL MOUSE MODEL OF MALIGNANT GLIOMA
Authors: Max Schaettler, Gavin Dunn
Journal: Neuro-Oncology (2021)

Abstract Adoptive cellular therapy in the form of CAR T cells or TCR engineered T cells has emerged as a novel approach in the treatment of both solid and hematologic malignancies. Neoantigens generated by tumor somatic mutations represent potentially attractive therapeutic targets in this context owing to their tumor-specific expression and circumvention of immunological tolerance. However, existing cell therapy systems generally target self-proteins or virally overexpressed antigens that fail to recapitulate the features of endogenous tumor neoantigens. Thus, there exists a need for a model in which tumor-specific neoantigens can be targeted via adoptive cellular therapy. Prior work from our lab identified the Imp3D81N mutation (mImp3) within GL261 as a neoantigen recognized by CD8 T cells in both intracranial tumors and draining cervical lymph nodes. To generate a system for targeting this neoantigen, we isolated and cloned mImp3-specific TCRs through a single-cell sort followed by a nested multiplexed PCR reaction. The specificity and functionality of these isolated TCRs was determined through introduction into a T cell hybridoma, identifying a top candidate based upon a high degree of cytokine production and specificity for the mutant epitope. A TCR transgenic mouse was then generated in which more than 90% of all T cells were CD8 T cells bearing this mImp3-specific TCR. T cells isolated from this mouse display specificity for the mImp3 peptide and display in vitro reactivity to GL261 and other cell lines in a mImp3-dependent manner. Therefore, this model represents the first TCR transgenic targeting a brain tumor neoantigen, opening the door for further investigation into cell therapy against this class of antigens.
Assessment of Circulating Tumor DNA in Newly Diagnosed DLBCL Patients Randomly Treated By R-CHOP or R-High Dose Chemotherapy Plus Autologous Stem Cell Support
Authors: Fabienne Desmots-Loyer, Delphine Rossille, Mikael Roussel, Steven Le Gouill, Thierry Lamy, Noel Milpied, Thierry Fest
Journal: Blood (2021)
57 Assessment of the spatial distribution of B cells subpopulations in the tumor microenvironment and tertiary lymphoid structures by Brightplex®, a sequential chromogenic multiplex assay
Authors: Alex Trinh, Aurélie Collignon, Marion Olive, Clémence Jaume, Maïté Chamourin, Nour Sfeir, Dylan Anselmo, Raana Ramouz-Charpentier, Georgia Culey, Christophe Haond, Jerome Galon, Jacques Fieschi-Meric
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Density and localization of T cells within the tumor microenvironment (TME) is critical to control tumor growth. Immunotherapy with antibodies against immune checkpoint inhibitors (ICI), which aim to reinvigorate exhausted T cells, despite inducing long-term response in many cancer types, remains ineffective for most patients. Other factors present in the TME may participate in the control of tumors, among several candidates, the role of B cells has been underestimated. Publications revealed that B-cells are associated with good prognosis in several indications. However, there are no general rules since neutral or even deleterious impact of the presence of B-cells in the tumor was reported. Among other hypotheses, we can suppose that the level of activation and isotype switch will be important to mediate activation of NK cells or ADCC within the tumor and will have a favorable impact on the prognosis. In addition, the spatial distribution of B-cells may be important since, in the TME, they are mostly located in Tertiary Lymphoid Structures (TLS) which are ectopic lymphoid organs. Mature TLSs contain zones where dendritic cells (DC) present antigen to T-cells and others where proliferating B-cells undergo class switch and maturation toward plasma cells. Antigen presentation by B cells to T cells is supported by DCs, therefore, the presence of these three types of cells within the TLS allows T cell activation in the TME. If B-cells are major players in the therapeutic efficacy of ICI antibodies, not all subtypes of tumor infiltrating B-cells are likely to participate in response to immunotherapy. Methods To decipher the roles of B cells, new tools are needed to identify the differentiation and activation status of individual B cells. We have developed a 7-plex panel of antibodies against biomarkers that allow the identification of main types of B cells. Results On a single FFPE tissue section: naïve, unswitched memory, switched memory, activated, plasmablast and plasma B cells, as well as T cells and DC are identified. Following images registration, complex cells phenotypes can be detected and quantified. Furthermore, digital pathology tools allow the evaluation of the spatial distribution within the TME of subtypes of B cells especially in association with TLSs. Conclusions This new tool unravels the heterogeneity of B cells in TME and could help clinical researchers to understand their contribution to the response to immunotherapy. Integrated into an Immunogram, this new Brightplex® Panel will be critical to understand the immune contexture of the tumor.
Abstract PO-082: Delineating the molecular basis of early dissemination of pancreatic cancer
Authors: Taelor J. Ekstrom, Dmytro Grygoryev, Terry Morgan, Kenneth S. Zaret, Jungsun Kim
Journal: Cancer Research (2021)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at advanced stages rendering the already limited therapeutic options ineffective for many patients. Earlier diagnosis permits for “curative” surgery; however, 95% of these patients experience recurrence locally or distally and die within ten years of treatment. One hypothesis that can explain high recurrence is the early dissemination of PDAC progression. At the time of surgery, systemic subclinical dissemination of predominantly dormant cells found ubiquitously within patient livers has already occurred prior to the development of overt metastatic disease or bona fide recurrent PDAC. However, remarkably little is known about early PDAC cell dissemination despite these dismal outcomes, mainly due to the lack of human models to study disease progression. We previously demonstrated the cellular reprogramming “proof-of-principle” to model human PDAC progression (designated “10-22 cells”) and its use as a discovery tool for early biomarkers by unveiling a marker for stage 1 PDAC in human patients. We further analyzed transcriptomes of genetically tagged 10-22 cells progressing from pancreatic intraepithelial neoplasia (PanIN) to PDAC in mice and validated the results using the TCGA PDAC dataset, human clinical PanIN, PDAC tissues, and a well-established murine PDAC model. We found that extracellular vesicle transport and neuronal cell differentiation pathways were derepressed in the progression of PanINs to PDAC. HMG-Box Transcription Factor 1 (HBP1) emerged as a potential master factor regulating dynamically expressed genes in neuronal cell differentiation and dissemination during PDAC progression. HBP1 expression are aberrantly regulated in human and murine PanINs and PDAC tissue samples, and their mRNA expressions are inversely correlated with PDAC patients' prognosis. Ectopic overexpression of HBP1 increased proliferation and migration of normal and cancerous pancreatic cells. Conversely, knocking out HBP1 in PDAC cells decreased proliferation and migration. Altogether, our data indicate that HBP1 may confer the cell dissemination capacity in early PDAC progression. We are on the way to further dissect the mechanisms by which HBP1 regulates pancreatic cell migration and confers neuronal migratory phenotypes and how these signaling influence PDAC progression and prognosis. Citation Format: Taelor J. Ekstrom, Dmytro Grygoryev, Terry Morgan, Kenneth S. Zaret, Jungsun Kim. Delineating the molecular basis of early dissemination of pancreatic cancer [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-082.
Abstract 12941: Using Deep Learning to Predict the Framingham Risk Score From Brain Magnetic Resonance Imaging
Authors: Camilo Bermudez Noguera, Lori Held, Susan Resnick, Quinn Wells, bennett landman
Journal: Circulation (2019)

Introduction: Cardiovascular disease (CVD) risk factors are increasingly recognized to adversely impact neurological function. However, it is unclear how CVD risk factors affect brain morphology. I...
The Tigit/CD226/CD155 Immunomodulatory Axis Is Deregulated in CLL and Contributes to B-Cell Anergy
Authors: Francesca Arruga, Andrea Iannello, Nikolaos Ioannou, Alberto Maria Todesco, Marta Coscia, Riccardo Moia, Gianluca Gaidano, John N. Allan, Richard Furman, Tiziana Vaisitti, Alan G. Ramsay, Silvia Deaglio
Journal: Blood (2021)
Rituximab-Lenalidomide(R2) Maintenance Is Superior to Rituximab Maintenance after First Line Immunochemotherapy in Mantle Cell Lymphoma: Results of the MCL R2 Elderly Clinical Trial
Authors: Vincent Ribrag, Violaine Safar, Hanneke Kluin-Nelemans, Lucie Oberic, Pierre Feugier, Olivier Casasnovas, Catherine Thieblemont, Nicolas Daguindau, Gandhi Laurent Damaj, Wolfram Klapper, Eva Hoster, Ludwig Fischer von Weikersthal, Mathias Haenel, Marc André, Maria Gomes da Silva, Fernando Carcinero, Ana Marin-Niebla, Michal Taszner, Jan Walewski, Rinske Boersma, Ilse Houtenbos, Marie-Helene Delfau-Larue, Steven Le Gouill, Martin H. Dreyling
Journal: Blood (2021)
Toripalimab plus intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma: an open-label single-arm, phase II trial
Authors: Yijun Hua, Rui You, Zhiqiang Wang, Peiyu Huang, Mei Lin, Yanfeng Ouyang, Yulong Xie, Xiong Zou, Youping Liu, Chongyang Duan, Yonglong Liu, Chenmei Gu, Rongzeng Liu, Qi Yang, Rou Jiang, Mengxia Zhang, Xi Ding, Siyuan Chen, Chao Lin, Rui Sun, Mingyuan Chen
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Toripalimab is a humanized immunoglobulin G 4 monoclonal antibody against programmed death 1. We aimed to investigate the efficacy and safety of toripalimab in combination with intensity-modulated radiotherapy (IMRT) for recurrent nasopharyngeal carcinoma (rNPC). Methods We conducted a single-arm, phase II trial with patients with rNPC who had biopsy-proven disease and were unsuitable for local surgery. Eligible patients received IMRT in combination with toripalimab administered via intravenous infusion of 240 mg once every 3 weeks for a maximum of seven cycles. The primary endpoint was the objective response rate at 3 months post radiotherapy. The secondary endpoints included safety profiles, progression-free survival (PFS). Results Between May 2019 and January 2020, a total of 25 patients with rNPC were enrolled (18 men (72.0%) and 7 women (28.0%); median (IQR) age, 49.0 (43.5–52.5) years). With a median (IQR) follow-up duration of 14.6 months (13.1–16.2) months, 19 patients (79.2%) achieved an overall response, and disease control was achieved in 23 (95.8%) patients at 3 months post radiotherapy. The 12-month PFS was 91.8% (95% CI 91.7% to 91.9%). The incidences of acute (grade ≥3) blood triglyceride elevation, creatine kinase elevation, skin reaction, and mucositis were 1 (4.0%), 1 (4.0%), 2 (8.0%), and 1 (4.0%), respectively. The incidences of late severe (grade ≥3) nasopharyngeal wall necrosis, nasal bleeding, and trismus were 28.0%, 12.0%, and 4.0%, respectively. Conclusions Toripalimab combined with IMRT was tolerable and showed promising antitumor activity in patients with rNPC. Trial registration number NCT03854838 .
Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Marginal Zone Lymphoma: Primary Analysis from a Phase 2 Study (CITADEL-204)
Authors: Tycel Phillips, Abraham Avigdor, Ronit Gurion, Caterina Patti, Paolo Corradini, Monica Tani, Amitkumar Mehta, Izidore S. Lossos, Pier Luigi Luigi Zinzani, Catherine Thieblemont, Wojciech Jurczak, Fred Zheng, Erica Rappold, Wanying Zhao, Peter Johnson
Journal: Blood (2021)
Ibrutinib Plus Rituximab Is Superior to FCR in Previously Untreated CLL: Results of the Phase III NCRI FLAIR Trial
Authors: Peter Hillmen, Alexandra Pitchford, Adrian Bloor, Angus Broom, Moya Young, Ben Kennedy, Renata Walewska, Michelle Furtado, Gavin Preston, Jeffrey R. Neilson, Nicholas Pemberton, Gamal Sidra, Nicholas Morley, Kate Cwynarski, Anna Schuh, Francesco Forconi, Nagah Elmusharaf, Shankara Paneesha, Christopher P. Fox, Dena Howard, Anna Hockaday, David Cairns, Sharon Jackson, Natasha Greatorex, Piers EM Patten, David Allsup, Talha Munir
Journal: Blood (2021)
Cost-Effectiveness Analysis of Dapagliflozin in the Treatment of Heart Failure with Reduced Ejection Fraction
Authors: Mohammed Habib
Journal: Clinical Cardiology and Cardiovascular Interventions (2020)

Bakground: The Dapagliflozin was associated with a reduction in cardiovascular mortality, all-cause mortality, and hospitalizations compared with enalapril. Objective: To estimate the cost-effectiveness of Dapagliflozin in Gaza Design, Setting, and Participants: Quality of life was based on trial EQ-5D scores. Hospital costs combined Medicare and private insurance reimbursement rates; medication costs included the wholesale acquisition cost for sacubitril/valsartan and Dapagliflozin. were performed on key inputs including: hospital costs, mortality benefit, hazard ratio for hospitalization reduction, drug costs, and quality-of-life estimates. Main Outcomes and Measures: Hospitalizations, quality-adjusted life-years (QALYs), costs, and incremental costs per QALY gained. Results: In DAPA HF trial: in patient with DM, the strategy of using dapagliflozin has an of $ 17287 per QALY gained and in patient without DM, the strategy of using dapagliflozin has an of $ 45192 per QALY gained. Indirect comparison between patients with dapagliflozin but without DM the strategy of using sacubitril/ valsartan has an ICER of $ 66000 per QALY gained and in patient with DM, ICER of 94 000 $ per QALY gained. Conclusions: For eligible patients with HF and reduced ejection fraction, Dapagliflozin was cost effective than the sacubitril/valsartan in Gaza.
Differential Activation of V γ4V δ1 and V γ9V δ2 Cord Blood Derived Gamma Delta T Cells upon Exposure to EBV-Lcl and K562 Cells
Authors: Jeremy Wee Kiat Ng, Joey Lai, Tony Kiat Hon Lim, William YK Hwang, Shang Li, Connie J. Eaves, Yeow Tee Goh, Alice Cheung
Journal: Blood (2021)
Redefinition to bilayer osmotic pump tablets as subterranean river system within mini-earth via three-dimensional structure mechanism
Authors: Abi Maharjan, Hongyu Sun, Zeying Cao, Ke Li, Jinping Liu, Jun Liu, Tiqiao Xiao, Guanyun Peng, Junqiu Ji, Peter York, Balmukunda Regmi, Xianzhen Yin, Jiwen Zhang, Li Wu
Journal: Acta Pharmaceutica Sinica B (2021)

Defining and visualizing the three-dimensional (3D) structures of pharmaceuticals provides a new and important tool to elucidate the phenomenal behavior and underlying mechanisms of drug delivery systems. The mechanism of drug release from complex structured dosage forms, such as bilayer osmotic pump tablets, has not been investigated widely for most solid 3D structures. In this study, bilayer osmotic pump tablets undergoing dissolution, as well as after dissolution in a desiccated solid state were examined, and visualized by synchrotron radiation micro-computed tomography (SR-μCT). In situ formed 3D structures at different in vitro drug release states were characterized comprehensively. A distinct movement pattern of NaCl crystals from the push layer to the drug layer was observed, beneath the semi-permeable coating in the desiccated tablet samples. The 3D structures at different dissolution time revealed that the pushing upsurge in the bilayer osmotic pump tablet was directed via peripheral "roadways". Typically, different regions of the osmotic front, infiltration region, and dormant region were classified in the push layer during the dissolution of drug from tablet samples. According to the observed 3D microstructures, a "subterranean river model" for the drug release mechanism has been defined to explain the drug release mechanism.