tbuckley/cabot-search huggingface dataset:
Microarray gene expression analysis to evaluate cell type specific expression of targets relevant for immunotherapy of hematological malignancies
Authors: M.J. Pont, M.W. Honders, A.N. Kremer, C. van Kooten, C. Out, P.S. Hiemstra, H.C. de Boer, M.J. Jager, E. Schmelzer, R.G. Vries, A.S. al Hinai, W.G. Kroes, R. Monajemi, J.J. Goeman, S. Bohringer, W.A.F. Marijt, J.H.F. Falkenburg, M. Griffioen
Journal: PLoS Medicine (2016)

Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate potential efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. We performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlations between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers.
AKAP18δ Anchors and Regulates CaMKII Activity at Phospholamban-SERCA2 and RYR
Authors: Cathrine R. Carlson, Jan Magnus Aronsen, Anna Bergan-Dahl, Marie Christine Moutty, Marianne Lunde, Per Kristian Lunde, Hilde Jarstadmarken, Pimthanya Wanichawan, Laetitia Pereira, Terje R.S. Kolstad, Bjørn Dalhus, Hariharan Subramanian, Susanne Hille, Geir Christensen, Oliver J. Müller, Viacheslav Nikolaev, Donald M. Bers, Ivar Sjaastad, Xin Shen, William E. Louch, Enno Klussmann, Ole M. Sejersted
Journal: Circulation Research (2021)

Background: The sarcoplasmic reticulum (SR) Ca 2+ -ATPase 2 (SERCA2) mediates Ca 2+ reuptake into SR and thereby promotes cardiomyocyte relaxation, whereas the ryanodine receptor (RYR) mediates Ca 2+ release from SR and triggers contraction. Ca 2+ /CaMKII (CaM [calmodulin]-dependent protein kinase II) regulates activities of SERCA2 through phosphorylation of PLN (phospholamban) and RYR through direct phosphorylation. However, the mechanisms for CaMKIIδ anchoring to SERCA2-PLN and RYR and its regulation by local Ca 2+ signals remain elusive. The objective of this study was to investigate CaMKIIδ anchoring and regulation at SERCA2-PLN and RYR. Methods: A role for AKAP18δ (A-kinase anchoring protein 18δ) in CaMKIIδ anchoring and regulation was analyzed by bioinformatics, peptide arrays, cell-permeant peptide technology, immunoprecipitations, pull downs, transfections, immunoblotting, proximity ligation, FRET-based CaMKII activity and ELISA-based assays, whole cell and SR vesicle fluorescence imaging, high-resolution microscopy, adenovirus transduction, adenoassociated virus injection, structural modeling, surface plasmon resonance, and alpha screen technology. Results: Our results show that AKAP18δ anchors and directly regulates CaMKIIδ activity at SERCA2-PLN and RYR, via 2 distinct AKAP18δ regions. An N-terminal region (AKAP18δ-N) inhibited CaMKIIδ through binding of a region homologous to the natural CaMKII inhibitor peptide and the Thr17-PLN region. AKAP18δ-N also bound CaM, introducing a second level of control. Conversely, AKAP18δ-C, which shares homology to neuronal CaMKIIα activator peptide (N2B-s), activated CaMKIIδ by lowering the apparent Ca 2+ threshold for kinase activation and inducing CaM trapping. While AKAP18δ-C facilitated faster Ca 2+ reuptake by SERCA2 and Ca 2+ release through RYR, AKAP18δ-N had opposite effects. We propose a model where the 2 unique AKAP18δ regions fine-tune Ca 2+ -frequency-dependent activation of CaMKIIδ at SERCA2-PLN and RYR. Conclusions: AKAP18δ anchors and functionally regulates CaMKII activity at PLN-SERCA2 and RYR, indicating a crucial role of AKAP18δ in regulation of the heartbeat. To our knowledge, this is the first protein shown to enhance CaMKII activity in heart and also the first AKAP (A-kinase anchoring protein) reported to anchor a CaMKII isoform, defining AKAP18δ also as a CaM-KAP.
Abstract 14001: Using the S2 Sound as an Early Marker of Aortic Valve Calcification
Authors: Valentina Dargam, Hooi H Ng, Sana Nasim, Camila Iansen Irion, Suhas Seshadri, Lina A Shehadeh, Joshua Hutcheson
Journal: Circulation (2021)

Introduction: Heart valve diseases (HVDs) often remain undiagnosed until late stages, especially in underserved populations, leading to significant comorbidities. Artificial intelligence has improved murmur detection in digital phonocardiograms (PCG). However, the presence of murmurs depends on hemodynamic factors unrelated to HVD. Screening tests that directly measure features of valvular remodeling regardless of symptoms would improve HVD diagnosis. We used a mouse model of chronic kidney disease (CKD) induced aortic valve (AoV) remodeling to determine whether S2 sound changes can be used to detect early stages of AoV calcification. Methods: Eight-week old C57BL/6J mice (n=24) were assigned the following diets for 12 weeks: 1) control group fed a normal chow diet, 2) CKD group fed an adenine-supplemented diet to induce CKD, and 3) CKD+HP group fed the CKD diet for 6 weeks, then an adenine and high phosphate (HP)-supplemented diet for another 6 weeks to induce AoV calcification. PCG signals were recorded every 6 weeks. Endpoint AoV calcification and echocardiogram measures of valvular function were assessed. We developed a clustering method based on time domain principal component analysis of S2 sounds collected at week 6 (W6) to classify week 12 (W12) S2 sounds and identify S2 sound alterations due to HP. Results: The high phosphate diet induced AoV calcification in CKD+HP mice (1a). Of the total number of S2 sounds per mouse, an average of 84.18% and 81.15% S2 sounds (1b and 1c) were accurately classified as control or CKD mice with a specificity and sensitivity of 90.91% and 100%, respectively. CKD+HP mice had an average of 59.22% W12 S2 sounds that neither classified as control nor CKD. Conclusions: Mice that have AoV calcification show distinct S2 sounds features that were absent in the control and CKD groups. In this study, we demonstrate the feasibility of using the S2 sound not only to detect AoV calcification prior to expected hemodynamic changes but also to detect CKD.
Abstract 13696: Temporal Trends In Chads2 And Cha2ds2vasc Comorbidities And Association With Outcomes In Atrial Fibrillation Patients Presenting With Acute Ischemic Stroke And Transient Ischemic Attack
Authors: Balaram J Hanumanthu, Yesha Rana, Apurva Sharma, Alvaro Vargas Pelaez, Deepika Misra
Journal: Circulation (2021)

Introduction: CHADSVASc and CHADS scores, developed early in the last decade, are used to predict risk of acute ischemic strokes and transient ischemic attacks(CVA/TIA) in Atrial fibrillation(Afib) Hypothesis: We wanted to study temporal trends of these scores and association with mortality and morbidity (defined as discharge to facility apart from home or to home with services). Methods: Admissions with CVA/TIA in Afib were identified using DRG codes from 2008 to 2017 from the National Inpatient Sample. Comorbidities were identified using ICD codes (ICD9 2008-2015 quarter3 and ICD10 from 2015 quarter 4-2017). Results: Total 66,280 admissions were identified. Mean CHADS and Mean CHADSVASC scores increased over time (4.01 ± 0.8) to (4.19 ± 0.8) and (5.88 ± 1.3) to (6.02 ± 1.3) in 2008 to 2017 respectively (p trend&lt;0.001). Prevalence of heart failure, hypertension, diabetes and peripheral vascular disease increased significantly whereas mean age, proportion of patients ≥75 and female decreased significantly across the years (p trend for all&lt;0.001). Inpatient mortality rates increased over the years (2.69 vs 2.90%) (p trend&lt;0.001). Higher CHADSVASC score and CHADS score were independently associated with mortality (OR1.35,p&lt;0.001;OR1.32,p&lt;0.001 respectively), discharge to a facility apart from home(OR1.26,p&lt;0.001;OR1.30,p&lt;0.001 respectively) or to home with services (OR1.30,p&lt;0.001;1.33,p&lt;0.001 respectively). Conclusions: We found that CHADSVASC/CHADS scores increased, with an increase in the prevalence of all risk actors except age and female gender from 2007 to 2018. High scores correlated with mortality and morbidity in these younger patients.
Abstract 14074: Machine Learning Applied on ECG Improves Cardiovascular Risk Prediction When Added to Coronary Artery Calcium Scoring in Patients With Cancer
Authors: Shruti Siva Kumar, Sadeer Al-Kindi, Nour Tashtish, Varun Rajagopalan, Pingfu Fu, Sanjay Rajagopalan, Anant Madabhushi
Journal: Circulation (2021)

Introduction: Patients with cancer are at increased cardiovascular (CV) risk. Both Coronary Artery Calcium (CAC) and 12-lead ECG features predict CV risk in the general population. However, the impact of these measures has not been investigated in patients with cancer. Hypothesis: We hypothesized that machine learning-based analysis of automatically-extracted ECG features, when added to CAC, can improve CV risk stratification in patients with cancer. Methods: We analyzed 1825 cancer patients with at least 1 CV risk factor who underwent CAC scoring and a standard 12-ECG as part of the CLARIFY (ClinicalTrials.gov Identifier: NCT04075162) registry. Events were defined as myocardial infarction, revascularization, stroke or death. A total of 445 ECG features were automatically extracted using a commercially available software (ECG Muse, GE healthcare). A LASSO-Cox method was used with 10-fold cross validation to select the most important ECG features with a novel ECG score derived using individual feature coefficients. We evaluated the ability of the combined ECG score with age, sex, and CAC to prognosticate a CV event in comparison to a model that was limited to age, sex, and CAC alone. The models were compared using an ANOVA test. Results: Over a median follow-up of 14 months, 224 patients had an event. Using the LASSO-Cox model, 25 ECG features were selected. The novel ECG score was associated with CV events (HR 8.6, 95% CI: 5.1-14.3, P&lt;0.001), which was not attenuated after adjusting for age, sex, and CACS (HR 7.3, 95% CI: 4.3-12.4, P&lt;0.001). Addition of ECG score to a model including age, sex, and CAC improved discrimination (C-Index 0.63 vs 0.72, P=0.0001). Conclusions: A novel ML-based ECG risk score using automatically extracted ECG features can improve CV risk stratification when added to CAC and demographics in patients with cancer.
Abstract 10269: Direct Oral Anticoagulation Therapy vs Vitamin K Antagonist in Chronic Thromboembolic Pulmonary Hypertension: A Systematic Review and Meta-Analysis
Authors: Mahmoud El Iskandarani, Ahmad Al Tamari, Muhammad Khalid, Timir K Paul
Journal: Circulation (2021)

Introduction: The use of direct oral anticoagulation therapy (DOAC) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) has recently increased, despite the scarce evidence to support their use in this condition. Our systematic review and meta-analysis aim to summarize the available data on the safety and effectiveness of DOAC. Hypothesis: DOAC is a safe and effective alternative anticoagulation therapy in CTEPH. Methods: Unrestricted search of the PubMed, EMBASE, and Cochrane databases from inception till May 1, 2021, for studies comparing DOAC with Vitamin K antagonist (VKA) in CTEPH patients. Relevant data were extracted and analyzed using Revman 5.3 software. Odds Ratio (OR) and 95% Confidence interval (CI) were calculated using the random-effects model. Results: A total of 3 observational studies were included examining 1,630 patients with CTEPH (386 DOAC vs 1,244 VKA). The most used DOAC was Rivaroxaban (79% of that population). There was no difference between DOAC and VKA in the incidence of recurrent venous thromboembolism OR 1.35 (95% CI 0.40-4.52), major bleeding OR 0.60 (95% CI 0.33-1.10), and clinically relevant non-major bleeding OR 1.42 (95% CI 0.86-2.33). Conclusions: DOAC is probably non-inferior to VKA in CTEPH patients. Since rivaroxaban is the most used DOAC in the included cohort, the safety, and efficacy of other DOAC remain unclear. Our findings need further validation with randomized clinical trials.
Biomarker Analysis of a Phase Ia/Ib Open-Label, Multicentre Study of Tiragolumab or Tiragolumab + Rituximab in Patients with Relapsed or Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL)
Authors: Shannon Ruppert, Vaikunth Cuchelkar, Raymond Meng, Eunpi Cho, Sean Lear, Cheryl Victoria Wong, Aparna Raval, Yann Nouet
Journal: Blood (2021)
Comprehensive Review: Extramedullary Hematopoiesis in Patients with Beta Thalassemia Major (transfusion dependent thalassemia)
Authors: Eihab A. Subahi, Fateen Ata, Hassan Choudry, Ashraf Tawfiq Soliman, Vincenzo Desanctis, Phool Iqbal, Mousa A AlHiyari, Mohamed A Yassin
Journal: Blood (2021)
Abstract 14331: Findings of a Novel Barbershop-Based Peripheral Artery Disease Screening Program and Intervention for Black Men
Authors: Khendi T White Solaru, Joseph E RAVENELL, Christopher Longenecker, Tyler Coy, Sarah J Delozier, Ellen Brinza, Jackson T Wright, Heather L Gornik
Journal: Circulation (2021)

Introduction: Peripheral artery disease (PAD) increases risk of cardiovascular events and limb events including amputations. Black race is a strong risk factor for PAD. Screening for PAD using the ankle-brachial index (ABI) can lead to early diagnosis and treatment. This is the first study to screen for PAD using the ABI in barbershops. Hypothesis: Barbershop-based screening and an educational intervention can detect PAD and increase PAD knowledge in a high-risk population. Methods: A screening pilot study was conducted at two barbershops in Cleveland from June-December 2020. Black male participants aged 40-89 completed an initial screening visit with automated ABI and a confirmatory visit with Doppler ABI. All were invited to watch an educational video on PAD and interviewed at 2-month follow-up. Automated blood pressure, health status, and knowledge about PAD were assessed at all visits. Results: 37 participants completed the initial screening, 31 (84%) completed the confirmatory testing visit, 29 (78%) completed the exit visit, and 27 (73%) watched the educational video. After screening with both automated and Doppler ABI, PAD was identified in 5/31 (16.1%) participants. PAD awareness was low, but among those who completed the study, 23 (82%) showed improved PAD awareness scores as well as improvement in their self-assessed knowledge of PAD ( p&lt; 0.001). An association was found between good PAD awareness at baseline and education: compared to those with some college education, those who did not graduate high school scored lower on PAD awareness ( p = .022), as did those who only had a high school diploma or GED ( p = .049). Conclusions: In a pilot study, barbershop-based screening for PAD among Black men revealed a higher than expected PAD prevalence and low PAD awareness. ABI screening and an educational video increased PAD awareness. ABI screening and educational outreach in the barbershop may be effective tools to diagnose PAD and increase awareness among Black men.
Abstract 11338: On-Clopidogrel Platelet Reactivity in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention and Association with Patient Characteristics
Authors: Diona Gjermeni, Hannah Vetter, Sofia Szabo, Viktoria Anfang, David Hesselbarth, Stefan Leggewie, Dietmar Trenk, Daniel Duerschmied, Christoph Bode, Christoph Olivier
Journal: Circulation (2021)

Introduction: On-clopidogrel platelet reactivity (PR) is associated with thrombotic and bleeding risk in patients undergoing percutaneous coronary intervention (PCI). Patient-related factors affect the level of PR. Patients with atrial fibrillation (AF) undergoing PCI are treated concomitantly with oral anticoagulants (OAC) potentially interacting with platelet function. This study aimed to investigate the association of PR with demographic and clinical characteristics in these patients. Methods: In this single-centre prospective observational cohort study, patients with AF with an indication for OAC were enrolled during hospitalization after PCI with clopidogrel. TRAP- and ADP- induced PR (TRAP 32 μM, ADP 6.4 μM) were assessed by multiple electrode aggregometry. ADP-induced PR was normalized to TRAP-induced PR (r-ADP-agg). Results: 159 patients were enrolled between May 2020 and May 2021. The median age was 78 years (interquartile range, IQR 72-82), 112 (70%) were male and 39 (25%) presented with ACS. 68 (43%) presented with chronic kidney disease (CKD), defined as GFR&lt;60. 54 (34%) patients received apixaban, 6 (4%) dabigatran, 18 (11%) edoxaban, 74 (47%) rivaroxaban and 4 (3%) marcumar. 128 (81%) patients received clopidogrel loading. Median ADP-induced PR was 12 U (IQR 6-17); median r-ADP-agg was 24% (IQR 14-39). ADP-induced PA is significantly correlated with age (r=-0.22; p=0.035) and platelet count (r=0.22; p=0.006). Compared to the patients without CKD,patients with CKD had a significantly lower ADP-induced PA (median 8 [IQR 10] vs. median 13 [IQR 10]; p&lt;0.001) and r-ADP-agg. (median 20 [IQR 25] vs median 28 [IQR 24]; p=0.003).In a multivariable linear regression, ADP-induced PR was significantly associated with age (r=-0.177, CI:-0.481 to -0.018, p=0.035), immature platelet count (r=0.178, CI: 0.003 to 0.729, p=0.048), and diabetes mellitus (r=0.21, CI: 1.192 to 9.087, p=0.011). CKD was associated with both: lower ADP-PR (r=-0.262, CI:-9.962 to -2.396, p=-0.002) and lower r-ADP-agg (r=-0.253, CI:-9.962 to -2.396, p=0.003). Conclusions: In this patient cohort the association of on-clopidogrel PR as assessed by multiple electrode aggregometry with patient related factors was weak and most pronounced for chronic kidney disease.
Transcriptional landscape of highly lignified poplar stems at single-cell resolution
Authors: Yang Chen, Shaofei Tong, Yuanzhong Jiang, Fandi Ai, Yanlin Feng, Junlin Zhang, Jue Gong, Jiajia Qin, Yuanyuan Zhang, Yingying Zhu, Jianquan Liu, Tao Ma
Journal: Genome biology (2021)

Plant secondary growth depends on the activity of the vascular cambium, which produces xylem and phloem. Wood derived from xylem is the most abundant form of biomass globally and has played key socio-economic and subsistence roles throughout human history. However, despite intensive study of vascular development, the full diversity of cell types and the gene networks engaged are still poorly understood.
Gamma delta TCR anti-CD3 bispecific molecules (GABs) as novel immunotherapeutic compounds
Authors: Eline van Diest, Patricia Hernández López, Angelo D Meringa, Anna Vyborova, Froso Karaiskaki, Sabine Heijhuurs, Jan Gumathi Bormin, Sanne van Dooremalen, Mara J T Nicolasen, Lucrezia C D E Gatti, Inez Johanna, Trudy Straetemans, Zsolt Sebestyén, Dennis X Beringer, Jürgen Kuball
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background γ9δ2 T cells hold great promise as cancer therapeutics because of their unique capability of reacting to metabolic changes with tumor cells. However, it has proven very difficult to translate this promise into clinical success. Methods In order to better utilize the tumor reactivity of γ9δ2T cells and combine this with the great potential of T cell engager molecules, we developed a novel bispecific molecule by linking the extracellular domains of tumor-reactive γ9δ2TCRs to a CD3-binding moiety, creating gamma delta TCR anti-CD3 bispecific molecules (GABs). GABs were tested in vitro and in vivo for ability to redirect T lymphocytes to a variety of tumor cell lines and primary patient material. Results GABs utilizing naturally occurring high affinity γ9δ2TCRs efficiently induced αβT cell mediated phosphoantigen-dependent recognition of tumor cells. Reactivity was substantially modulated by variations in the Vδ2 CDR3-region and the BTN2A1-binding HV4-region between CDR2 and CDR3 of the γ-chain was crucial for functionality. GABs redirected αβT cells against a broad range of hematopoietic and solid tumor cell lines and primary acute myeloid leukemia. Furthermore, they enhanced infiltration of immune cells in a 3D bone marrow niche and left healthy tissues intact, while eradicating primary multiple myeloma cells. Lastly, GABs constructed from natural high affinity γ9δ2TCR sequences significantly reduced tumor growth in vivo in a subcutaneous myeloma xenograft model. Conclusions We conclude that GABs allow for the introduction of metabolic targeting of cancer cells to the field of T cell engagers.
Unraveling Heterogeneity of Aged Hematopoietic Stem Cells By Single-Cell RNA Sequence Analysis
Authors: Shuhei Koide, Motohiko Oshima, Akira Nishiyama, Koichi Murakami, Yuta Yamada, Naoki Itokawa, Yaeko Nakajima-Takagi, Zhiqian Zheng, Tomohiko Tamura, Atsushi Iwama
Journal: Blood (2021)