tbuckley/cabot-search huggingface dataset:
<scp>CD19</scp> Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus
Authors: Jule Taubmann, Fabian Müller, Melek Yalcin Mutlu, Simon Völkl, Michael Aigner, Aline Bozec, Andreas Mackensen, Ricardo Grieshaber‐Bouyer, Georg Schett
Journal: Arthritis & Rheumatology (2023)

B cell generation of autoantibodies is a crucial step in the pathogenesis of systemic lupus erythematosus (SLE). After their differentiation in the bone marrow, B cells populate the secondary lymphatic organs, where they undergo further maturation leading to the development of memory B cells as well as antibody‐producing plasmablasts and plasma cells. Targeting B cells is an important strategy to treat autoimmune diseases such as SLE, in which B cell tolerance is disturbed and autoimmune B cells and autoantibodies emerge. This review discusses the functional aspects of antibody‐ and cell‐based B cell–depleting therapy in SLE. It thereby particularly focuses on lessons learned from chimeric antigen receptor (CAR) T cell treatment on the role of B cells in SLE for understanding B cell pathology in SLE. CAR T cells model a deep B cell depletion and thereby allow understanding the role of aberrant B cell activation in the pathogenesis of SLE. Furthermore, the effects of B cell depletion on autoantibody production can be better described, ie, explaining the concept of different cellular sources of (auto‐) antibodies in the form of short‐lived plasmablasts and long‐lived plasma cells, which differ in their susceptibility to B cell depletion and require different targeted therapeutic approaches. Finally, the safety of deep B cell depletion in autoimmune disease is discussed.
Abstract 12982: Underutilization of Intravenous Iron in a Contemporary Population of Ambulatory Heart Failure Patients in Canada
Authors: Fahad Alajmi, Mehima Kang, Abbas Altamimi, Brian Clarke, Margot Davis, Sean Virani, Mustafa Toma
Journal: Circulation (2023)

Background: Intravenous iron has been shown to improve quality of life and exercise capacity in patients with heart failure and reduced ejection fraction (HFrEF) with iron deficiency anemia. We undertook this study to understand the utilization rates of IV iron in a Canadian heart function clinic. Methods: This retrospective analysis was carried out on all heart failure (HF) patients referred to a tertiary care Heart Function Clinic (HFC) who would have been eligible for intravenous iron therapy from January 2020 until December 2022. Our inclusion and exclusion criteria were based on the FAIR HF trial. Inclusion criteria was left ventricular ejection fraction (LVEF) of ≤40% for patients with New York Heart Association (NYHA) class II or ≤45% for NYHA class III, hemoglobin level of 95 to 135 g/L and iron deficiency. The data and decision to recommend IV iron was based on initial HFC consultation and pre-appointment investigations. Results: Out of 1360 charts reviewed, 920 patients had a complete data set in order to determine eligibility. Of those, 127 (13.8%) met IV iron eligibility criteria as per the FAIR HF trial. Of those eligible, 64.6% were male, 98.4% had HFrEF and 1.6% had heart failure with mildly reduced ejection fraction (HFmrEF) (p&lt;0.001). The mean LVEF for those meeting criteria for IV iron was 28.3±7.6% vs 36.1±13.7% for those ineligible (p&lt;0.001). Mean NYHA class for those meeting criteria for IV iron was 2.3±0.5 vs 2.1±0.7 for those ineligible (p&lt;0.001). Only 3 (2.4%) of the eligible patients were recommended or received IV iron, while 2 (1.6%) others had received IV iron prior to HFC visit (Fig). There were no significant differences in the proportion of patients receiving optimal quadruple therapy HF management between both cohorts (p=0.07). Conclusion: Our study demonstrates a significant underutilization of IV iron administration in eligible HFC patients, presenting many missed opportunities to improve patient quality of life.
Abstract 16831: Deficiency of Cholesterol Efflux Pathways in Smooth Muscle Cells Enhances Vasoconstriction but Does Not Affect Atherosclerosis
Authors: Benedek Halmos, Marit Westerterp
Journal: Circulation (2023)

Smooth muscle cells (SMCs) regulate blood flow distribution via vasoconstriction mediated by α-adrenergic receptors (α-ARs). Plasma membrane cholesterol may affect α 1 -AR signaling, but consequences for SMC-mediated vasoconstriction are unclear. Cholesterol loading promotes SMC to macrophage transition in vitro , which may enhance atherosclerotic plaque vulnerability. However, the role of ATP Binding Cassette A1 and G1 (ABCA1/G1)-cholesterol efflux pathways in SMC-mediated vasoconstriction and atherogenesis remains poorly understood. We generated mice with SMC-specific Abca1/g1 deficiency on the low-density lipoprotein receptor deficient ( Ldlr -/- ) background by crossbreeding Abca1 fl/fl Abcg1 fl/fl Ldlr -/- mice with Myh11-Cre ERT2 transgenic mice and feeding them tamoxifen-diet. To induce SMC cholesterol accumulation and atherogenesis, we fed Myh11-Cre ERT2 Abca1 fl/fl Abcg1 fl/fl Ldlr -/- and Myh11-Cre ERT2 Ldlr -/- mice Western-type diet (WTD) for 16 weeks. Combined SMC-Abca1/g1 deficiency increased vasoconstriction in aortic rings induced by the α 1 -AR agonist phenylephrine, with reversal by methyl-β-cyclodextrin, substantiating its cholesterol-dependency. Unexpectedly, SMC - Abca1/g1 deficiency induced urinary bladder enlargement by &gt;20-fold, resembling bladder outlet obstruction (BOO). This was reversed by the α 1 -AR antagonist tamsulosin, indicating its dependence on SMC constriction. Moreover, SMC - Abca1/g1 deficiency decreased SMC markers and increased macrophage- and fibroblast-markers in the bladder wall, enhancing collagen deposition, consistent with SMC transdifferentiation. However, after 16 weeks WTD, SMC - Abca1/g1 deficiency did not affect atherosclerotic lesion size, fibrous cap thickness, necrotic core, collagen, or macrophage content, suggesting that SMCs in atherosclerotic plaques were not affected. This may be due to low Abca1/g1 expression in intimal SMCs. We uncover a new role of SMC cholesterol efflux pathways in suppressing α 1 -AR mediated vasoconstriction and bladder SMC transdifferentiation, decreasing BOO. Our data may provide a mechanistic link for the association between BOO and diabetes in humans, particularly because diabetes is associated with decreased cholesterol efflux.
Unveiling the hidden AP-1: revealing the crucial role of AP-1 in ccRCC at single-cell resolution
Authors: Jie Zheng, Fengling Liu, Cheng Su
Journal: Molecular Cancer (2023)

Abstract Clear cell renal cell carcinoma (ccRCC), as the most common histological subtype of kidney cancer, has been reported to originate primarily from proximal tubule (PT) cells in the kidney. However, the current research on its associated molecular mechanisms remains relatively limited. In our study, we analyzed multiple single-cell multi-omics datasets obtained from various research teams, revealing the significant role of the activator protein 1 (AP-1) in ccRCC tumorigenesis. The motif activity analysis of transcription factors (TFs) showed a predominant activation of AP-1 in ccRCC cancer cells compared to PT cells. Furthermore, our findings at single-cell resolution revealed a notable absence of AP-1 expression in PT cells when compared to ccRCC cancer cells. In bulk-RNA of discovery cohort, no differential expression of AP-1 was detected in normal kidney and ccRCC samples, which may be attributed to confounding effects in bulk-RNA sequencing. Meanwhile, spatial transcriptomics analysis demonstrated a broader expression range of the AP-1 compared to the ccRCC marker CA9. Moreover, we observed chromatin accessibility of the AP-1 in various cell-types, including PT cells, suggesting that the transcriptional expression of AP-1 in PT cells may be influenced by subsequent transcriptional modifications, reflecting the complex regulatory mechanism of AP-1 transcription. These findings provide important insights for a deeper understanding of the function and regulatory mechanisms of AP-1 in ccRCC, thereby establishing a theoretical foundation for future clinical research and the development of treatment strategies.
Abstract 352: Automated Deep Learning Algorithms Outperforms Gray-White Matter Ratio for the Detection of Severe Cerebral Edema in Cardiac Arrest Survivors
Authors: Zihao Wang, Jacob Dodelson, Annelise Kulpanowski, William Copen, Brandon Hancock, Eric S Rosenthal, Brian L Edlow, W T Kimberly, Edilberto Amorim, Michael B Westover, Mingming Ning, Pamela Schaefer, Rajeev Malhotra, Joseph Giacino, David M Greer, Ona Wu
Journal: Circulation (2023)

Introduction: Significant knowledge gaps remain in predicting neurological outcomes for comatose cardiac arrest survivors. Severe cerebral edema (SCE) development offers an objective imaging surrogate for neurologic injury. Aim: We have previously shown that deep learning (DL) algorithms can detect SCE on CT. We aim to determine whether our model will perform equivalently on an independent external cohort. We also compared the performance of the DL model with one based on the gray-white matter ratio (GWR) for detecting SCE. Method: We retrospectively analyzed CT data (299 patients, 55±17 years, 71% male, 65 with SCE). Scans whose radiology reports described herniation or more than minimal ventricular effacement were classified as SCE. Datasets were randomly split (balancing for SCE) into training, validation, and testing cohorts. We used transfer learning with a 3D residual neural network framework to train our model. The probability of SCE was calculated. We applied the model to an external cohort (151 patients, 58±17 years, 63% male, 29 with SCE). Regions of interest (ROIs) were drawn in the caudate nuclei (CN) and posterior limbs of the internal capsule (PLIC). GWR was calculated as the ratio of mean x-ray attenuation values in the CN and the PLIC. Areas under the receiver operating curves (AUC) for the DL and GWR models were compared (bootstrap test). Results: The optimal model achieved comparable accuracies for the internal validation cohort (84% [95% CI: 78-89%], n=60) and reserved test cohort (83% [95% CI: 76 to 89%], n=61). The external cohort consisted of 175 scans. The model’s accuracy was 87% [95% CI: 81% to 91%], comparable to the results from the testing and internal validation cohorts. AUC for DL was significantly greater than for GWR (92% vs. 73%, P=0.001) (see Figure). Conclusions: Our result shows that deep transfer learning is a promising method to automate SCE detection on CT images and outperforms GWR measurements.
Abstract 15626: Novel Function Annotation Tool Revealed Obesity-Induced Inflammation is Exacerbated by miR-150 Regulated B Cell Receptor Signaling
Authors: Alyssa J Matz, Lili Qu, Keaton Karlinsey, Ivy Li, Anthony T Vella, Derek Aguiar, Beiyan Zhou
Journal: Circulation (2023)

B cells exacerbate obesity-induced metabolic dysfunction and become the second most abundant immune lineage in obese adipose tissue. However, high-resolution strategies to interrogate cellular dynamics driving B cell responses under chronic obesity stress are lacking, stifling innovative B cell-targeted therapies against obesity-induced health&amp;nbsp;risk. Our previous work established the potent role of&amp;nbsp;miR-150 in adipose tissue&amp;nbsp;B cells’ (ATB) pro-inflammatory responses under obesity. This project aims to elucidate the mechanism of miR-150 regulated ATB actions that bolster obesity-induced inflammation. Method: We employed single-cell techniques to decipher obesity-perturbed signaling networks in B cell-specific miR-150 gain/loss of function mouse models&amp;nbsp; in vivo and&amp;nbsp; ex vivo . We utilized our novel B cell function annotation tool, B-RAY, to&amp;nbsp;quantify&amp;nbsp;B cell cytokine production, antibody secretion, and antigen presentation from single-cell RNA-Seq. These strengths permitted several key findings: Result: A) miR-150 overexpression in mature B cells alone improved systemic glucose tolerance in obesity, despite similar body adiposity. In line, miR-150 knock-out worsened glucose tolerance. B) In obese adipose tissue, B cells were skewed towards higher cytokine production and antigen presentation and away from antibody secretion compared to lean tissue. Importantly, ATBs in obesity displayed increased activity of miR-150 direct targets, Myb, Etf1, and Elk1, and reduced expression of miR-150. C) ATBs in obesity were enriched in B cell receptor (BCR) signaling and downstream cascades. miR-150 overexpression B cells exhibited reduced BCR-mediated Syk phosphorylation and calcium influx, while miR-150 knock-out yielded enhanced responses. Conclusion: These results support the hypothesis that miR-150 regulation of ATBs limits chronic inflammation in obese adipose tissue via modulating BCR signaling to prevent excessive B cell cytokine production and antigen presentation. Future work will investigate ATB actions and BCR activation in&amp;nbsp;miR-150 gain/loss of function mice&amp;nbsp;across time in diet-induced obesity. Collectively, this work will elucidate an important immunoregulatory network bolstering obesity-induced inflammation and health risk.
Abstract 18520: Impaired Ubiquitin-Proteasome Function in Right Ventricular Myocardium Correlates to Postoperative Outcomes in Tetralogy of Fallot
Authors: Jonathan J Edwards, Yifan Yang, Genevieve Uy, Hari Rajagopal, Mark K Friedberg, Zoltan Arany, Sushma Reddy, Laura M Mercer-Rosa
Journal: Circulation (2023)

Introduction: At the time of initial repair, patients with Tetralogy of Fallot (TOF) undergo a sudden shift from a pressure to volume loaded right ventricle (RV). It is difficult to predict how TOF RVs will respond to this hemodynamic transition. Identifying mechanisms and targets may enable interventions to improve outcomes. Hypothesis: RV myocardial gene expression profiles at the time of TOF repair correlate to pre- and early postoperative clinical outcomes. Methods: RNAseq was performed from RV myocardium resected at the time of initial TOF repair (n=44). Gene expression profiling was performed using a weighted gene correlation network analysis (WGCNA) against pre- and post-op clinical variables. Mouse pulmonary artery band (PAB, n=9) stratified by degree of RV dilation was used to correlate pathways. Results: WGCNA identified a gene module that was associated with younger age at repair and worse TOF postop outcomes (prolonged milrinone, decreased right atrial and right ventricular strain) without a concomitant association with preop oxygen saturation. Biological process gene-set enrichment analysis using the 2023 Gene Ontology library revealed enrichment of regulators for ubiquitination, cell cycle/mitosis, DNA repair, microtubule polymerization, and Rho/GTPase. PAB mouse RV demonstrated a RV-dilation severity-dependent increase in bound ubiquitin (R 2 =0.61, p=0.01) and loss of free ubiquitin (R 2 =0.72, p=0.004; Figure). Conclusions: WGCNA reveals a RV myocardial gene expression profile that is associated with preoperative characteristics and early postoperative outcomes, and which is enriched for ubiquitination regulators. The PAB mouse recapitulates a severity-dependent increase in bound ubiquitin and loss of free ubiquitin which is consistent with literature suggesting proteostatic dysfunction and accumulation of misfolded proteins in RVF. Targeting proteostatic disruption prior to TOF repair may improve postoperative outcomes.
Abstract 16838: Relation of Clinical Status in Heart Failure to Cardiac Lysophosphatidylethanolamine Accumulation in Hypertrophic Cardiomyopathy
Authors: Takenori Ikoma, Keitaro Akita, Kyoko Unno, Kazuto Ohno, Ryota Sato, Terumori Satoh, Keisuke Iguchi, Atsushi Sakamoto, Kenichiro Suwa, Yuichiro Maekawa
Journal: Circulation (2023)

Background: Patients with hypertrophic cardiomyopathy (HCM) represents diverse symptoms, morphology, and cardiovascular events. Although myocardium metabolism in patients with HCM has been studied, it is not well elucidated. In this study, we assessed the association between biomarkers, heart failure-related findings, genetic mutations, and myocardium lipid metabolism in HCM patients using imaging mass spectrometry. Method: We prospectively enrolled patients with HCM in Hamamatsu University hospital from July 2020 to October 2022. All patients underwent endomyocardial biopsy and genetic analysis. Obtained myocardial specimens were analyzed using a desorption electrospray ionization source attached to a mass spectrometer. Differences among groups were statistically evaluated with the Fisher’s exact test and Mann-Whitney U test. Correlations between the two values were analyzed using Spearman’s correlation coefficient values. Results: A total of 31 Japanese patients were enrolled in this study. These patients included 18 (58.0%) women, and the mean age was 67.6 ± 10.6 years. Genetic analysis revealed that six (19.4%) patients had pathogenic or likely pathogenic variant. (Frequency of causal genes was as follows: MYBPC3 2 [6.5%], TNNI3 2 [6.5%], MYH7 1 [3.2%], and MYOZ2 1 [3.2%].) We divided the patients into two groups according to their median intensity of candidate molecule to reveal between group differences. The group of high lysophosphatidylethanolamine (LPE) showed lower N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (330.0 [147.0-614.0] pg/mL vs. 933.0 [699.5-2576.5] pg/mL, P = 0.001). A correlation was observed between the intensity of LPE and the NT-proBNP levels (r = -0.455, P = 0.012). There was no association between the presence of genetic mutations and New York Heart Association class and LPE intensity. Conclusion: HCM patients with the high intensity of LPE in myocardial tissue had relatively low NT-proBNP levels.
Abstract 14656: Virtual Cardiac Rehabilitation is Rarely Used but May Augment Overall Attendance
Authors: Whitney Fu, Hechuan Hou, Donald S Likosky, Jeffrey McCullough, Devraj Sukul, Steven J Keteyian, Chad Ellimoottil, Mike P Thompson
Journal: Circulation (2023)

Introduction: The COVID-19 public health emergency temporarily expanded Medicare reimbursement of cardiac rehabilitation (CR) to cover virtual CR. The purpose of this study was to evaluate the frequency of virtual CR use in Medicare and describe this emerging population of virtual CR patients, as there is currently limited data on the rates and patterns of virtual CR utilization. Methods: The study sample included 100% of Medicare beneficiaries undergoing surgical/percutaneous coronary revascularization or aortic valve replacement between July 2019 and December 2021 in the Medicare Virtual Research Data Center. Professional claims were used to identify CR use within one year of discharge using CPT codes (93797, 93798), and the disaster-related modifiers (“CR” or “DR”) were used to categorize CR visits as synchronized virtual sessions. Descriptive analysis compared patient characteristics and number of CR sessions attended between patients using virtual and facility-based CR. Results: Overall CR use was 32.5% in the entire sample (167066/513735). Any CR use was more prevalent among patients who were male, White, or 65-85 years old, and similar between coronary revascularization vs. aortic valve procedures. Only 14 states reported any virtual CR visits (CA, FL, GA, IL, IN, MI, MN, MO, NY, OR, PA, TN, TX, WI). Within these states, only 1% (886) of all CR users had at least one virtual CR session. The characteristics of patients who utilized virtual CR were largely similar to those who attended facility-based only CR. The median number of virtual sessions was 21 (IQR 26). Of patients who utilized virtual CR, 17.7% (157) also attended at least one facility-based CR session. Notably, combined virtual and facility-based CR utilizers attended a median of 33 (IQR 14) total CR sessions, compared to 25 (IQR 23) CR sessions for patients who attended only facility-based CR. Conclusion: Virtual CR was not widely available or used despite expanded Medicare reimbursement, yet our data suggests that the combined use of virtual and facility-based CR may be associated with a greater number of sessions attended (vs. facility-based only CR). Further research is needed to inform long-term policy decisions, particularly as it pertains to continued Medicare coverage of virtual CR.
A Biomimetic Upconversion Nanobait‐Based Near Infrared Light Guided Photodynamic Therapy Alleviates Alzheimer's Disease by Inhibiting β‐Amyloid Aggregation
Authors: Xu Wang, Wenjing Zhang, Lili Hou, Wei Geng, Jingwen Wang, Yu Kong, Chang Liu, Xianshun Zeng, Dexin Kong
Journal: Advanced Healthcare Materials (2023)

Aberrant β-amyloid (Aβ) fibrillation is the key event in Alzheimer's disease (AD), the inhibition and degradation of which are recognized as a promising therapeutic strategy to alleviate the nerve damage of AD. Photodynamic therapy (PDT) holds great potential for modulation of Aβ self-assembly, which is nevertheless limited by the inefficient utilization of reactive oxygen species (ROS). Herein, an erythrocyte membrane (EM)-modified core-shell upconversion nanoparticle (UCNP/Cur@EM) is designed and fabricated as a biomimetic nanobait to improve the PDT efficiency in AD. The UCNP with the outlayer of mesoporous silica is synthesized to load a high amount of the photosensitizer (curcumin), the unique optical feature of which can trigger curcumin to generate ROS upon near-infrared light (NIR) irradiation. Integration of EM enables the biomimetic nanobait to attract Aβ peptides trapped in the phospholipid bilayer, restraining the growth of Aβ monomers to form aggregates and improving the utilization rate of ROS to degrade the preformed Aβ aggregates. In vivo studies demonstrate that UCNP/Cur@EM irradiated by NIR enables to decrease Aβ deposits, ameliorates memory deficits, and rescues cognitive functions in the APP/PS1 transgenic mouse model. A biocompatible and controllable way is provided here to inhibit the amyloid protein-associated pathological process of AD.
Abstract 218: Effect of Airway Pressure and Localized Sternal Compression Upon Hemodynamics During Cardiopulmonary Resuscitation
Authors: Lyra Clark, Brian Harvey, Joshua W Lampe, George Beck, Karen L Moodie, Norman A Paradis
Journal: Circulation (2023)

Background: During cardiopulmonary resuscitation (CPR), chest compression (CC) and mechanical ventilation are cyclic in nature and each modulate the intrathoracic pressure (ITP). ITP is increased during the compression phase of CC, causing an increase in aortic pressure (AoP) and right atrial pressure (RAP) to drive forward blood flow. Similarly, positive pressure ventilation increases ITP during the inspiratory phase as pressure is transmitted through the lungs, which also has an impact on hemodynamics. The purpose of this analysis was to examine differences in hemodynamics during ventricular fibrillation (VF) arrest due to ventilation alone and during localized sternal CC of varying depths in a porcine model of cardiac arrest. Methods: Domestic swine (n = 8) underwent electrically induced VF with ten-minute downtime, followed by resuscitation with mechanical ventilation and CC with active lift to neutral chest position. Mechanical ventilation was delivered using pressure-controlled synchronized intermittent mandatory ventilation (SIMV) mode (Vt 10 mL/kg, 10 bpm, trigger -6 cmH 2 O, PEEP 5 cmH 2 O, FiO 2 100). CPR was initiated with three minutes of ventilation only, followed by one minute of break-in CC at 1.0 in and 1.5 in prior to increase to depth of 2.0 in. AoP, RAP, esophageal pressure (Pes), and airway pressure (Paw) were examined over the ventilation cycle to determine the effect of each treatment upon parameters. Results: Positive pressure ventilation caused similar changes to the Pes, RAP, and AoP values (3-5 mmHg). CC caused similar changes to Pes (3-5 mmHg), but much larger changes to the RAP and AoP (10-130 mmHg) depending on compression depth. Conclusions: The ITP is not uniform during CC, creating only modest changes to Pes. This suggests that CC generate blood pressures, and presumably flows, through mechanisms other than ITP modulation. Understanding this interaction could improve our understanding of blood flow during CPR.