tbuckley/cabot-search huggingface dataset:
Abstract 10460: Urinary Fatty Acid Binding Protein 1 is a Biomarker for Impaired Proximal Tubular Protein Reabsorption and is Synergistically Enhanced by Concurrent Liver Injury
Authors: Ryo Kawakami, Miki Matsui, Ayumu Konno, Ryosuke Kaneko, Hiroaki Sunaga, Hirofumi Hanaoka, Masaru Obokata, Hiroki Matsui, Norimichi Koitabashi, Hirokazu Hirai, Masahiko Kurabayashi, Tatsuya Iso
Journal: Circulation (2021)

Introduction: Urinary fatty acid binding protein 1 (FABP1, also known as liver-type FABP) has been implicated as a biomarker of acute kidney injury (AKI) in humans. However, the precise biological mechanisms underlying its elevation remain elusive. Here, we show that urinary FABP1 primarily reflects impaired protein reabsorption in proximal tubule epithelial cells (PTECs). Methods and Results: Bilateral nephrectomy resulted in a marked increase in serum FABP1 levels, suggesting that the kidney is an essential organ for removing serum FABP1. Injected recombinant FABP1 was filtered through the glomeruli and robustly reabsorbed via the apical membrane of PTECs. Urinary FABP1 was significantly elevated in mice devoid of megalin, a giant endocytic receptor for protein reabsorption. Elevation of urinary FABP1 was also observed in patients with Dent disease, a rare genetic disease characterized by defective megalin function in PTECs. Urinary FABP1 levels were exponentially increased following acetaminophen overdose, with both nephrotoxicity and hepatotoxicity observed. FABP1-deficient mice with liver-specific overexpression of FABP1 showed a massive increase in urinary FABP1 levels upon acetaminophen injection, indicating that urinary FABP1 is liver-derived. Lastly, we employed transgenic mice expressing diphtheria toxin receptor (DT-R) either in a hepatocyte- or PTEC-specific manner, or both. Upon diphtheria toxin (DT) administration, massive excretion of urinary FABP1 was induced in mice with both kidney and liver injury, while mice with either injury type showed marginal excretion. Conclusions: Collectively, our data demonstrated that intact PTECs have a considerable capacity to reabsorb liver-derived FABP1 through a megalin-mediated mechanism. Thus, urinary FABP1, which is synergistically enhanced by concurrent liver injury, is a biomarker for impaired protein reabsorption in AKI. These findings address the use of urinary FABP1 as a biomarker of histologically injured PTECs that secrete FABP1 into primary urine, and suggest the use of this biomarker to simultaneously monitor impaired tubular reabsorption and liver function.
Application of antibody-conjugated small intestine submucosa to capture urine-derived stem cells for bladder repair in a rabbit model
Authors: Yu-Ting Song, Yan-Qing Li, Mao-Xuan Tian, Jun-Gen Hu, Xiu-Ru Zhang, Peng-Cheng Liu, Xiu-Zhen Zhang, Qing-Yi Zhang, Li Zhou, Long-Mei Zhao, Jesse Li-Ling, Hui-Qi Xie
Journal: Bioactive Materials (2021)

The need for bladder reconstruction and side effects of cystoplasty have spawned the demand for the development of alternative material substitutes. Biomaterials such as submucosa of small intestine (SIS) have been widely used as patches for bladder repair, but the outcomes are not fully satisfactory. To capture stem cells in situ has been considered as a promising strategy to speed up the process of re-cellularization and functionalization. In this study, we have developed an anti-CD29 antibody-conjugated SIS scaffold (AC-SIS) which is capable of specifically capturing urine-derived stem cells (USCs) in situ for tissue repair and regeneration. The scaffold has exhibited effective capture capacity and sound biocompatibility. In vivo experiment proved that the AC-SIS scaffold could promote rapid endothelium healing and smooth muscle regeneration. The endogenous stem cell capturing scaffolds has thereby provided a new revenue for developing effective and safer bladder patches.
US State-Level Legal Interventions Related to COVID-19 Vaccine Mandates
Authors: Breanna Fernandes, Mark Christopher Navin, Dorit Rubinstein Reiss, Saad B. Omer, Katie Attwell
Journal: JAMA (2021)

Mandates can increase vaccine uptake, 1 but their effectiveness is associated with who is covered, penalties, and exemptions. 2 The US federal government recently required federal employees to be vaccinated against SARS-CoV-2 and developed standards for large employers. 3However, individual states traditionally take the lead in regulating public health via vaccine mandates. 4Some states have attempted to introduce requirements to increase uptake of COVID-19 vaccines. 5However, others have attempted to impede COVID-19 vaccine mandates.Most efforts have been considered by legislatures; also, some governors and regulatory agencies have issued executive orders.We assessed state-level legal interventions to promote or impede COVID-19 vaccine mandates since the beginning of the pandemic.
Abstract 11378: Reference Intervals of Activated Clotting Time in Pediatric Patients Undergoing Cardiac Surgery
Authors: Arhamatoulaye Maiga, Julie Tremblay, Benoit Lamoureux-Asselin, Carine Nyalendo, Baruch Toledano, Nancy C Poirier, Georges-Étienne Rivard, Arnaud Bonnefoy
Journal: Circulation (2021)

Introduction: Monitoring the anticoagulant effect of heparin is critical to prevent thrombosis and/or bleeding during cardiac surgery. This evaluation is usually performed by assessing the activated clotting time (ACT) with a POC device. Despite the relevance and widespread use of ACT, there are currently limited reference values to use as a target. Furthermore, compared to the adult population, infants have been described with a longer ACT, reinforcing the need to establish a separate reference interval for this segment of the population. Aim: The present work aims to propose reference intervals of ACT in pediatric patients. Methods: We collected data on 155 consecutive patients, ranging in age from 1 day to 18 years, undergoing cardiac surgery from 01-2019 to 01-2021 at Sainte-Justine hospital. Prior to surgery, patients were given UFH as a bolus of 3 mg/kg, and Hemochron Signature Elite ACT+ (Accriva Diagnostics, Inc.) was used to measure ACT before and promptly after heparin injection. Data were subsequently analyzed by using a parametric method. Lower and upper reference limits are the values at the 2.5 and 97.5 percentile, respectively. Results: The ACT before heparin injection followed a normal distribution with a lower reference limit at 85 seconds and an upper limit at 147 seconds compared to the range of 70-120 seconds proposed for the general population. Interestingly, the ACT after heparin bolus exhibited a non-gaussian distribution. Since neonates have been previously described with a greater heparin resistance compared to older infants; patients were separated into two age groups: patients &lt; 1-month of age (Group A; n=31) and patients &gt; 1-month (group B; n=124). Afterward, we performed a log transformation of the ACT values after heparin injection to approximate a Gaussian distribution, yielding mean ACT value of 392 seconds (limits 291-529 seconds) for Group A and 473 seconds (limits 314-996 seconds) for Group B (Welch test p value = 4.4 10 -6 ). No significant difference in ACT values prior to heparin bolus was found between the two groups. Conclusion: Overall, our results provide reference values of ACT measured using an Hemochron device, in a pediatric context, paving the way for improved patient care during cardiac surgery.
The extracellular matrix of hematopoietic stem cell niches
Authors: Cornelia Lee-Thedieck, Peter Schertl, Gerd Klein
Journal: Advanced Drug Delivery Reviews (2021)

Hematopoietic stem cells (HSCs) are the life-long source of all types of blood cells. Their function is controlled by their direct microenvironment, the HSC niche in the bone marrow. Although the importance of the extracellular matrix (ECM) in the niche by orchestrating niche architecture and cellular function is widely acknowledged, it is still underexplored. In this review, we provide a comprehensive overview of the ECM in HSC niches. For this purpose, we first briefly outline HSC niche biology and then review the role of the different classes of ECM molecules in the niche one by one and how they are perceived by cells. Matrix remodeling and the emerging importance of biophysics in HSC niche function are discussed. Finally, the application of the current knowledge of ECM in the niche in form of artificial HSC niches for HSC expansion or targeted differentiation as well as drug testing is reviewed.
CBIO-26. A NEW MODEL OF THE GABP-TERT REGULATORY AXIS IN MAINTAINING IMMORTALITY OF TERT PROMOTER MUTANT TUMOR CELLS
Authors: Nicholas Stevers, Carter Barger, Olivia Lenzo, Chibo Hong, Andrew McKinney, Joseph Costello
Journal: Neuro-Oncology (2021)

Abstract Tumor cell immortality is a fundamental hallmark of human cancers. Normally silenced during somatic cell differentiation, 90% of human tumors reactivate Telomerase Reverse Transcriptase (TERT) expression to achieve cellular immortality. TERT, the catalytic subunit of telomerase, complexes with the RNA template molecule TERC to maintain telomeres. Mutations in the TERT promoter (TERTp) are the most common non-coding mutation across all cancer types and the most frequent mutation within many cancers, such as IDH wildtype glioblastoma (GBM), Melanoma, and Bladder Cancer. TERTp mutations generate de novo E26 Transformation Specific (ETS) binding motifs that are spaced full helical turns from TERTp native ETS sites. Together the de novo and native ETS motifs specifically recruit the GABP tetrameric complex but not the GABP dimer. CRISPR-cas9 mediated insertion/deletion mutagenesis of the unique exon of GABP tetramer forming subunit, GABPB1L (B1L), reduces TERT transcriptional activity in a TERT promoter-mutation dependent manner. Here we show that GABPB1S (B1S), the GABP dimer restricted alternative isoform of GABPB1, is consistently and significantly increased following B1L reduction, a process we have determined to be driven by a conserved homeostatic mechanism whereby the GABP tetramer suppresses expression of one of its own components, GABPB1. In contrast to the native setting, in the absence of B1L the elevated B1S expression leads to dimer binding to the mutant TERTp and maintenance of TERT expression. Indeed, co-targeting B1L and B1S together, but not B1L alone, via CRISPR-cas9 knockout resulted in a near complete elimination of GABP recruitment to the TERTp and TERT expression, and lead to tumor cell death and eventual senescence in a telomere length dependent manner. Together, this data suggests a new model of the TERT-GABP axis involving the tetramer and dimer and highlights a new and potentially more potent therapeutic strategy to eliminate TERT expression and reverse tumor cell immortality.
Abstract 12376: Coronary Artery Bypass Graft Surgery in Spontaneous Coronary Artery Dissection
Authors: Angie S Lobo, Sharonne Hayes, Patricia J Best, Rajiv Gulati, Marysia Tweet
Journal: Circulation (2021)

Introduction: Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic cause of acute coronary syndrome. While most patients are managed conservatively, some patients may require percutaneous or surgical revascularization. Limited data exist on SCAD patients referred for coronary artery bypass graft (CABG) surgery. Hypothesis: Examine the clinical characteristics, management, and outcomes of SCAD patients referred for CABG. Methods: Retrospective study of patients enrolled in the Mayo Clinic SCAD Registry between 2010-2020 who underwent CABG during the initial management of acute SCAD episode. Results: Among the 81 patients with SCAD referred for CABG, 3 (4%) were men, mean age was 40.6 +/- 8.4 years; the majority were white (91%), and 24 (30%) had pregnancy-associated SCAD (P-SCAD). The most common presenting symptom was chest pain 80 (99%); 57 (70%) presented with ST elevation myocardial infarction (STEMI), and 21 (26%) presented with non-ST elevation MI. Multivessel dissection occurred in 40 (49%), left anterior descending artery (LAD) involvement occurred in 66 (81%) and left main (LM) in 32 (40%). Left ventricular ejection fraction was &lt;50% in 40 patients (49%) at time of initial SCAD. The most common reasons for CABG were the presence of high-risk anatomy (56%), hemodynamic instability/active ischemia (7%), failed PCI (9%), and other/unknown (12%). Most patients received venous plus arterial bypass grafts 42 (52%), saphenous vein grafts in 20 (25%), and left internal mammary artery in 17 (21%). Screening for underlying arteriopathy was performed in 50 (62%) of whom 29 (36%) had fibromuscular dysplasia. Recurrent SCAD occurred in 10 (12%) after an average of 6.2 +/- 5 years after initial SCAD. Of those with recurrent SCAD, none required repeat surgical revascularization and 6 required percutaneous intervention (PCI). There were no deaths. Conclusions: Patients undergoing CABG for SCAD commonly present with STEMI, LM, or multivessel dissection, and failed percutaneous intervention attempts. In addition, CABG for P-SCAD was more frequent than expected and may relate to the increased prevalence of multivessel dissection. CABG was associated with low mortality, but recurrent SCAD may still occur.
Unexplained metabolic acidosis
Authors: James McCaffrey, Kieren Allinson
Journal: BMJ (2021)

A man in his 20s was found to be unresponsive after experiencing headache and vomiting for two days. His medical history included depression, paracetamol (acetaminophen) overdose on several occasions, and an episode of unexplained encephalopathy five months earlier. He experienced two generalised tonic-clonic seizures during initial assessment in the emergency department. Clinical examination revealed a Glasgow coma scale score of 3/15, with global hypotonia, areflexia, and size 6 pupils that were unresponsive to light.

A systematic ABCDE approach was taken, with a focus on securing the airway because of the patient’s decreased level of consciousness.1

Arterial blood gas test results showed a metabolic acidosis with raised levels of lactate. Table 1 summarises the patient’s laboratory test results on presentation to the emergency department.

View this table:

Table 1 
Laboratory test results on presentation to emergency department



The patient was intubated and transferred to the intensive care unit.

1 What laboratory investigations are required for patients with metabolic acidosis?

2 What do the laboratory test results in table 1 show?

3 What are the differential diagnoses in this case?

1 What laboratory investigations are required for patients with metabolic acidosis?

When patients present with metabolic acidosis,123 perform …
RADT-16. CLINICAL CHARACTERISTICS AND PROGNOSIS OF ADULT BRAIN STEM GLIOMA: A SINGLE-CENTER 10-YEAR RETROSPECTIVE STUDY OF 81 PATIENTS
Authors: Jiangfen Zhou, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE Adult brain stem glioma (ABSG) is a subset of brain tumor with a low incidence rate. This study reviewed the clinical characteristics and the risk factors affecting the prognosis of ABSG in a single center and explored the proper therapeutic mode for ABSG. METHODS The clinical data of adult patients (age over 18 years old) with brain stem gliomas from January 2010 to January 2021 of Guangdong Sanjiu brain hospital were retrospectively analyzed. Overall survival (OS) were determined by the Kaplan-Meier method, and Log-rank test was used for univariate analysis, COX proportion hazards regression was used for multivariate analysis. P &amp;lt; 0.05 was considered to be statistically significant. RESULTS Eighty-one ABSGs, including 46 males and 35 females, were analyzed. The median age of patients was 37 years (range, 19 to 67), and the median follow-up time was 17 months (range, 3 to 108) . The median OS of 81 patients was 18 months, and the OS for 1, 2, 3, and 5 years was 87.4%, 75.8%, 61.0%, and 36.5%, respectively. Univariate analysis demonstrated that the lesions enhancement on MRI, the WHO classifications, the expression status of H3K27M, radiotherapy status, and the status of adjuvant chemotherapy were related to prognosis. Multivariate Cox regression analysis revealed that age, the WHO classifications, radiotherapy status, and the maintenance chemotherapy followed radiotherapy were independent predictors for OS. CONCLUSIONS Radiotherapy is still the main treatment of ABSGs, and patients can be benefit from maintenance chemotherapy followed radiotherapy. The age &amp;gt; 40 years and WHO IV grade were two independent unfavorable prognostic factors. Research with expanded patient volume would help to further explore the influence of H3K27M expression on ABSG prognosis.
Clinical Outcomes of Patients with Newly Diagnosed Myelodysplastic Syndrome with <i>MLL</i> Aberrations
Authors: Maria Siddiqui, Ghayas C. Issa, Koji Sasaki, Guillermo Montalban-Bravo, Kelly S. Chien, Elias J. Jabbour, Carlos E. Bueso-Ramos, Rashmi Kanagal-Shamanna, Hagop Kantarjian, Guillermo Garcia-Manero
Journal: Blood (2021)
Abstract 13225: In vivo Sino-Atrial Node Mapping in Children and Adults With Congenital Heart Disease
Authors: Mathijs S van Schie, Rohit Kharbanda, Nawin Ramdat Misier, Fons J Wesselius, Yannick J Taverne, Ad Bogers, Natasja M de Groot
Journal: Circulation (2021)

Introduction: Sinus node dysfunction (SND) is a common sequel in patients with congenital heart disease (CHD) and encompasses disturbances in sino-atrial node (SAN) impulse generation and/or its propagation from SAN exit sites towards the atrial myocardium. At present, the underlying pathophysiological mechanisms of SND in patients with CHD are incompletely understood. Therefore, we performed epicardial mapping of SAN activity in pediatric and adult patients with CHD undergoing primary surgical correction. Methods: Intra-operative epicardial mapping (interelectrode distance 2 mm) of the right atrium (RA) was performed during SR in 12 pediatric patients (0.6 [0.4-2.4] years) and 15 adults (46±14 years) to compare potential characteristics of SAN activation. Results: In all pediatrics, SAN activity was solely observed near the junction of the superior caval vein and RA, while SAN activity in adults was observed even up to the middle part of the RA. Within a radius of 8 mm from the SAN exit site, more conduction disorders (11 [8-13] % vs 6 [5-8] %, p=0.011) were seen in adults compared to pediatric patients, while there was no difference in conduction velocity (71 [64-75] cm/s vs 67 [62-75] cm/s, p=0.258). However, within 2 mm of the SAN exit site conduction was significantly slower in adult patients (47 [30-56] cm/s vs 25 [9-50] cm/s, p=0.010). Potential morphology recorded from pediatric patients consisted of a broad monophasic S-wave with high amplitude (4.9 [3.4-6.0] mV) and an R/S ratio close to 1 (0.98 [0.96-1.00]), while the potentials in adults contained smaller S-wave amplitudes (2.6 [1.9-4.2] mV, p=0.014), larger R-wave amplitudes (0.2 [0.1-0.5] mV, p=0.036) and smaller R/S ratio (0.92 [0.87-0.96], p&lt;0.001). In adults, potential duration was substantially longer (45 [37-50] ms vs 66 [60-70] ms, p&lt;0.001) and was more often fractionated. Conclusions: For the first time we characterized electrophysiological properties of SAN activation in pediatric and adult patients with CHD. Solely in adults, SAN activation was observed at the middle part of the RA, which may indicate changes in preferential SAN exit site. These novel insights into SAN activation in patients with CHD may partly explain why this population is prone to develop SND relatively early in life.
Abstract 13581: Heart Rhythm versus Heart Rate Control Strategy in Patients With Pre-Capillary Pulmonary Hypertension and Atrial Arrhythmias
Authors: Mark Anthony Sammut, Robin Condliffe, Abdul Hameed, Alex M Rothman, Andreas Kyriacou, Robert A Lewis, Charlotte Durrington, Charlie A Elliot, Alfred A Thompson, Ian Sabroe, David G Kiely, Athanasios Charalampopoulos
Journal: Circulation (2021)

Introduction: Atrial tachyarrhythmias in patients with pre-capillary pulmonary hypertension are often poorly tolerated leading to increased morbidity and mortality. Sinus rhythm restoration seems to improve outcomes but a direct comparison between rate and rhythm control has not been investigated. We sought to determine any difference in effectiveness between the two strategies. Methods: We performed a retrospective study in 88 patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) and new-onset atrial flutter or fibrillation seen in our centre from 2005-2020. Patients were divided into 3 groups based on management strategy: rate control (n=20), rhythm control with medication only (n=24) and rhythm control with DC cardioversion (DCCV) and medication (n=44) (Table 1). Differences in WHO functional class and incremental shuttle walk test distance (ISWTD) at arrhythmia onset and after treatment were measured. Results: Sinus rhythm was successfully restored in 42/44 (95%) of patients treated with DCCV and medication compared to 13/24 (54%) treated with amiodarone only (p&lt;0.001). Cardioverted patients reported a significant improvement in functional class compared to patients treated with rate control (p&lt;0.001). A similar improvement in ISWTD (≥15%) was also reported (p=0.004) (Table 2). No serious complications were reported with either strategy. Conclusions: A rhythm control strategy including DCCV and medication is a safe and effective way to restore sinus rhythm in patients with PAH/CTEPH and atrial tachyarrhythmias. Restoration and maintenance of sinus rhythm led to an improvement in their functional status.
Abstract 6949: Particulate Matter Increases Inflammation and Impairs Electrical Activity in IPSC-Derived Cardiac Organoids
Authors: Mariana A Argenziano, Maliheh Najari Beidokhti, jiajia yang, Mariana Burgos Angulo, Nadia Orona, Alexander Bertalovitz, Thomas V McDonald
Journal: Circulation (2021)

Introduction: Exposure to particulate matter (PM) is associated with increased heart failure (HF) hospitalizations and death. Animal models to study PM-related cardiovascular disease (CVD) are complicated by effects on multiple organs and differing physiology from humans. A recent alternative is the generation of patient-specific induced pluripotent stem cells (IPSCs) to study interactions between the patient’s genome and environmental factors. Given that the heart relies on a network of cells that participate in the development of CVD, we propose a cardiac organoid (hCO) model to study the effects of PM 2.5 . Hypothesis: We hypothesize that air pollution exposure causes heart remodeling, which exacerbates HF. Methods: IPSCs were differentiated to cardiomyocytes (iCMs), cardiac fibroblasts (iCFs), endothelial cells (iECs) and macrophages (iMø). Cell suspensions containing 50% iCMs and 50% nonmyocyte (4:2:1 ratio of iECs:iCFs:iMø) were mixed and seeded in agarose microwells. Beating hCOs were cultured for 5 days before exposure to 100μg/ml of PM 2.5 for 48h. Immunostaining, qPCR, and Multielectrode Array (MEA) were performed in control (CT) and PM-treated hCOs (PM) (n=10 hCO/ group). Results: Treatment with PM caused loss of hCO circularity (CT:0.86±0.02 vs. PM:0.56±0.08, p&lt;0.05, n=5), changes in the beat amplitude, and more frequent premature extrasystoles. Gene expression analysis showed downregulation of SCN5A and upregulation of TNNT2 and GJA1 . Upregulation of inflammatory markers such as IL6 , IL1b , CD80 , and TNFa was also observed in PM-treated hCOs. Moreover, PM caused upregulation of MMP1 , CCL2 , CASP3 , SOD1 , and SOD2 . MEA experiments revealed a longer FPD duration and a decrease in spike slope and beating period along with shortening of the action potential (APD90: CT 577±20ms vs. PM 489±16ms, p&lt;0.05, n=10) and higher beat period irregularity (CT 3.2±0.7% vs. PM 13.1±1.6%, p&lt;0.001, n=10). Conclusions: We conclude that PM plays a direct role in the development of CVD, increasing inflammation, apoptosis, oxidative stress, and affecting the electrophysiology of the heart. Further studies in hCOs from HF patients will provide evidence of the effects of PM on the phenotype of the disease.