tbuckley/cabot-search huggingface dataset:
Abstract 11001: Wnt/Planar Cell Polarity Pathway Mutations Are Over-Represented in Children with Concomitant Congenital Cardiac and Cleft Malformations
Authors: Omar Toubat, Naikhoba C Munabi, David W Craig, William Magee, Ram Kumar Subramanyan
Journal: Circulation (2021)

Introduction: We have demonstrated a high association between cleft lip and/or palate (CL/P) and outflow tract congenital heart disease (CHD) in the pediatric population. Despite this strong phenotypic association, the molecular genetics underlying these concomitant disease processes remains unclear. Hypothesis: Genomic profiling of concomitant outflow tract CHD+CL/P patients will unravel mutations in signaling pathways with overlapping importance in heart and palatal development. Methods: Patients with outflow tract CHD+CL/P and no previously known genetic syndromes or positive chromosomal microarrays at our institution between January 2004 and December 2018 were identified. Whole exome sequencing was performed on blood specimens collected from patients and phenotypically normal parents. Gene ontology and pathway analysis of de novo variants identified in probands was performed using PANTHER and DAVID databases and reinforced with a primary literature search. Functional assessment of non-canonical Wnt signaling variants was performed through siRNA-knockdown and wound-healing assays in murine myoblasts. Results: De novo loss-of-function mutations were observed in all 17 probands, in a total of 28 genes. Five genes (18%) have previously been implicated in both heart and palate development (CHD7, MED12, NDST1, GRHL2, SMARCA4). Three genes (11%) were mutated in more than one proband (CHD7, CELSR3, SAPCD2). Gene ontology and pathway analysis of deleterious de novo variants predicted involvement in binding (n=11, 39%), gene-specific transcription (n=9, 32%), and molecular and transcriptional function (n=8, 29%). The Wnt pathway (n=14, 50%) was the most strongly enriched signaling pathway, mutated in 10 (59%) probands, followed by Semaphorin and Endothelin signaling (n=2 variants, 7.1%, each). Knockdown of Wnt/PCP genes SAPCD2, CELSR3, and CCDC88C disrupted myoblast cellular migration in vitro, validating the functionality of these gene candidates. Conclusion: Our study is the first to characterize the genomic profile of patients with concomitant outflow tract CHD+CL/P. Excess de novo mutations in genes involved in Wnt pathway signaling suggests that this pathway plays a crucial role in CHD+CL/P disease pathogenesis.
SHP1 Loss Augments DLBCL Cellular Response to Ibrutinib: A Candidate Predictive Biomarker
Authors: Y. Lynn Wang, Ji Ma, Vinay Mallikarjuna, Pin Lu, Shengchun Wang, Sahar Poureghbali, Mariusz A Wasik, Reza Nejati, Wenjun Wu
Journal: Blood (2021)
Abstract 11656: Chagas Disease Reactivation After Heart Transplant in an Endemic Country
Authors: Lukas Salazar, Ramon Medina, Juan Felipe F Vasquez, John Ramirez, Mónica López, Maria J Rodriguez
Journal: Circulation (2021)

Introduction: Chagas disease (CD) is a common cause of advanced heart failure in Colombia and the third cause of heart transplant in our center. For transplanted patients the immunomodulatory therapy is crucial, but it makes them susceptible to CD reactivation. Fiorelli et al showed a frequency of reactivation of 40% based in histological diagnosis; also, Gray et al reported a frequency of 61% using quantitative PCR. The estimation of this phenomenon in our population is essential to improve its management. Methods: We performed a retrospective cohort study of patients with heart transplant due to chagasic cardiomyopathy. The primary outcome was the prevalence of CD reactivation. Secondary outcomes included the description of clinical manifestations, immunomodulatory therapies used and the time elapsed since the transplant until the reactivation. Reactivation was defined as a positive RT-PCR for T.cruzi after heart transplant or a compatible endomyocardial biopsy. The RT-PCR test was performed if clinical deterioration, ventricular disfunction, or either randomly according to physician criteria. Results: Fifteen patients were included in the analysis. The age at the moment of the transplant was 54 YO (IQR 43-56), 67% were men. CD reactivation was diagnosed in the 67% of patients (Figure 1a). The median of the time to CD reactivation after the transplant is 12 months (95%-CI:3,16-20,8) (Figure 1b). The mortality during follow-up was 0% and the longest follow-up time was 11 years.The most frequently used drugs in patients with reactivation were cyclosporine, tacrolimus and corticosteroids. All of the patients with reactivation received benznidazole. Conclusions: There is a high prevalence of CD reactivation in heart transplanted patients due to Chagasic cardiomyopathy, especially during the first year. Protocols for screening these condition are necessary for an adequate care of these patients. Cualitative RT-PCR test and myocardial biopsy should be considered.
Abstract P515: Dynamics Of Cardiomyocyte Differentiation In Isogenic Induced Pluripotent Stem Cells Derived From Trisomy21 Patients Hints Molecular Pathology Of Congenital Heart Defects In Down Syndrome
Authors: Malay Chaklader, Beverly A Rothermel
Journal: Circulation Research (2021)

Down syndrome (DS) is the most frequently occurring human chromosomal disorder and is responsible for a range of both congenital defects and progressive, degenerative conditions. For instance, an estimated 50% DS neonates are born with congenital heart defects (CHD) and more than 50% of DS adults develop early onset Alzheimer’s. Using induced pluripotent stem cells (iPSCs) derived from DS patients and isogenic controls we previously demonstrated the presence of a hyper-metabolic, hyper-fused mitochondrial network in trisomic iPSCs (3S-iPSCs) compared to disomic (2S-iPSCs) controls. Furthermore, mitochondrial function was normalized by siRNA depletion of RCAN1, an inhibitor of the protein phosphatase calcineurin (CN). Both CN signaling and mitochondrial metabolism have been implicated in a variety of steps during the progression from embryonic stem cells to cardiac progenitors, including self-renewal, exit from pluripotency, and commitment to cardiac verses hematopoietic lineages. Based on this, we hypothesized that the dynamics of many of these processes will be altered over the course of differentiation of 3S-iPSCs to cardiomyocytes when compared to 2S-iPSCs. Here, we investigate the temporal expression of pluripotency associated genes and lineage associated genes as well as cardiac mesoderm and mature cardiomyocyte specific genes. We also define and compare changes in CN activity, expression of specific CN isoforms, mitochondrial expansion, ROS generation, and activation of stress responses. Our study identifies early developmental and metabolic sequelae capable of contributing to CHD in DS that may result from a disruption in the normal balance in crosstalk between CN and RCAN1.
Quantitative analysis of submucosal excision depth in endoscopic resection for early Barrett’s cancer
Authors: Jenny Krause, Thomas Rösch, Stefan Steurer, Till Clauditz, Susanne Sehner, Udo Schumacher, Horst Neuhaus, Helmut Messmann, Brigitte Schumacher, Andreas Probst, Guido Schachschal, Hanno Ehlken, Michael Vieth, Rüdiger Schmitz
Journal: Endoscopy (2021)

BACKGROUND : Following endoscopic resection of early-stage Barrett's esophageal adenocarcinoma (BEA), further oncologic management then fundamentally relies upon the accurate assessment of histopathologic risk criteria, which requires there to be sufficient amounts of submucosal tissue in the resection specimens. METHODS : In 1685 digitized tissue sections from endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) performed for 76 early BEA cases from three experienced centers, the submucosal thickness was determined, using software developed in-house. Neoplastic lesions were manually annotated. RESULTS : No submucosa was seen in about a third of the entire resection area (mean 33.8 % [SD 17.2 %]), as well as underneath cancers (33.3 % [28.3 %]), with similar results for both resection methods and with respect to submucosal thickness. ESD results showed a greater variability between centers than EMR. In T1b cancers, a higher rate of submucosal defects tended to correlate with R1 resections. CONCLUSION : The absence of submucosa underneath about one third of the tissue of endoscopically resected BEAs should be improved. Results were more center-dependent for ESD than for EMR. Submucosal defects can potentially serve as a parameter for standardized reports.
Abstract 9358: Individualizing Cardiovascular Benefits of Canagliflozin Based on Multidimensional Computational Phenomaps of the CANVAS Trials
Authors: Evangelos K Oikonomou, Marc A Suchard, Darren K McGuire, Rohan Khera
Journal: Circulation (2021)

Introduction: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have well-documented cardioprotective effects in broad groups of patients with type 2 diabetes mellitus (T2DM) but are underused, in part due to high cost. Individualized prediction of the magnitude of cardiovascular risk reduction may allow more targeted use. Hypothesis: A machine learning decision support tool can predict ASCVD effect of canagliflozin therapy in T2DM based on each patient’s unique phenotypic profile. Methods: We constructed a topological representation of the Canagliflozin Cardiovascular Assessment Study (CANVAS) using 75 baseline variables collected from 4327 patients with T2DM randomly assigned to canagliflozin (n=2886) or placebo (n=1441). Within each patient’s 5% topological neighborhood, we calculated age- and sex-adjusted risk estimates for major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, stroke). An extreme gradient boosting algorithm was trained to predict the personalized MACE effect of canagliflozin using features consistently associated with benefit in topological analyses and was validated in the independent CANVAS-R trial (n=5808, randomized 1:1 to canagliflozin or placebo). Results: In CANVAS (mean age 60.9±8.1 years, 33.9% women) 1605 (37.1%) patients had a neighborhood hazard ratio lower (more protective) than the overall effect estimate of 0.86 for the primary composite outcome of time to MACE ( A ). A 15-variable tool, INSIGHT, was developed in CANVAS ( B ), and subsequently tested in CANVAS-R (mean age 62.4±8.4 years, 2164 (37.3%) women) where it identified patient phenotypes with higher MACE benefit of canagliflozin (adj. HR 0.60 [95% CI: 0.41-0.89] ( C ) versus 0.99 [95% CI: 0.76-1.29] ( D ); P-value for interaction=0.04). Conclusions: We present an evidence-based, machine learning-guided algorithm to personalize the prescription of SGLT2 inhibitors for cardiovascular benefit in patients with T2DM.
South Africa's Health: New South Africa's doctors: a state of flux
Authors: R. Kale
Journal: BMJ (1995)

Over 25 000 doctors are registered in South Africa, and they serve a population of about 40 million. The doctor to population ratio in South Africa is higher than that in countries like Mozambique, Nigeria, and Chile but lower than that in other countries like Brazil, Greece, and Britain (table 1). The number of doctors who are actually in practice is probably fewer because of emigration. The exact number of doctors who have left South Africa is not known. Dr David Green, director of Profession Development for the Medical Association of South Africa, said that doctors who leave the country continue to be members of the association and often provide another South African address, making it difficult for the association to know if they have left. Some data are available for the period before 1989.1 In 1986, the number of doctors registered with the South African Medical and Dental Council dropped from 20477 to 20229, largely because of migration, and in 1987, 72 family practitioners and 21 specialists migrated.

View this table:

TABLE I 
Doctors per 1000 population (1988–92)



White men dominate the profession, but this is changing. Data available for 1985 show that 94% of specialists and 83% of non-specialists were men, and that 88% of all doctors were white.1 The number of non-white students admitted to medical colleges has increased in the last few years. Professor J R van Dellen, dean of the faculty of medicine of the University of Natal, and Professor J P de V van Niekerk, dean of the University of Cape Town Medical School, provided data that show a definite increase in the numbers of non-white students admitted to their colleges (fig 1,2).



Fig 1 
Graduates from University of Natal Medical School, 1957-92





Fig 2 
New admissions, University of Cape Town Medical School, 1981-94



The distribution of doctors is skewed …
Abstract 10824: High Bleeding Risk is Associated with a Higher Prevalence of Severe Calcified Plaque in Patients Requiring Percutaneous Coronary Intervention
Authors: Takako Nagata, Yoshiyasu Minami, Yusuke Muramatsu, Takuya Nakata, Kiyoshi Asakura, Masahiro Katamine, Daisuke Kinoshita, Junya Ako
Journal: Circulation (2021)

Introduction: Optimal revascularization strategy and shorter duration of dual antiplatelet are required in patients with coronary artery disease concomitant with high bleeding risk (HBR). More complex percutaneous coronary intervention (PCI) and subsequent high thrombotic risk in patients with HBR have been also demonstrated. However, the characteristics of culprit plaque in patients with HBR remains to be elucidated. Hypothesis: HBR is associated with more complex plaque in culprit lesion in patients requiring PCI. Methods: A total of 362 consecutive patients with stable coronary disease, who underwent optical coherence tomography (OCT) imaging of the culprit lesion during PCI were included. The characteristics of culprit plaque assessed by OCT were compared between the HBR group (n=196) and the non-HBR group (n=166), which were classified based on the Academic Research Consortium for High Bleeding Risk (ARC-HBR). Results: The prevalence of severe calcified plaque (angle &gt;180 degee, thickness &gt;0.5mm and length &gt;5mm) was significantly higher in the higher HBR group than in the non-HBR group (48 vs. 35%, p =0.016), although other characteristics were comparable (Panel A). Among patients with HBR, the incremental prevalence of severe calcified plaque according to the number of major ARC-HBR criteria met was observed ( p &lt;0.001) (Panel B). Conclusions: HBR was associated with a higher prevalence of severe calcified plaque in culprit lesion in patients with stable coronary disease requiring PCI. The greater number of major ARC-HBR criteria met was associated with a higher prevalence of severe calcified plaque among patients with HBR.
Abstract 10425: Epigenetic Regulation of Notch Signaling by Prenatal Alcohol Exposure Impacts Cardiac Outflow Tract Defect Development
Authors: Drayton C Harvey, Prashan De Zoysa, Omar Toubat, Ram Kumar Subramanyan
Journal: Circulation (2021)

Introduction: Prenatal alcohol exposure (PAE) leads to congenital heart defects (CHD) with incomplete penetrance and phenotypic heterogeneity. We have demonstrated a gene-environment interaction in this context wherein acute PAE synergizes with second heart field (SHF) haploinsufficiency of Notch signaling, resulting in highly penetrant outflow tract (OFT) defects. Hypothesis: We hypothesize that acute PAE-induced hyperacetylation at histone marker 3 lysine residue 9 (aH3K9) epigenetically inhibits Notch signaling. This potentiates the impact of a pre-existing genetic defect that results in partial loss of Notch signaling leading to loss of viability of SHF progenitors necessary for OFT elongation and alignment. Methods: We studied the effects of acute PAE in vivo in our murine model (two injections of 3g/kg 30% ethanol on E6.5) on acetylation, SHF viability, OFT length, and Notch intracellular domain (NICD) localization. Complimentarily, we evaluated alcohol exposure in vitro using our established thoracic organ culture model. Acetylation was reversed using pan-histone acetyltransferase inhibitor anacardic acid. Results: At E9.5, acute PAE resulted in a significant increase in H3K9 acetylation in SHF associated with restriction of NICD to the cell membrane. This resulted in a 0.28-fold reduction in Notch signaling, as evidenced by reduced Notch reporter expression, and 0.52-fold reduction in SHF cell proliferation (both p&lt;0.001). Loss of SHF progenitors needed for incorporation into the developing OFT reduced OFT length 26% (p&lt;0.001). In vitro thoracic organ culture analyses recapitulated increased acetylation, NICD restriction to cell membrane and reduced SHF proliferation by 60% (p&lt;0.001). Anacardic acid reversed the increase of aH3K9 and allowed NICD nuclear translocation. Notch signaling and SHF proliferation returned to baseline. Conclusions: Acute PAE induces hyperacetylation in the SHF and inhibits Notch signaling by restricting NICD translocation. Lack of Notch signaling reduces SHF viability and prevents elongation of the developing OFT. This hereto unexplored impact of alcohol on the Notch pathway provides a novel area of investigation regarding gene-environment interaction in alcohol teratogenesis.
Abstract 12534: Incidence of Cardiotoxicity After Immune Checkpoint Inhibitor Therapy
Authors: Danette Flint, Javid Moslehi, Stephen Kearing, Ashleigh King, Lauren Gilstrap
Journal: Circulation (2021)

Introduction: Immune checkpoint inhibitors (ICI) have transformed care for cancer patients but can lead to immune-mediated toxicities in multiple organ systems. Cardiovascular toxicities are thought to be infrequent, but existing data likely underestimate this. We utilized Medicare claims data to define the incidence of cardiotoxicity after ICI therapy at a population level. Methods: We identified all fee-for-service beneficiaries who received an ICI, including CTLA-4 inhibitors, PD-1 inhibitors or PD-L1 inhibitors, between March 2011 through December 2018 using 100% Medicare Parts A and B. Demographic information, preexisting cardiac conditions, other comorbidities and cancer types were determined in the year prior to ICI exposure. Cardiac toxicities were identified using ICD-9/10 codes in the year after initial exposure. Results: In total, 40,676 patients were identified. Most (75%) received a PD-1 inhibitor and a significant minority (10%) received combination therapy. Across all ICI therapies, the incidence of myocarditis and related complications (ventricular arrhythmia, sudden cardiac death, heart block and cardiogenic shock) was 2.95% at one year. The incidence of acute decompensated heart failure was 10.76%, acute coronary syndrome 3.06% and death 1.92%. The highest incidence of myocarditis and associated cardiac diagnoses was seen with combination therapy (3.56%). Conclusions: Immune checkpoint inhibitors are associated with myocarditis and other serious cardiac toxicities. Results from our population level study suggest the incidence of cardiotoxicity after ICI exposure is likely higher than previously reported. The incidence of myocarditis and related complications is highest with combination therapy, as reported in prior studies.
PATH-21. THE SINGLE-CELL PATHOLOGY LANDSCAPE OF PEDIATRIC GLIOMA
Authors: Julie Messiaen, Pouya Nasari, Yannick Van Herck, Ben Verhaaren, Ivey Sebastian, Giorgia Milli, francesca Bosisio, Jon Pey, Steven De Vleeschouwer, Philippe De Vloo, Bart Depreitere, Isabelle Vanden Bempt, Raf Sciot, Asier Antoranz, Sandra Jacobs, Frederik De Smet
Journal: Neuro-Oncology (2021)

Abstract High-grade glioma are the main cause of cancer-related death in children. Despite extensive research, their prognosis remains poor with very few treatment options. This can be attributed to the highly heterogeneous and plastic nature of glioma tumor cells and their interactions with the microenvironment, although quantitative data are still largely missing. Here, we used high-dimensional, multiplexed immunohistochemistry to map the spatial, single-cell tissue architecture of 31 pediatric glioma samples covering 9 histologic diagnoses. This novel approach allowed us to map the spatial distribution of the various tumoral subtypes, which typically occur in specific tumoral niches, and how these interact with their local immune-microenvironment. Finally, by aligning these findings to the clinical data of the patients and comparing these to adult glioblastoma, we are now able to more precisely describe the heterogeneous landscape of pediatric glioma at single-cell resolution.
Abstract 10378: A Novel Selectively Flexible Mitral Annuloplasty Ring Designed Based on Human Imaging with Superior Performance in Hemodynamics, Biomechanics, and Annular Dynamics - A Comprehensive Bench to in vivo Large Animal Analysis
Authors: Yuanjia Zhu, Annabel M Imbrie-moore, Matthew H Park, Tyler E Cork, Robert J Wilkerson, Nicholas Tran, Mateo Marin-Cuartas, Sam Baker, Yuko Tada, Danielle Mullis, Vicky Wang, Sidarth V Ethiraj, Sarah Madira, Shreya Anilkumar, Haley Lucian, Kimberly Morris, Jack Mulligan, Ok Kim, Yasuhiro Shudo, Daniel Ennis, Y J Woo
Journal: Circulation (2021)

Introduction: We designed a novel mitral annuloplasty ring based on healthy human imaging to allow for the mitral valve (MV) annular conformational changes while restricting the anteroposterior (AP) distance. The objectives were to evaluate ex vivo biomechanics of the novel ring and to validate the annular dynamics after ring implantation in vivo. Methods: Cardiac MRI exams were obtained for 3 healthy volunteers. The MV annulus was tracked (Fig. A-C). Based the imaging data, a novel ring was manufactured (Fig. D-F). An ex vivo annular dilation model of mitral regurgitation was used in a left heart simulator (Fig. G, H) to measure hemodynamics and chordal forces at dilated baseline and after repair using the novel, rigid, and flexible rings in 5 porcine MVs. Novel (n = 6) or rigid rings (n = 5) were implanted into male Dorset sheep. Pre- and post-operative cardiac MRI exams were analyzed. Results: Repair using the novel, rigid, and flexible ring reduced regurgitation fraction from 30.0 ± 5.8% at dilated baseline to 4.7 ± 2.7%, 2.4 ± 3.2%, and 17.8 ± 10.0% ( p &lt; .0001, Fig. I-N ). Peak forces on the primary chordae decreased after ring annuloplasty repair ( p &lt; .0001, Fig. O ). The novel ring also showed lower peak forces compared to the rigid ring (p = .03) in secondary chordae ( Fig. P ). MV annular motion was preserved in vivo using the novel ring but restricted to a planar geometry using the rigid ring ( Fig. Q-S ). Annular height to intercommissure ratio at midsystole were similar pre-repair (0.2 ± 0.1) and after novel ring repair (0.2 ± 0.0, p = .89). The variance of AP distance during the cardiac cycle was similar between the novel (0.4 ± 0.3) and rigid ring (0.5 ± 0.1, p = .58). Conclusions: This novel mitral annuloplasty ring demonstrated excellent capability in reducing AP dimension and repairing regurgitation with a superior chordal force profile while facilitating the annular flexible motion. Future studies will focus on evaluating repair durability and effect on left ventricular remodeling.