tbuckley/cabot-search huggingface dataset:
Assessing the prognostic utility of smoldering multiple myeloma risk stratification scores applied serially post diagnosis
Authors: Alissa Visram, S. Vincent Rajkumar, Prashant Kapoor, Angela Dispenzieri, Martha Q. Lacy, Morie A. Gertz, Francis K. Buadi, Suzanne R. Hayman, David Dingli, Taxiarchis Kourelis, Wilson Gonsalves, Rahma Warsame, Eli Muchtar, Nelson Leung, Linda B. Baughn, Robert A. Kyle, Shaji Kumar
Journal: Blood Cancer Journal (2021)

Abstract The Mayo-2018 smoldering multiple myeloma (SMM) risk score is used routinely in the clinical setting but has only been validated at diagnosis. In SMM patients, the progression risk decreases over time. However, the utility of applying risk stratification models after diagnosis is unknown. We retrospectively studied 704 SMM patients and applied the Mayo 2018 and IMWG-2020 risk stratification models at annual landmark timepoints up to 5 years post diagnosis. The Mayo-2018 and IMWG-2020 models reliably stratified patients based on progression risk when applied post diagnosis. The respective 2-year progression risk in Mayo-2018 high risk patients versus IMWG-2020 intermediate-high risk patients was 51% versus 62% at the 1-year landmark and 47% versus 45% at the 4-year landmark. We showed that patients categorized at Mayo-2018 high-risk at follow-up had a similar risk of progression if the baseline risk assessment was low-intermediate versus high-risk (HR 1.04, 95% CI 0.46–2.36, p = 0.931 at 5-year landmark). Patients migrating to a higher risk category during follow up had a higher progression risk compared to patients with stable/decreased risk categorization. Our findings support the use of these risk scores post-diagnosis and suggest that patients evolving to a high-risk category may benefit from early intervention therapeutic approaches.
Abstract 14465: Sex Has an Effect on the Relationship Between Intracoronary Acetylcholine and Coronary Blood Flow
Authors: Ali Ahmad, Takumi Toya, Michel Corban, Ilke Ozcan, Jaskanwal D Sara, Lilach Lerman, Amir Lerman
Journal: Circulation (2021)

Introduction: The endothelium controls coronary blood flow (CBF) by regulating microvascular tone, which is an important index of microcirculatory health. The difference in vasomotor response of the microvasculature between males and females is not well described. Hypothesis: Males and females react differently to different doses of intracoronary (IC) acetylcholine (Ach) injections. Methods: Patients with angina and non-obstructive coronary artery disease (&lt;50% stenosis) that underwent coronary reactivity study were enrolled. A doppler wire was positioned and incremental IC Ach doses were injected (10 -6 , 10 -5 , and 10 -4 mol/L). CBF (mL/min) was then calculated from CAD and doppler-derived flow velocity. Comparisons between the 2 sexes were performed. Results: A total of 1927 patients (mean age 51±13 years, 67% females) were included. Males were significantly younger (49±13 vs 53±12, P&lt;0.0001) than females and had a higher smoking exposure rate (56% vs 41%, P&lt;0.0001). Baseline (B) CBF was significantly lower in males (27.7 [19.2; 40.8] vs 30.2 [20.6; 43.4], P=0.04). The gap between females and males widened the first 2 doses, but then diminished after the highest dose (41.2 [24.5; 67.8] vs 44.5 [25.9; 72.0], P=0.09) (Fig 1A) . On multivariable analyses, female sex was an independent predictor of higher CBF at all doses (Estimate±StdError) (B= 1.14±0.53; 10 -6 : 1.59±0.61; 10 -5 : 2.54±0.82; 10 -4 : 2.70±1.2; P&lt;0.05 for all). When calculating the %ΔCBF, females had a significantly larger augmentation of flow after the first 2 doses of IC Ach (10 -6 : 3 [-14; 24] vs. -2 [-16; 19], P=0.02; 10 -5 : 21 [-7;68] vs. 12 [-10; 50], P=0.003). However, with the highest Ach dose, there was an equalization of overall augmentation (10 -4 : 49 [-1; 109] vs. 46 [-5; 106], P=0.46) (Fig 1B). Conclusions: Females had higher CBF regardless of given Ach concentration. Females have a higher sensitivity to Ach at smaller doses, while males exhibit a greater vasodilatory reaction at higher doses.
Abstract 12458: Protein L-isoaspartyl O-methyltransferase Attenuates Endothelial Activation Through Inhibitory Interaction With TRAF6 and ICAM1
Authors: Chen Zhang, Bing Yi, Xiaobo Sun, Kyosuke Kazama, Jianxin Sun
Journal: Circulation (2021)

Introduction: Endothelial activation provokes expression of cell surface adhesion molecules to facilitate circulating leukocyte diapedesis, which demands rigorous surveillance to prevent excessive inflammation response and host damage. As a repair enzyme, protein L-isoaspartyl O-methyltransferase (PIMT) methylates and converts isoaspartyl (isoAsp) residuals back to conventional form to avoid protein damage and aging. However, the role of PIMT in vascular homeostasis remains to be delineated. Methods and Results: Murine acute lung injury (ALI) model was deployed to investigate the significance of PIMT in endothelial activation and vascular inflammation. Results showed that mice harboring heterozygous deletion of PIMT displayed exacerbated pulmonary vascular inflammation. Ectopic overexpression of PIMT protected endothelial cells against endotoxin stimulated endothelial activation, as characterized by attenuated expression of inflammatory cytokines, chemokines, cell adhesion molecules and monocytic adherence to activated endothelial cells. Mechanistically, we found that PIMT inhibits lipopolysaccharide (LPS)-induced endothelial NF-κB transactivation. Tumor necrosis factor receptor-associated factor 6 (TRAF6) was identified as a dynamic binding partner and substrate of PIMT in regulating NF-κB signaling. PIMT catalyzed methylation at an asparagine derived isoAsp residual of TRAF6 directly prevented its oligomerization and auto-ubiquitination. Strikingly, we also found that PIMT specifically impeded N-glycosylation at multiple sites of endothelial intercellular adhesion molecule 1 (ICAM1). The hypo-glycosylated ICAM1 elicited impaired interaction with cell skeletal and reduced stability, which further diminished endothelial activation. Conclusions: PIMT negatively modulates endothelial activation through restricting activation of TRAF6 and inhibiting N-glycosylation of adhesion molecules. Our study provides a novel insight into the role of protein O-methylation in regulating endothelial inflammation and suggest that targeting PIMT may have potential therapeutic applications in treating inflammatory vascular disorders.
The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C
Authors: John V. Pluvinage, Jerry Sun, Christel Claes, Ryan A. Flynn, Michael S. Haney, Tal Iram, Xiangling Meng, Rachel Lindemann, Nicholas M. Riley, Emma Danhash, Jean Paul Chadarevian, Emma Tapp, David Gate, Sravani Kondapavulur, Inma Cobos, Sundari Chetty, Anca M. Pașca, Sergiu P. Pașca, Elizabeth Berry-Kravis, Carolyn R. Bertozzi, Mathew Blurton-Jones, Tony Wyss-Coray
Journal: Science Translational Medicine (2021)

An oligodendrocyte-derived protein in cerebrospinal fluid impairs microglial lysosome function.
Abstract 11994: Proteomic Evaluation And Biomarker Identification In Tricuspid Regurgitation
Authors: Si-Yeung Yu, Yi Kei Stephanie Tse, Hang Long Li, Qingwen Ren, Meizhen Wu, Kwan Yu LI, Pui Fai Wong, Lok Yee Jane Lam, Shuk Yin Yu, Kai Hang Yiu
Journal: Circulation (2021)

Introduction: Not only are mechanisms involved in tricuspid regurgitation (TR) incompletely understood, there is no established means of risk stratification for patients undergoing tricuspid valve interventions. A better understanding of underlying biological mechanisms allows for identification of therapeutic targets as well as biomarkers for disease staging, monitoring, and prediction following intervention. Methods: Preoperatively, 276 patients undergoing tricuspid annuloplasty, divided into training and validation cohorts, were assessed and followed-up for adverse events defined as death or heart failure requiring hospitalisation. Preoperative plasma samples were analysed for levels of cardiac troponin-T, NTproBNP, as well as 91 other markers (Olink multiplex assay). Correlated network analysis was used for clustering plasma markers. The relations of clusters to echocardiographic parameters and adverse outcomes were assessed by linear and Cox regression respectively. Pathway overrepresentation analysis was conducted to ascertain biological mechanisms overrepresented in relevant clusters by enrichment with reference to existing knowledge. Results: Over a median follow-up period of 3.7 years, 83 adverse events occurred. Two clusters of biomarkers in the training cohort significantly correlate with right chamber and tricuspid annular dilatation, regurgitant jet area, effective regurgitant orifice area and/or adverse outcomes following tricuspid annuloplasty (P&lt;0.05). The two clusters are represented by hub proteins TNF Receptor Superfamily Member 10A and TRAIL receptor 2. Overrepresented biological pathways in the two clusters include immunological responses, cytokine production regulation, and responses to lipids. Both clusters are conserved in the validation cohort. Conclusion: Immunoinflammatory pathways may be implicated in tricuspid regurgitation, and markers related to such pathways show prognostic significance.
Abstract 10165: The Correlation of Age and Extension Length in Debakey Type I Aortic Dissection: Are Septuagenarians at a Lower Risk?
Authors: Julia Merkle-Storms, Thorsten Wahlers, Manuel Feisst, Jochen Poeling, Bartosz Rylski, Daniel S Dohle, Christian Hagl, Tobias Krueger, Jens Brickwedel, Tomas Holubec, Christian D Etz, Thilo Noack, RAWA ARIF, Andreas Boening, Maximilian Luehr
Journal: Circulation (2021)

Introduction: Elderly patients have been suggested to be more prone to acute aortic dissection due to a higher incidence of age-related atherosclerosis and stiffness of the thoracic aorta. Hypothesis: Younger patients suffer more extensive DeBakey type I dissections due to aortic wall integrity, potentially allowing unhindered extension. The study's aim was to correlate age and dissection extension length in a large contemporary multi-center cohort. Methods: The perioperative data of 3385 patients with acute aortic dissection were retrospectively analyzed with regard to postoperative outcome and dissection extent. DeBakey type I aortic dissections (n=2510) were identified and divided into two groups: &lt;70 years (n=1741) and &gt;70 years (n=769). Patients with DeBakey type II and connective tissue disease were excluded (n=875). Results: Septuagenarians (&gt;70 yrs) had a higher incidence of atherosclerosis (32.0% vs. 18.9%; p&lt;0.001) and showed significantly more often a limitation of dissection extension until the aortic arch level (40.9% vs. 29.2%; p&lt;0.001). In younger patients, aortic dissections involved the supraaortic vessels more often (52.0% vs. 40.1%; p&lt;0.001) and extended significantly further downstream the aorta: descending aorta (68.5% vs. 57.1%; p&lt;0.001), abdominal aorta (54.7% vs. 42.0%; p&lt;0.001) and iliac bifurcation (36.6% vs. 26.0%; p&lt;0.001) ( Fig.1 ). Clinically, younger patients presented with significantly higher incidences of preoperative cerebral (p=0.002), spinal (p=0.003), visceral (p=0.002) and peripheral (p&lt;0.001) malperfusion. In-hospital mortality rates in patients &lt;70 yrs and &gt;70 yrs were 18.9% and 22.2% (p=0.067), respectively. Conclusions: Extensive DeBakey type I aortic dissection is less frequent in septuagenarians. Conversely, younger patients suffer significantly more often from preoperative organ malperfusion and associated complications. Postoperative mortality remains high irrespective of age groups.
Endothelial ARHGEF26 is an angiogenic factor promoting VEGF signalling
Authors: Qiuyu Martin Zhu, Bryan T MacDonald, Taiji Mizoguchi, Mark Chaffin, Alison Leed, Alessandro Arduini, Edyta Malolepsza, Kasper Lage, Virendar K Kaushik, Sekar Kathiresan, Patrick T Ellinor
Journal: Cardiovascular Research (2021)

Abstract Aims Genetic studies have implicated the ARHGEF26 locus in the risk of coronary artery disease (CAD). However, the causal pathways by which DNA variants at the ARHGEF26 locus confer risk for CAD are incompletely understood. We sought to elucidate the mechanism responsible for the enhanced risk of CAD associated with the ARHGEF26 locus. Methods and results In a conditional analysis of the ARHGEF26 locus, we show that the sentinel CAD-risk signal is significantly associated with various non-lipid vascular phenotypes. In human endothelial cell (EC), ARHGEF26 promotes the angiogenic capacity, and interacts with known angiogenic factors and pathways. Quantitative mass spectrometry showed that one CAD-risk coding variant, rs12493885 (p.Val29Leu), resulted in a gain-of-function ARHGEF26 that enhances proangiogenic signalling and displays enhanced interactions with several proteins partially related to the angiogenic pathway. ARHGEF26 is required for endothelial angiogenesis by promoting macropinocytosis of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) on cell membrane and is crucial to Vascular Endothelial Growth Factor (VEGF)-dependent murine vessel sprouting ex vivo. In vivo, global or tissue-specific deletion of ARHGEF26 in EC, but not in vascular smooth muscle cells, significantly reduced atherosclerosis in mice, with enhanced plaque stability. Conclusions Our results demonstrate that ARHGEF26 is involved in angiogenesis signaling, and that DNA variants within ARHGEF26 that are associated with CAD risk could affect angiogenic processes by potentiating VEGF-dependent angiogenesis.
Frequency and Outcome of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with BCR-ABL1 Clonal Hematopoiesis after Blast Clearance: Results from the Graaph-2014 Trial
Authors: Rathana KIM, Philippe Rousselot, Jean-Michel Cayuela, Yves Chalandon, Marie Passet, Xavier Thomas, Nicole Straetmans, Patrice Chevallier, Francoise Huguet, Celine Berthon, Georg Stüssi, Sébastien Maury, Sylvain Chantepie, Jean-Baptiste Micol, Isabelle Plantier, Sylvie Chevret, Jean Soulier, Norbert Ifrah, Veronique Lheritier, Hervé Dombret, Nicolas Boissel, Emmanuelle Clappier
Journal: Blood (2021)
Abstract 10541: Clinical Risk Factors and Myocardial Fibrosis in Subjects Who Died Suddenly: Pilot Data from A 10-Year Post-Mortem Data Registry
Authors: Daanyal Hussain, Vinesh Jonnala, Ariba Hashmi, Iain Thompson, Matthew Simson, Mahyar Khazaeli, Yan Yatsynovich, Saraswati Pokharel, Lili Tian, Umesh C Sharma
Journal: Circulation (2021)

Introduction: Sudden cardiac death (SCD) is responsible for approximately 380,000 deaths per year. One third of the patients dying of heart disease present with SCD as the first manifestation. There are limited data on the clinico-pathological determinants of SCD. Hypothesis: We hypothesized that, compared to overall deaths, silent coronary atherosclerosis and myocardial fibrosis could be associated with increased frequency of SCDs. Methods: We reviewed the post-mortem data registry from two tertiary care hospitals located at the Buffalo-Niagara Region. Of the 1,314 subjects that underwent comprehensive post-mortem analysis, we identified 187 subjects that died suddenly. For this initial pilot data analysis protocol, we compared the demographic, clinical, electrocardiographic and coronary vascular and myocardial histopathological characteristics of 109 subjects with sudden death vs. 34 age-matched controls with non-sudden death. Results: We found that, of the total 1,314 subjects screened, 14% had SCD. Comparison of age-matched SCD with non-SCD subjects (age in years, SCD: 60±14; non-SCD: 61±20) showed that SCD groups had larger cardiac size (heart weight in grams, SCD: 550±150; non-SCD: 480±117, P=0.03), increased wall thickness (posterior wall thickness in cm, SCD: 1.7±0.4; non-SCD: 1.5±0.2, P=0.01), but reduced LV function reported before the event (LV ejection fraction in %, SCD: 41±17; non-SCD: 58±9, P=0.007). In addition, SCD groups had higher frequency of coronary atherosclerosis (SCD, 76% vs., non-SCD, 52%, P=0.007), and myocardial fibrosis involving both left ventricular free wall (SCD, 47% vs., non-SCD, 26%, P=0.03), and interventricular septum (SCD, 29% vs., non-SCD, 3%, P=0.02). There were no differences on serum electrolytes, circulating biomarkers and the extent of right ventricular fibrosis. Conclusions: The subjects that died suddenly had larger cardiac size, reduced contractile function with myocardial interstitial fibrosis, and silent coronary atherosclerosis. Further studies are in progress to fully examine the clinico-pathological correlates of SCD in our longitudinal study cohorts.
Abstract 13977: Identification of Intermediate Right Ventricular Phenotypes Using Consensus Clustering in Patients With Pulmonary Hypertension
Authors: Alexandra M Janowski, Keeley Ravellette, Joe G Garcia, Franz Rischard, Rebecca Vanderpool
Journal: Circulation (2021)

Introduction: Current right ventricular (RV) function phenotypes in pulmonary hypertension (PH) rely on few hemodynamic parameters to quantify RV dysfunction disease severity. The aim of the study was to identify novel RV phenotypes using RV hemodynamics and unsupervised machine learning in patients with PH. Methods: Participants were identified from the UArizona PH Registry (n=190). Correlation analyses identified 9 RV variables to include in clustering analysis. Consensus clustering was used to identify an unsupervised clustering method with a large inter-cluster, and small intra-cluster distance (Fig 1A). Significance was tested with Dunn and chi-square tests. Results: K-Medoids with a Pearson distance matrix over &gt;1000 resampling iterations identified 5 clusters (consensus range: 0.8-0.9). World Symposium PH groups were distributed across clusters (Fig 1B). Clusters 1, 2 and 5 exhibit mild RV dysfunction with low diastolic stiffness (Eed) and afterload (Ea, Fig 1C). However, RV-PA coupling (Ees/Ea) was decreased in clusters 1 and 5. Clusters 3 and 4 have moderate to severe RV dysfunction with increased Eed and Ea but cluster 4 had decreased Ees/Ea. For pulmonary hemodynamics, clusters 3 and 4 have increased mean PA pressure (mPAP), increased pulmonary vascular resistance (PVR) and decreased PA compliance (Ca) compared to clusters 1 and 2. Cluster 5 has increased mPAP and high cardiac output resulting in moderately elevated PVR and decreased Ca. Conclusions: Unsupervised clustering identified 5 unique RV phenotypes ranging from mild to severe dysfunction. Further investigations are needed to identify factors modulating intermediate phenotypes to provide insight into RV dysfunction and disease progression.
Abstract 11700: Hemodynamic Impact of Severe Pulmonary Regurgitation in Patients With Right Ventricular Hypertension Secondary to Peripheral Pulmonary Arterial Stenosis
Authors: Jonathon A Hagel, Anthony Ruberto, Diego Porras, Nicola Maschietto
Journal: Circulation (2021)

Introduction: Severe pulmonary regurgitation (PR) is a common sequela of surgery for dysfunctional right ventricular outflow tract (RVOT). Peripheral pulmonary arterial stenosis (PPS) is frequently associated with conotruncal anomalies like Tetralogy of Fallot. Whether severe PR, which increases the right ventricular stroke volume, worsens right ventricular hypertension (RVHTN) in patients with PPS has not been previously investigated. Hypothesis: In patients with RVH secondary to PPS, the abolishment of severe PR ameliorates the degree of RVH. Methods: Retrospective longitudinal study of patients with PPS and severe PR, who underwent transcatheter pulmonary valve replacement (TPVR) at Boston Children’s Hospital between 01/2016 and 12/2019. Patients were included if they met all 3 of the following criteria: (1) PPS, (2) RVHTN immediately before TPVR (defined as an RV to Ao systolic pressure ratio [RV/AO] of at least 0.5 after interventions on the RVOT/PPS and before TPVR), and (3) severe PR. Patients with missing data were excluded. Hemodynamic data were collected at baseline, before TPVR (following the interventions for PPS and on the RVOT), and after TPVR. Variables were analyzed using a repeated-measure non-parametric ANOVA (Friedman test). A post-hoc analysis with Dunn-Bonferroni adjustment was performed. Results: In the study period, 17 patients (median age 14.6 years, IQR 10.1-19.7) met the inclusion criteria and had available hemodynamic data. Right ventricle systolic pressure, RVOT gradient, and RV/AO changed significantly overtime (all p&lt;0.001). While there was no significant difference in RVOT gradient before and after TPVR, re-establishment of valve competence did result in a further significant drop in RV pressure (Table 1). Conclusion: In patients with RVHTN secondary to PPS and severe PR, reestablishment of pulmonary valve competence significantly decreases the degree of RV hypertension compared to RVOT/PPS interventions alone.
Diagnosing Temporal Arteritis—Reply
Authors: David B. Hellmann
Journal: JAMA (2002)

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CSIG-19. DISRUPTION OF DNA DAMAGE RESPONSE MODULATES THE EFFICACY OF LOCAL IMMUNOTHERAPIES IN EXPERIMENTAL GLIOMA
Authors: Marilin Koch, Mykola Zdioruk, Michal Nowicki, Katharina Schregel, E Antonio Chiocca, Ghazaleh Tabatabai, Sean Lawler
Journal: Neuro-Oncology (2021)

Abstract RATIONALE Herpes virus thymidine kinase (HSV-TK) suicide gene therapy is a well-established approach for in situ tumor cell killing after administration of ganciclovir (GCV), due to the induction of lethal DNA damage in HSV-TK expressing cells. Here we investigated the effects of HSV-TK gene delivery with a non-replicating serotype 5 adenovirus (AdTK) in murine glioblastoma models in combination with the ATR-inhibitor AZD6738 to disrupt the DNA damage response (DDR). METHODS We investigated the effects of disrupted DDR signaling on AdTK therapy in vitro using cytotoxicity, cytokine and flow cytometry assays in glioblastoma cell lines and in vivo with an orthotopic syngeneic murine glioblastoma model. Therapy response was monitored with MRI. Changes in the tumor microenvironment were analyzed with CyTOF. RESULTS The combination of AZD6738 with AdTK was synergistic in cytotoxicity assays, which was complemented by a significant increase of γH2AX foci. Complex modulations of the tumor microenvironment were observed with significantly reduced expression of PD-L1, MICA/B and the pro-tumorigenic cytokines IL1b and IL-4. In vivo, the combination with AZD6738 led to an increase in long-term surviving animals (66.7%) compared to GMCI (50%) and proved to be highly significant in contrast to untreated controls (p=0.0022). However, the combination treatment did not block the growth of tumors upon rechallenge in long-term survivors. CONCLUSION DDR signaling is crucial in the therapeutic efficacy of AdTK/GCV. It significantly enhances cytotoxicity in vitro and in vivo while having complex ramifications at the immunological level, requiring further studies to determine ideal conditions for a maximized therapeutic benefit.