tbuckley/cabot-search huggingface dataset:
Abstract 9038: Success of Online CME at Improving Competence and Confidence Related to Treatment Adherence in Pulmonary Arterial Hypertension
Authors: Margaret Harris, Kelly Hanley, Alison O'Connor, Lih-Fan Chang, Victor Hatcher, Catherine Capparelli
Journal: Circulation (2021)

Introduction: Despite treatment advances in PAH, many patients have difficulty adhering to therapy, resulting in decreased persistence and poor outcomes. We sought to determine if online continuing medical education (CME) could improve the competence and confidence of cardiologists related to strategies to improve treatment adherence in PAH. Methods: This CME intervention comprised of a 15-minute online video-based rapid-fire discussion between 2 expert faculty. A repeated pairs pre-/post-assessment study design was used and McNemar’s test assessed significance (P &lt;.05 is considered significant), with Cohen’s d being used to assess educational impact (.20-.49 a small effect, .50-.79 a moderate effect, and &gt; .80 a large effect). The activity launched October 1, 2020 and data were collected through January 11, 2021. Results: In total, 180 cardiologists were included in the analysis. Overall, there were competence and confidence improvements seen among participants from pre- to post-assessment: • 13% of cardiologists (P&lt;.01) improved at selecting the most appropriate PAH therapy for better adherence for a patient who requires treatment escalation due to intermediate-risk status yet struggles to follow a rigid medication schedule • 27% of cardiologists (P&lt;.001) improved at selecting the most appropriate strategy to manage PAH treatment-related side effects • 36% of cardiologists had a measurable increase in confidence in ability to manage side effects during uptitration of PAH specific therapiesContinued educational gaps:• 61% of cardiologists failed to choose appropriate therapy to improve adherence for an intermediate-risk patient who struggles to follow a rigid medication schedule • 50% of cardiologists failed to select the most appropriate strategy to manage PAH treatment-related side effects Conclusions: This study demonstrates the success of online CME on improving competence and confidence of pulmonologists related to treatment adherence in PAH. Continued gaps were identified for future educational targets.
Simultaneous enhancement of T<sub>1</sub> and T<sub>2</sub> magnetic resonance imaging of liver tumor at respective low and high magnetic fields
Authors: Huan Li, Zijuan Hai, Liwei Zou, Lele Zhang, Lulu Wang, Longsheng Wang, Gaolin Liang
Journal: Theranostics (2021)

: Nowadays, magnetic resonance imaging (MRI) is routinely applied in clinical diagnosis. However, using one contrast agent (CA) to simultaneously enhance the T
Decarbonising healthcare in low and middle income countries: potential pathways to net zero emissions
Authors: Fawzia N Rasheed, Jerome Baddley, Poornima Prabhakaran, Enrique Falceto De Barros, K Srinath Reddy, Nelzair Araujo Vianna, Robert Marten
Journal: BMJ (2021)

<i>Healthcare in low and middle income countries has a high carbon footprint. Reducing emissions should be integral to plans for universal health coverage, say </i><b><i>Fawzia Rasheed and colleagues</i></b><i></i>
VIP152 Is a Novel CDK9 Inhibitor with Efficacy in Chronic Lymphocytic Leukemia
Authors: Steven Sher, Larry Beaver, Katie Williams, Shelley Orwick, Brandi R. Walker, Charles Thomas Gregory, Matthew Purcell, Alexander Pan, Pearlly S. Yan, Amy J. Johnson, Melanie M. Frigault, Joy M. Greer, Ahmed Hamdy, Raquel Izumi, Stuart Hwang, James S. Blachly, John C. Byrd, Rosa Lapalombella
Journal: Blood (2021)
Neutrophil DREAM Promotes Neutrophil Recruitment in Vascular Inflammation Via Nuclear Factor Kappa B-Dependent and Independent Mechanisms
Authors: Tripti Kumari, Jing Li, Andrew Barazia,, Vishwanath Jha, Amber Hansch, Mijeong Kim, Zhimin Song, Regina A. Clemens, Babak Razani, Jonghwan Kim, Mary C. Dinauer, Jaehyung Cho
Journal: Blood (2021)
35 Chemokine-driven spatial organization of immune cell microaggregates marks oropharyngeal squamous cell carcinomas containing tumor-specific T cells
Authors: Ziena Abdulrahman, Saskia Santegoets, Gregor Sturm, Pornpimol Charoentong, Marieke Ijsselsteijn, Antonios Somarakis, Thomas Höllt, Francesca Finotello, Zlatko Trajanoski, Sylvia van Egmond, Dana Mustafa, Marij Welters, Noel de Miranda, Sjoerd van der Burg
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Oropharyngeal squamous cell carcinoma (OPSCC) is the most prevalent type of head and neck cancer. The survival of patients with OPSCC is tightly linked to the intratumoral presence of tumor-specific CD4+ and CD8+ T cells. Yet, immunotherapy is currently far from effective in OPSCC partly due to our limited understanding of its immune microenvironment. Methods Here a multi-modal, high-dimensional approach was used to dissect the immune landscape in a unique cohort of pre-therapy OPSCC patient samples (n=20) in which intratumoral tumor-specific T cells were either detected (immune response positive, IR+) or not (IR-). This included imaging mass cytometry (Hyperion) for high-dimensional phenotyping, spatial localization and interaction analyses of the cells in the tumor mircoenvironment with our newly developed imaging processing pipeline employing machine learning, Nanostring PanCancer IO360 panel analysis of immune signaling pathways, and combined single-cell gene expression profiling and T cell receptor sequencing (scRNAseq) to characterize the transcriptional states of clonally expanded tumor-infiltrating T cells. Results Immune cell infiltration in IR+ tumors is stronger and highly coordinated, with a distinct spatial phenotypic signature characterized by microaggregates of tumor-resident (CD103+) CD8+ and CD4+ T cells and dendritic cells within the tumor cell beds, which retained after permutation based correction for differences in cell frequencies. Furthermore, the increased expression of CXCL12 and LTB produced by CD4+ T cells, both involved in the spatial organization of immune cell infiltration, and the clonal expansion of CD8+ T cells producing the DC-attracting chemokines CCL4 or XCL1 in IR+ OPSCC, indicate that tumor-reactive T cells act as a positive feedback loop in the formation of these aggregates. The impact of these chemokines on local immunity and clinical outcome was confirmed in an independent TCGA OPSCC cohort. In contrast, the IR- OPSCC signature comprised spatial interactions between lymphocytes and different subpopulations of immunosuppressive myeloid cells. Conclusions Our study reveals that the chemokine-driven spatial immune signature of OPSCC has strong potential as a prognostic and predictive biomarker. While the immune signature of IR+ OPSCC suggests potential benefit from neoadjuvant immunotherapeutic approaches to limit the side effects of current radio(chemo)therapy, that of IR- OPSCC calls for strategies focused on stimulating T cells and counteracting immune suppressive mechanisms.
Abstract PR-008: Kdm6 demethylases are critical regulators of pancreatic cancer initiation, progression and subtype specification
Authors: Laura Leonhardt, Lucia Y. Li, David I. Berrios, Sudipta Ashe, Audrey M. Hendley, Grace E. Kim, Matthias Hebrok
Journal: Cancer Research (2021)

Abstract Aberrant epigenetic regulation is a hallmark of pancreatic cancer. Since changes in histone methylation are potentially reversible, they present an attractive target for therapeutic intervention. Kdm6a and Kdm6b belong to a family of histone demethylases specific for lysine 27 of histone 3 and have been implicated in multiple types of cancer, including pancreatic ductal adenocarcinoma (PDA). We have gathered data from the extensive investigation of a mouse model of PDA in which either Kdm6b or both Kdm6a and Kdm6b have been deleted with concomitant activation of oncogenic KrasG12D restricted to adult acinar cells. While prior work had demonstrated an important role for Kdm6a in PDA formation, our data now show that the closely related Kdm6b is implicated in PDA tumorigenesis as well. Partial or complete loss of Kdm6b results in accelerated acinar-to-ductal metaplasia (ADM) and formation of pancreatic intraepithelial neoplasia (PanIN) with increased inflammation and fibrosis. Accelerated ADM formation was also observed ex vivo upon culturing acinar cells in the absence of oncogenic Kras, indicating that Kdm6b activity is critical for the maintenance of acinar identity and suppresses the early stages of pancreatic neoplasia development. However, only mice heterozygous for Kdm6b continue to exhibit a reduced overall median survival compared to KrasG12D alone, while complete loss of Kdm6b results in a similar overall median survival compared to KrasG12D. This suggests a requirement for oncogenic Kdm6b function during later progression of PanIN to invasive cancer. Conversely, concomitant loss of Kdm6a and Kdm6b protects against ADM and PanIN formation in vivo and ex vivo and double mutants display a trend towards an increased overall median survival compared to mice carrying only the KrasG12D mutation. Strikingly, the resulting tumors of Kdm6a/Kdm6b deficient mice exhibit features of an extremely rare subtype of sarcomatoid pancreatic cancer found in human patients. Taken together, this suggests that Kdm6 demethylase function is required during the initiation and progression of PDA. Furthermore, targeting Kdm6a/Kdm6b with specific inhibitors at distinct stages might provide opportunities for novel treatment avenues for pancreatic cancer. Citation Format: Laura Leonhardt, Lucia Y. Li, David I. Berrios, Sudipta Ashe, Audrey M. Hendley, Grace E. Kim, Matthias Hebrok. Kdm6 demethylases are critical regulators of pancreatic cancer initiation, progression and subtype specification [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PR-008.
Mapbatch: Conservative Batch Normalization for Single Cell RNA-Sequencing Data Enables Discovery of Rare Cell Populations in a Multiple Myeloma Cohort
Authors: Chern Han Yong, Shawn Hoon, Sanjay De Mel, Stacy Xu, Jonathan Adam Scolnick, Xiaojing Huo, Michael Lovci, Wee Joo Chng, Limsoon Wong
Journal: Blood (2021)
Abstract 9437: Impact of Telemedicine Use on Blood Pressure Control During the Covid-19 Pandemic
Authors: Siqin Ye, David E Anstey, Anne K Grauer, Gil Metser, Nathalie Moise, Joseph E Schwartz, Ian M Kronish, Marwah Abdalla
Journal: Circulation (2021)

Background: Telemedicine use vastly expanded during the Covid-19 pandemic, with uncertain impact on cardiovascular care. quality. Objectives: To examine the association between telemedicine use and blood pressure (BP) control. Methods: This is a retrospective cohort study of 32,727 adult patients with hypertension (HTN) seen in primary care and cardiology clinics at an urban, academic medical center from February to December, 2020. The primary outcome was poor BP control, defined as having no BP recorded OR if the last recorded BP was ≥140/90 mmHg. Multivariable logistic regression was used to assess the association between telemedicine use during the study period (none, 1 telemedicine visit, 2+ telemedicine visits) and poor BP control, adjusting for demographic and clinical characteristics. Results: During the study period, no BP was recorded for 486/20,745 (2.3%) patients with in-person visits only, for 1,863/6,878 (27.1%) patients with 1 telemedicine visit, and for 1,277/5,104 (25.0%) patients with 2+ telemedicine visits. After adjustment, telemedicine use was associated with poor BP control (odds ratio [OR], 2.06, 95% confidence interval [CI] 1.94 to 2.18, p&lt;0.001 for 1 telemedicine visit, and OR 2.49, 95% CI 2.31 to 2.68, p&lt;0.001 for 2+ telemedicine visits; reference, in-person visit only). This effect disappears when analysis was restricted to patients with at least one recorded BP (OR 0.89, 95% CI 0.83 to 0.95, p=0.001 for 1 telemedicine visit, and OR 0.91, 95% CI 0.83 to 0.99, p=0.03 for 2+ telemedicine visits). Conclusions: BP is less likely to be recorded during telemedicine visits, but telemedicine use does not negatively impact BP control when BP is recorded.
Carbamylated sortilin associates with cardiovascular calcification in patients with chronic kidney disease
Authors: Vera Jankowski, Turgay Saritas, Mads Kjolby, Juliane Hermann, Thimoteus Speer, Anika Himmelsbach, Kerstin Mahr, Marina Augusto Heuschkel, Stefan J. Schunk, Soren Thirup, Simon Winther, Morten Bottcher, Mette Nyegard, Anders Nykjaer, Rafael Kramann, Nadine Kaesler, Joachim Jankowski, Juergen Floege, Nikolaus Marx, Claudia Goettsch
Journal: Kidney International (2021)

Sortilin, an intracellular sorting receptor, has been identified as a cardiovascular risk factor in the general population. Patients with chronic kidney disease (CKD) are highly susceptible to develop cardiovascular complications such as calcification. However, specific CKD-induced posttranslational protein modifications of sortilin and their link to cardiovascular calcification remain unknown. To investigate this, we examined two independent CKD cohorts for carbamylation of circulating sortilin and detected increased carbamylated sortilin lysine residues in the extracellular domain of sortilin with kidney function decline using targeted mass spectrometry. Structure analysis predicted altered ligand binding by carbamylated sortilin, which was verified by binding studies using surface plasmon resonance measurement, showing an increased affinity of interleukin 6 to in vitro carbamylated sortilin. Further, carbamylated sortilin increased vascular calcification in vitro and ex vivo that was accelerated by interleukin 6. Imaging by mass spectrometry of human calcified arteries revealed in situ carbamylated sortilin. In patients with CKD, sortilin carbamylation was associated with coronary artery calcification, independent of age and kidney function. Moreover, patients with carbamylated sortilin displayed significantly faster progression of coronary artery calcification than patients without sortilin carbamylation. Thus, carbamylated sortilin may be a risk factor for cardiovascular calcification and may contribute to elevated cardiovascular complications in patients with CKD.
Early Signals of Anti-Tumor Efficacy and Safety with Autologous CD5.CAR T-Cells in Patients with Refractory/Relapsed T-Cell Lymphoma
Authors: Rayne H. Rouce, LaQuisa C. Hill, Tyler S. Smith, Lina Yang, Blakely Boriskie, Madhuwanti Srinivasan, Huimin Zhang, Silvana Perconti, Birju Mehta, Olga Dakhova, Bambi J. Grilley, Helen E. Heslop, Malcolm K. Brenner, Maksim Mamonkin
Journal: Blood (2021)
Two-Year Efficacy and Safety of Ravulizumab in Adults and Children with Atypical Hemolytic Uremic Syndrome (aHUS): Analysis of Two Phase 3 Studies
Authors: Bradley P. Dixon, Alvaro Domingo Madris-Aris, Brigitte Adams, David Kavanagh, Hee Gyung Kang, Jimmy Wang, Katherine Garlo, Kazuki Tanaka, Laurence Greenbaum, Masayo Ogawa, Nils Heyne, Seong Heon Kim, Spero Cataland, Sung-Soo Yoon, Yoshitaka Miyakawa, Yosu Luque, Melissa Muff-Luett
Journal: Blood (2021)
Abstract 9026: Endogenous Ca2+/Calmodulin-Dependent Protein Kinase II Overactivation Exacerbates Cardiac Dysfunction and Beta-Adrenergic Desensitization in a Mouse Model With Type 2 Diabetes
Authors: Jing Cao, Xiaoqiang Sun, Yixi Liu, Zhe Chen, Tiankai Li, David M Herrington, Dalane W Kitzman, David Zhao, Che Ping Cheng, Heng Cheng
Journal: Circulation (2021)

Background: Emergent evidence indicates that CaMKII overactivity in diabetes (DM) plays a crucial role in the pathophysiology of diabetic cardiomyopathy (DCM) by targeting a diverse array of proteins involved in cardiac electrical, structural and functional remodeling. CaMKII has been proposed to be a therapeutic target for DCM. However, although chronic inhibition of CaMKII has been associated with cardioprotection in several cardiovascular diseases, the direct cardiac effects of CaMKII activation in type 2 (T2) DM are unclear. Moreover, whether and how DCM alters cardiac responses to CaMKII are undefined. We tested the hypothesis that in DCM, CaMKII is upregulated, which alters cardiac contractile behavior. Endogenous CaMKII activation may produce direct depressions in LV myocyte basal function and β-adrenergic reserve. Acute inactivation of CaMKII with KN93 would have a beneficial impact in DCM. Methods: LV myocyte CaMKIIδ expression and activity and myocyte functional responses were compared in 2 groups (n=9/group) of wild-type female mice: Vehicle Control (C) , animals fed chow for 14 weeks (W); T2DM, i nduced with a high-fat diet (HFD) intake for 14 W, but after fed HFD for 4 W receiving streptozotocin (STZ, 40 mg/kg/day, i.p. for 5 days). In T2DM, we further assessed myocyte contractile and [Ca 2+ ] i transient ([Ca 2+ ] iT ) responses with and without acute treatment of myocytes with KN93 (10 -6 M, 30 min). Results: Versus C, in T2DM myocytes, the CaMKIIδ protein levels (28%, 0.51 vs 0.40) and CaMKIIδ phosphorylation (79%, 0.52 vs 0.29) were significantly increased. These changes were followed by significantly reduced cell contraction (dL/dt max , 76.0 vs 137.3 μm/s), relaxation (dR/dt max , 61.7 vs 116.0 μm/s) and [Ca 2+ ] iT (0.16 vs 0.21). ISO-stimulated increases dL/dt max (39% vs 58%), dR/dt max (35% vs 54%) and [Ca 2+ ] iT (20% vs 30%) were also significantly reduced. Moreover, in T2DM myocytes, superfusion with KN93 significantly improved myocyte basal contraction (104.2 μm/s), relaxation (79.3 μm/s) and [Ca 2+ ] iT (0.21). Conclusions: In T2 diabetes-induced DCM, upregulation of CaMKIIδ has adverse functional effects. Acute endogenous CaMKII activation exacerbates LV myocyte dysfunction. The inhibition of CaMKII has a significant beneficial impact.
Improvement in Annualized Bleed Rate in Patients with Hemophilia A Initiating Emicizumab - Physician Reported Outcomes from the Adelphi Hemophilia a Disease Specific Programme™
Authors: Rahul Khairnar, Marquita Decker-Palmer, Jennifer Mellor, Keisha Golden, Susanna Libby, Stevie Olsen, Christian Taylor, Craig S Meyer, James Pike, Richard H. Ko
Journal: Blood (2021)
Mutations of the Novel Tumor Suppressor Gene SAMHD1 Are Frequent and Correlate with Decreased Protein Expression in Peripheral T-Cell Lymphomas (PTCL)
Authors: Georgia Kokaraki, Ioanna Xagoraris, Pedro Farrajota Neves Da Silva, Lesley Ann Sutton, Raul Maia Falcão, Jorge Estefano Santana de Souza, Anders Österborg, Valtteri Wirta, Richard Rosenquist Brandell, Georgios Z. Rassidakis
Journal: Blood (2021)
41 Assessment of the spatial distribution of CD4+ T cells subpopulations in the tumor microenvironment by Brightplex®, a sequential chromogenic multiplex assay
Authors: Aurelie Collignon, Alex Trinh, Marion Olive, Clémence Jaume, Maïté Chamourin, Nour Sfeir, Dylan Anselmo, Raana Ramouz-Charpentier, Georgia Culey, Christophe Haond, Jerome Galon, Jacques Fieschi-Meric
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Cancer immunotherapy reinvigorates tumor-specific T cell responses of CD8+ cytotoxic T lymphocytes that detect intracellular antigens that are presented by MHC class I molecules expressed by all tumor cell types. Because most tumors do not express MHC class II, the potential antitumor protective role of CD4 T cells, which bind MHC class II molecules on target cells, has been less studied. However, CD4+ T cells are also required for efficacious antitumor immunity; they are core components of adaptive immunity that differentiate into lineages responsible for effector activities. Both TH1 and TH2 cell types mediate antitumor immunity, although TH1 cells may be more potent due to the production of large amounts of IFN-γ, as well as chemokines that enhance the priming and expansion of CD8 cells. TH1 cells help in recruiting natural killer cells and type I macrophages to tumor sites, which can act in concert toward tumor eradication. The ability of TH2 cells to mobilize innate cells, may represent a general pathway for their impact on the host antitumor response. Tumor infiltrating TFH cells play a key role in immune cell recruitment to the tumor and in the formation of intratumoral follicular structures, which correlate with a positive prognosis. On the contrary, cells from the TH17 subset induces inflammatory responses resulting in a tumor-promoting environment. CD4+ Tregs which are critically important for the maintenance of self-tolerance, impede effective immunity against the tumor when they are present in the tumor microenvironment (TME).Therefore, beyond the detection of total CD4+ T cells within the TME, it is of critical importance to determine to which subpopulation each CD4+ T cell belongs to decipher their roles in tumor rejection. Methods We have developed a multiplex 7-plex panel of of antibodies against biomarkers to identify main types of CD4+ T cells Results On a single FFPE tissue section, main types of CD4+ T cells: TH1, TH2, TFH, TH17 and Tregs are identified by a combination of antibodies against transcription factors and membrane proteins. Following images registration, complex cells phenotypes can be detected and quantified. Furthermore, digital pathology tools allow the evaluation of the spatial distribution of CD4+ T cells within the TME. Conclusions This new tool unravels the diversity of CD4+ T cells in TME and could help clinical researchers to design more effective immunotherapies in cancer treatment. Integrated into an Immunogram, this new Brightplex® Panel will also be critical to understand the immune contexture of tumors.
Abstract 9526: Fto Demethylase Mediates Altered N6-methyladenosine (m6a)-rna Modification in Human Failing Heart and Stressed-Induced Rat Cardiomyocytes
Authors: Praveen K Dubey, Shubham Dubey, Mallikarjun Patil, Sarojini Singh, Paras Ahuja, Steven pogwizd, Prasanna Krishnamurthy
Journal: Circulation (2021)

Background: N6-methyladenosine (m6A) methylation is one of the important posttranscriptional modification of RNA, which affects RNA splicing, translation and stability. These modifications are dynamically regulated by writers, readers and erasers, and their alteration affects m6A modification and have shown to play key regulatory role in numerous biological processes. Fat mass- and obesity-associated (FTO) gene, known as a nucleic acid demethylase removes the methyl group from RNA and has been shown to be associated with progression of heart diseases. In this study, we determined m6A methylation in human failing heart, and evaluated if FTO regulates m6A-methylation of transcripts related to inflammation in cultured rat cardiomyocytes under various stress conditions. Methods and Results: m6A RNA-methylation was increased in human failing hearts as compared to heart samples from non-failing subjects. Interestingly, failing hearts were associated with significant decrease in FTO mRNA and protein expression. Furthermore, cultured rat cardiomyoblasts (H9C2) cells exposed to stressors (hypoxia or isoproterenol) for 24hrs showed significant decrease of FTO and an associated increase in m6A-RNA methylation (dot blot analysis). To further test if stress-induced increase in m6A-RNA modification is mediated through FTO, we knocked-down FTO, treated with isoproterenol for 24hrs and evaluated m6A methylation status of RNA. Interestingly, dot blot analysis showed significant increase in m6A methylation levels and proinflammatory cytokines (IL6 and TNFa) in FTO knockdown cells as compared to scramble, both at basal level and after exposure to stress. Furthermore, we evaluated the effect of FTO on methylation of RNA transcripts that encode inflammatory cytokines. MeRIP assay (Methylated RNA immunoprecipitation using m6A antibody and analysis of m6A-transcript by qRT-PCR) demonstrated that the gene expression of proinflammatory cytokines, IL6 and TNF-alpha was significantly increased in FTO knockdown cells as compared to scramble control cells . Conclusion: This data suggests stress-induced loss of FTO in the heart might mediate m6A-RNA methylation and therefore potential leading to upregulation of inflammatory response in the myocardium.