tbuckley/cabot-search huggingface dataset:
Immunization with short peptide particles reveals a functional CD8<sup>+</sup>T-cell neoepitope in a murine renal carcinoma model
Authors: Xuedan He, Shiqi Zhou, Melissa Dolan, Yuhao Shi, Jianxin Wang, Breandan Quinn, Dushyant Jahagirdar, Wei-Chiao Huang, Moriya Tsuji, Roberto Pili, Fumito Ito, Joaquin Ortega, Scott I Abrams, John M L Ebos, Jonathan F Lovell
Journal: Journal for ImmunoTherapy of Cancer (2021)

Induction of CD8+ T cells that recognize immunogenic, mutated protein fragments in the context of major histocompatibility class I (MHC-I) is a pressing challenge for cancer vaccine development.Using the commonly used murine renal adenocarcinoma RENCA cancer model, MHC-I restricted neoepitopes are predicted following next-generation sequencing. Candidate neoepitopes are screened in mice using a potent cancer vaccine adjuvant system that converts short peptides into immunogenic nanoparticles. An identified functional neoepitope vaccine is then tested in various therapeutic experimental tumor settings.Conversion of 20 short MHC-I restricted neoepitope candidates into immunogenic nanoparticles results in antitumor responses with multivalent vaccination. Only a single neoepitope candidate, Nesprin-2 L4492R (Nes2LR), induced functional responses but still did so when included within 20-plex or 60-plex particles. Immunization with the short Nes2LR neoepitope with the immunogenic particle-inducing vaccine adjuvant prevented tumor growth at doses multiple orders of magnitude less than with other vaccine adjuvants, which were ineffective. Nes2LR vaccination inhibited or eradicated disease in subcutaneous, experimental lung metastasis and orthotopic tumor models, synergizing with immune checkpoint blockade.These findings establish the feasibility of using short, MHC-I-restricted neoepitopes for straightforward immunization with multivalent or validated neoepitopes to induce cytotoxic CD8+ T cells. Furthermore, the Nes2LR neoepitope could be useful for preclinical studies involving renal cell carcinoma immunotherapy.
Abstract 11025: Markers of Heart Rate Variability Represent Strong and Independent Predictors of All-Cause Death in Heart Failure - Results from the Myovasc Study
Authors: Silav Zeid, Gregor Buch, David Velmeden, Jakob Soehne, Andreas Schulz, Alexander Schuch, Sven-Oliver Troebs, Marc Heidorn, Felix Mueller, Katrin Coboeken, Karl J Lackner, Tommaso Gori, Thomas Muenzel, Juergen H Prochaska, Philipp Wild
Journal: Circulation (2021)

Introduction: Although different measures of heart rate variability (HRV) have been proposed as markers of autonomic dysfunction (AD) in heart failure (HF), evidence on their clinical relevance is limited. Methods: Data from the MyoVasc study (NCT04064450; N=3,289), a prospective cohort study on chronic HF, were analyzed. Study participants received a highly standardized, 5-hour examination including 24-hour Holter ECG recording. RR intervals were extracted to evaluate HRV markers from time and frequency domain analyses, and non-linear markers derived via phase space reconstruction, phase-rectified signal averaging, and entropy analyses. HRV markers of interest were selected using a systematic literature screen, and a random survival forest model predicting cardiac death. Reference values were determined in a healthy subsample. To evaluate clinical relevance, HRV markers were investigated in multivariable Cox regression analyses for their relationship to all-cause death considering potential confounders and mediators. Results: Holter ECG recordings were available for analysis in 1,001 study participants (mean age 64.5±10.5 years; female sex: 35.4%). While the top 10 most frequently reported HRV markers in literature screen were from the time and frequency domains, the data-driven approach revealed predominantly non-linear HRV measures. Values outside reference ranges for SDANN, rMSSD, frequency bands (i.e., ULF, VLF, LF, total power, ULF MED wavelet ), acceleration capacity (AC), deceleration capacity (DC), and time lag, were strong predictors of all-cause death in Cox regression analysis (median follow-up time: 6.1 [IQR 4.7/7.1] years) adjusted for age, sex, clinical profile and medication. In linear Cox regression analyses of the total sample, LF/HF (hazard ratio per SD (HR SD ) 0.78 [95% confidence interval (CI) 0.62, 0.98], p=0.034), time lag (HR SD 1.23 [95%CI 1.05, 1.44], p=0.0095), AC (HR SD : 1.57 [95%CI 1.24, 1.99], p=0.0002), and DC (HR SD 0.67 [95%CI 0.53, 0.85], p=0.0012) were strong predictors for all-cause mortality independent of age, sex, clinical profile and medication. Conclusions: HRV markers reflecting AD are strong predictors of all-cause death in HF, suggesting clinical relevance and potential for intervention.
Abstract 14684: Single Cell Sequencing Reveals Novel Insights Into Endothelial Plasticity After Myocardial Infarction
Authors: Lukas S Tombor, David John, Yosif Manavski, Elvira Forte, Milena Furtado, Nadia Rosenthal, Wesley Abplanalp, Stefanie Dimmeler
Journal: Circulation (2018)

After myocardial infarction (MI), endothelial cells (ECs) proliferate and migrate into the infarct area, thereby mediating new vessel growth. ECs have a remarkable plasticity and can convert into a...
Abstract 14027: National Trends and County-Level Patterns of Prescription for PCSK-9 Inhibitors Among Medicare Beneficiaries in the United States
Authors: Arash Aghajani Nargesi, Jonathan Hanna, Rohan Khera
Journal: Circulation (2021)

Introduction: PCSK9i are expensive but effective adjunctive lipid lowering therapies but their uptake in clinical practice has largely remained unknown. Hypothesis: We evaluated national trends and patterns of prescription for PCSK9i among Medicare beneficiaries. Methods: We identified lipid-lowering prescriptions in national Medicare Part D database for 2015-2018. To evaluate county level features associated with PCK9i prescriptions, data was merged with AHRQ sociodemographic measures, public health indices from County Health Ranking, and deprivation rank from Neighborhood Atlas. We evaluated trends and county level variation in proportionate PCK9i prescriptions relative to statins. Results: The number of PCSK9i prescribers increased from 16 in 2015 to 9621 in 2018, representing an increase from 0.01% to 3.0% of statin prescribers. There were 2980 counties with ≥10 statin prescribers in 2018, of which only 161 (5.3%) had any PCSK9i prescriptions. Even among counties with PCK9i use, relative to a median 8762 [IQR 7491-10767] for statin-receiving beneficiaries per 100k population, the rates of use were 6.1 [3.0-12.2] beneficiaries for PCSK9i and 177 [111-264] for ezetimibe. At a county level, proportionate PCSK9i beneficiaries relative to statin significantly correlated with county population (r=0.34), education (r=0.22), younger age (r=0.16), household income (r=0.14), lower prevalence of obesity (r=0.14), and lower deprivation rank (r=0.10). After accounting for sociodemographic and cardiometabolic risk factors in logistic regression, county population, education, lower median age, and lower prevalence of obesity significantly predicted PCK9i use. Conclusion: Despite an increased uptake of PCK9i during 2015-2018, only 3% of statin prescribers nationally use any PCSK9i among Medicare beneficiaries. The use is also restricted to only 5% of US counties, which were affluent, suggesting a need for an evaluation to ensure equitable use.
Amphiphilic small molecular mates match hydrophobic drugs to form nanoassemblies based on drug-mate strategy
Authors: Leiqiang Han, Shuang Liang, Weiwei Mu, Zipeng Zhang, Limin Wang, Shumin Ouyang, Bufan Yao, Yongjun Liu, Na Zhang
Journal: Asian Journal of Pharmaceutical Sciences (2021)

Nanomedicine has made great progress in the targeted therapy of cancer. Here, we established a novel drug-mate strategy by studying the formulation of nanodrugs at the molecular level. In the drug-mate combination, the drug is a hydrophobic drug that is poorly soluble in water, and the mate is an amphiphilic small molecule (SMA) that has both hydrophilic and lipophilic properties. We proposed that the hydrophobic drug could co-assemble with a suitable SMA on a nanoscale without additive agents. The proof-of-concept methodology and results were presented to support our hypothesis. We selected five hydrophobic drugs and more than ten amphiphilic small molecules to construct a library. Through molecular dynamic simulation and quantum chemistry computation, we speculated that the formation of nanoassemblies was related to the binding energy of the drug-mate, and the drug-mate interaction must overcome drug-drug interaction. Furthermore, the obtained SF/VECOONa nanoassemblieswas selected as a model, which had an ultra-high drug loading content (46%), improved pharmacokinetics, increased bioavailability, and enhanced therapeutic efficacy. In summary, the drug-mate strategy is an essential resource to design exact SMA for many hydrophobic drugs and provides a reference for the design of a carrier-free drug delivery system.
Abstract 11027: Short-and Long-Term Prognostic Value of Multiple Cardiac Biomarker Measurement in Patients Undergoing Elective Coronary Artery Bypass Graft Surgery
Authors: Matthias Thielmann, Sebastian Cymorek, Daniel WENDT, Anja K Oßwald, Wolfgang Ristau, Sharaf-Eldin Shehada, Bastian Schmack, Alexander Weymann, Markus Kamler, Petra Kleinbongard, Arjang Ruhparwar
Journal: Circulation (2021)

Introduction: Coronary artery bypass grafting (CABG) is associated with defined degree of myocardial injury reflected by perioperative rise of cardiac biomarkers. The present study aimed to evaluate multiple cardiac biomarkers and their association with short- and long-term outcome following CABG. Methods: In this prospective study, a total of 1030 patients with coronary artery disease (CAD) were enrolled between 07/2008 and 11/2018, undergoing elective, isolated, on-pump CABG. Perioperative cardiac troponin I and T (cTnI, cTnT) or ultra-sensitive (us-) cTnI were measured over 72hrs after surgery. Mean Follow-up was 5.5±2.7years with 100% completeness. Primary study endpoint was in-hospital mortality (IHM) and major adverese cardiac and cerebrovascular event (MACCE) rate at 30 days, as well as mortality in the long-term, defined as death from any cause. Results: Patients were 67.6±9.4years of age, 81.8% male, presenting 3-vessel CAD in 82% and/or left-main disease in 38%. Log EuroSCORE-I was 4.3±3.7%. Perioperative serum concentrations of cTnI ( P =0.05), us-cTnI ( P =0.02), but not cTnT ( P =0.79) differed significantly between survivors and non-survivors and cTnI ( P &lt;0.001) and us-cTnI ( P &lt;0.001) between patients with and without MACCE within the first 30 days after surgery (2-way ANOVA). Kaplan-Meier analysis for time to event variables, clearly showed poor long-term prognosis in patients with high perioperative cTnI, having a 1-, 5- and 10-years survival of 93.5%, 81.3% and 54.5%, as compared to patients with medium or low cTnI ( P =0.03). Multivariable logistic regression analyses revealed cTnI, but not cTnT and us-cTnI, as a strong and independent predictor for IHM ( P &lt;0.001) and MACCE ( P =0.02). In a receiver operating curve (ROC) analysis, cTnI of 9.2ng/mL with an area under curve (AUC) of 0.72 ( P =0.02) was identified as an optimal cut-off value for predicting IHM and a cut-off value of 6.38ng/mL with an AUC of 0.85 ( P &lt;0.001) for the prediction of MACCE. Conclusion: Serial perioperative cTnI measurment and/or its ultra-sensitive isoform allows for identifying patients with worse clinical short- and long-term outcomes following CABG. CTnT however, failed to identify patients at risk and was inferior in predicting short- and long-term outcomes.
2020 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis With Polyangiitis
Authors: Joanna C Robson, Peter Grayson, Cristina Ponte, Ravi Suppiah, Anthea Craven, Andrew Judge, Sara Khalid, Andrew Hutchings, Richard Watts, Peter Merkel, Raashid A. Luqmani
Journal: Annals of the Rheumatic Diseases (2021)
Abstract 12005: Increased Risk of Cancer Therapy-Related Cardiomyopathy in Patients With Treated Immune Checkpoint Inhibitors and Concomitant Cardiotoxic Agents
Authors: seonhwa lee, Iksung Cho, Seng Chan You, Min Jae Cha, Jee suk Jang, William Kim, Kyu-yong Go, Dae-Young Kim, Jiwon Seo, Chi Y Shim, Geu-Ru Hong, Jong-Won Ha, Hyo-song Kim
Journal: Circulation (2021)

Introduction: There is scarce data on whether immune checkpoint inhibitor (ICI) increase the risk of cardiomyopathy, especially when used with cardiotoxic agents. Hypothesis: We evaluated the cardiotoxicity of the ICI in sarcoma patients receiving doxorubicin with or without ICI by echocardiographic parameters and left ventricular global longitudinal strain (LVGLS). Methods: A total of 89 patients were included. Echocardiography and LVGLS were evaluated at baseline and follow-up (after 3 and 6months) and compared between the doxorubicin (n=67) and concomitant ICI with doxorubicin (n=22) groups. Cancer-therapy related cardiac dysfunction (CTRCD) was defined as LVEF drop of &gt;10% and LVEF of &lt;50% (definite CTRCD) and LVEF drop of &gt;10%, LVEF of &gt; 50% and LVGLS relative reduction of &gt;15% (probable CTRCD) at 6months. Results: There was no significant difference in age, cumulative dose of doxorubicin and cardiovascular risk factors between two groups. At baseline, LVEF was similar between two groups (p=0.493). In doxorubicin group, LVEF decreased to 59±6 % (p&lt;0.001) and LVGLS decreased from -16.5±3.2 to -14.6±3.2 % (p&lt;0.001) at 6-month. In concomitant ICI and doxorubicin group, LVEF decreased to 55±9 % (p&lt;0.001), along with significantly decreasing LVGLS (-18.6±1.9 to -15.3±3.6 %, p&lt;0.001). Over a median follow-up of 192 days, there were no cases with clinical manifestation of myocarditis. In doxorubicin group, definite and probable CTRCD were 7 (10.1%) and 5 (7.4%) patients, respectively. In concomitant ICI and doxorubicin group, definite and probable CTRCD were 4 (19%) and 4 (19%) patients, respectively. Total CTRCD occurred significantly more in concomitant ICI and doxorubicin than doxorubicin group (38.1% vs. 17.4%, p=0.042). Conclusions: ICI increases risk of CTRCD, when concomitantly treated with cardiotoxic agents. Thus, cardiomyopathy should be monitored in patients with ICI by comprehensive echocardiographic assessment including myocardial strain.
Abstract 10191: Dapagliflozin versus Empagliflozin for Improving Outcomes of Non-Diabetic Patients with Heart Failure and Reduced Ejection Fraction
Authors: Ronen Arbel, Joseph Azuri, Enis Aboalhasan, Ariel Hammerman
Journal: Circulation (2021)

Introduction: Patients with HF and reduced ejection fraction (HFrEF) are at high risk for CV mortality and HF-related hospitalizations (HHF). The Sodium-Glucose Transport protein 2 inhibitors (SGLT2i) dapagliflozin and empagliflozin improve the outcomes of non-diabetic patients with HFrEF. We aimed to compare their value for money for this indication. Hypothesis: Empagliflozin and dapagliflozin have comparable value for money for improving the HF outcomes of non-diabetic patients with HFrEF. Methods: SGLT2i data was extracted from published results of empagliflozin and dapagliflozin in the subgroups of patients without diabetes. The primary clinical outcome measure was a composite of HHF or CV mortality events. The economic measure was the cost needed to treat (CNT) to prevent one event, calculated by multiplying the one-year number needed to treat (NNT) to prevent one event by the annual cost of each therapy. Drug costs were based on the 2021 US National Average Drug Acquisition Cost prices. Secondary outcomes were the CNT to prevent one event of HHF and CV mortality as separate clinical outcomes. Sensitivity analysis was performed to mitigate differences between the trial’s populations Results: Treatment with empagliflozin in EMPEROR-REDUCED has resulted in an NNT of 29 (95% CI: 18-212) compared to 32 (95% CI: 21-72) with dapagliflozin in DAPA-HF. Accordingly the CNT to prevent one event of CVM or HHF was $139,115 (95% CI: $86,347-$1,016,976) and $144,751 (95% CI: $94,993-$325,690), respectively. The sensitivity analysis confirmed the primary results, but the CNT to prevent CV mortality is significantly lower with dapagliflozin (Fig. 1) Conclusions: Empagliflozin and dapagliflozin have comparable value for money for improving HF outcomes of non-diabetic patients with HFrEF, with an advantage for dapagliflozin in CV mortality.
Abstract 12227: Atherosclerotic Risk Factors Associated With Carotid Plaque Progression Are Different Depending on the Severity of Plaque Stage: A Longitudinal Study in General Population
Authors: Satoko Ojima, Takuro Kubozono, Shin Kawasoe, Takeko Kawabata, Anwar A Salim, Hironori Miyahara, Koichi Tokushige, Masaaki Miyata, Yoshiyuki Ikeda, Mitsuru Ohishi
Journal: Circulation (2021)

Background: Carotid plaque is a well-known prognostic factor for cardiovascular disease and stroke. However, it is unclear which atherosclerotic risk factors are related to plaque transformation in the non-pharmacological population. Purpose: To examine the atherosclerotic risk factors associated with the progression of carotid plaque according to the severity of atherosclerosis Methods: We investigated 738 male participants without medication who underwent the 1 st and the 2 nd health checkups (mean duration: 2.0±1.6 years). We measured carotid plaque thickness (PT) evaluated by using ultrasonography at three points of the right and left carotid artery. Plaque score (PS) was calculated by summing all the PT. We divided into three groups following previous reports: normal stage, PS&lt;1.1 mm; early stage, 1.1 mm &lt; PS&lt;5.1 mm; advanced stage, PS &gt; 5.1 mm. We used the risk factors such as age, body mass index, systolic blood pressure (SBP), fasting blood sugar, low-density lipoprotein cholesterol (LDL-C), smoking habits, and exercise habits for analysis. Results: At 1 st health checkup, 108 participants had already progressed to the advanced stage of carotid plaque, 454 participants had the early stage, and 176 participants had the normal stage. 14% of participants with the early stage at 1 st health checkup had progressed to the advanced stage at 2 nd health checkup, and 42% of participants with the normal stage at 1 st health checkup had progressed the early stage at 2 nd health checkup. In multivariate logistic regression analysis, SBP was an independent risk factor for progression of PS stage from the normal stage at 1 st health checkup to the early stage at 2 nd health checkup (SBP; OR 1.27, CI 1.01-1.60, p&lt;0.05). In addition, LDL-C was an independent risk factor associated with further progression of carotid plaque from the early stage at 1 st health checkup to the advanced stage at 2 nd health checkup (LDL-C; OR 1.10, CI 1.00-1.21, p&lt;0.05). Conclusions: SBP was associated with the carotid plaque progression of early atherosclerosis, while LDL-C was associated with the progression of advanced atherosclerosis. We should be aware of risk factors according to the stage of plaque progression.
Abstract 12267: Impact of a Comprehensive ST-Elevation Myocardial Infarction Protocol on Key Process Metrics in African American STEMI Patients
Authors: Raunak Nair, Nicholas Kassis, Anirudh Kumar, Chetan P Huded, Michael J Johnson, Kathleen A Kravitz, Grant W Reed, Amar Krishnaswamy, Venu Menon, A M Lincoff, Stephen Meldon, Damon M Kralovic, Samir R Kapadia, Umesh N Khot
Journal: Circulation (2021)

Background: Optimizing STEMI care processes for African Americans is a critical matter with important public health implications. We aimed to study if a comprehensive ST-elevation myocardial infarction (STEMI) protocol (CSP) could improve key process metrics in the African American (AA) population. Methods: We developed a 4-step CSP which included, 1) Emergency Department catheterization lab activation; (2) STEMI Safe Handoff Checklist; (3) immediate catheterization lab transfer; (4) and radial-first percutaneous coronary intervention (PCI). Baseline characteristics and procedural characteristics were compared between all consecutive STEMI patients who underwent PCI at the Cleveland Clinic main campus between January 1, 2011, to July 14, 2014 (pre-CSP group) and July 15, 2014, to July 15, 2019 (post-CSP group). Results: There were a total of 208 AA patients in the pre-CSP group compared to 271 AA patients in the post-CSP group. Baseline characteristics were quite similar between the two groups except for a lower rate of MI in the post-CSP group (45% vs 30%, P=0.001). After implementation of our CSP, guideline-directed medical therapy increased from 71.6% to 81.9% (P=0.011), radial utilization went up from 14.4% to 73.8% (P&lt;0.001), door to balloon time decreased from 90 minutes (median IQR 64-120) to 70 minutes (median IQR 45-95) (P&lt;0.001), fluoro dose decreased from 1610 mGy (median IQR 980.25-2592.25) to 1147 mGy (median IQR 742-1844) (P&lt;0.001), and contrast dose decreased from 197.07 ml to 152.98 ml (P&lt;0.001). Conclusion: Implementing a CSP was able to significantly improve the key STEMI process metrics for African American patients. Optimizing key STEMI process metrics is an important initiative to ensure equitable STEMI care.
Abstract 12043: Computed Tomography Angiography Assessment of Left Atrial Appendage Post Occluder Device
Authors: Tyler Miller, David Hana, Saikrishna Patibandla, Daniel Brito Guzman, Juan Carlo C Avalon, Irfan Zeb, Madhavi Kadiyala, Jim Mills, Sudarshan Balla, Mohammad Kawsara, Bryan Raybuck, Ramesh Daggubati, Partho P Sengupta, Yasmin S Hamirani
Journal: Circulation (2021)

Introduction: Device related thrombosis (DRT) is an indication for continuation of anticoagulation for patients undergoing left atrial appendage (LAA) occlusion. There is a paucity of data in regards to the definition of DRT on coronary CT angiography (CTA) in patients with WATCHMAN FLX TM (Boston scientific) device implantation. Methods: This is a single center experience of using CTA for follow up in patients post WATCHMAN FLX TM implantation. 37 consecutive patients who underwent WATCHMAN FLX TM implantation at our center and had CTA performed at first follow up were included. CTA images were analyzed for the presence of hypo-attenuated thickening (HAT) on the device, device positioning, peridevice gap, angulation, compression percentage, depth of implant from coumadin ridge and enhancement in the LAA compared to left atrium (LA). Results: Among 37 patients with CTA follow up, HAT was noted in 28 patients (75%). 38% of these patients had HAT &gt;3 mm. LAA patency (LAA/LA ratio of &gt;25%) was seen in 7 patients (10%), 4 with gaps around the device and the rest secondary to trans-fabric leak. Gap around the device was noted in 13 patients (35%). 6 of these 13 patients had &gt;4 mm gap; 5/6 patients had HAT and 3/6 patients had &gt;25% enhancement in the LAA compared to LA. Increased compression % on both CTA and intraprocedural TEE was associated with absence of HAT (p=0.0003) as well as better sealing on CTA (LAA/LA ratio of &gt;25%) (p=0.04). 6 months follow up is available on only 18 patients; only one of these patients had stoke and that patient did not have HAT on the CT scan. Conclusions: Definition of thrombus on WATCHMAN FLX TM device is not clearly defined on CTA. HAT on CTA could be artifact from the device knob and gutter or visible endothelialization around the device. Further studies with multimodality imaging and clinical correlation are needed to help determine normal cut offs for HAT on these CTAs.