tbuckley/cabot-search huggingface dataset:
Abstract 10868: Risk Factors and Long-Term Outcomes of Cardiogenic Shock in Young Patients with Myocardial Infarction - The Mass General Brigham Young-MI Registry
Authors: Hasan K Siddiqi, Ersilia M Defilippis, David W Biery, Avinainder Singh, Wanda Wu, Sanjay Divakaran, Adam N Berman, Erin Bohula, Garrick Stewart, MARCELO DI CARLI, Deepak L Bhatt, Ron Blankstein
Journal: Circulation (2021)

Introduction: Cardiogenic shock complicating acute myocardial infarction (CS-AMI) is associated with high morbidity and mortality, yet data among younger individuals are limited. Methods: Retrospective cohort study of consecutive AMI patients aged 18-50 years admitted to 2 tertiary care academic centers from 2000-2016. CS was determined by physician review of electronic health records (EHR) using the SCAI CS classification system. Baseline characteristics, treatment and outcomes including all-cause mortality (ACM), cardiovascular mortality (CVM) and 1-year hospitalization for heart failure (HHF) were adjudicated by physicians using EHR and death records. Mahalanobis distance matching was used to define a comparator group in the non-CS cohort. Results: The study included 2097 AMI patients (mean age 44 ± 5.1 years, 74% white, 81% male), with CS-AMI identified in 148 (7%) patients. There were no significant differences in age, sex or race between groups, although CS-AMI patients were more likely to have public or no insurance (p=0.02). Independent factors associated with CS-AMI included female sex, STEMI at presentation, out of hospital cardiac arrest, left main coronary disease, diabetes and peripheral artery disease. Over a median follow up of 11.2 years, compared to 461 matched non-CS-AMI patients and controlling for relevant covariates, CS-AMI patients had significantly higher ACM (aHR 2.84, p&lt;0.001), CVM (aHR 4.09, p&lt;0.001), and 1-year HHF (aHR 6.18, p=0.001) (Figure 1). In landmark analyses, CS-AMI patients who survived to discharge continued to have significantly higher risk of CVM (aHR 2.76, p=0.016) compared with matched non-CS AMI patients. All results were similar in the full cohort comparison. Conclusion: Cardiogenic shock is infrequent amongst young AMI patients, but associated with substantially higher overall and post-discharge mortality, and 1-year heart failure hospitalizations after AMI compared to those without cardiogenic shock.
Letermovir Prophylaxis Versus Pre-Emptive Therapy for Cytomegalovirus after Hematopoietic Stem-Cell Transplantation
Authors: Giulia Gabrielli, Danilo Giuseppe Giuseppe Faraci, Aurora Martin, Giuseppe Lia, Sara Butera, Irene Dogliotti, Cerrano Marco, Giovannino Ciccone, Simone Ferrero, Anna Castiglione, Elisa Zanotto, Rossana Cavallo, Chiara Maria Dellacasa, Alessandro Busca, Benedetto Bruno, Luisa Giaccone
Journal: Blood (2021)
Abstract 13033: Cavin/Caveolin Interaction Modulates BMP/Smad Signaling in Pulmonary Artery Endothelial Cells
Authors: Shinya Tomita, Naohiko Nakanishi, Takehiro Ogata, TAKAOMI SUGA, Yumika Tsuji, Yusuke Higuchi, Satoaki Matoba
Journal: Circulation (2021)

Background: Pulmonary hypertension (PH) is a progressive disease associated with poor prognosis. Caveolin-1 (Cav1) and Cavin-1 are components of caveolae, and both interact with each other and influence the composition and stabilization of caveolae. Cav1 is identified as a related gene of pulmonary arterial hypertension (PAH). Gene mutation of bone morphogenetic protein type II receptor (BMPRII) is the most common cause of PAH. BMPRII is localized in caveolae and associates with Cav1. However, the role of the Caveolin-Cavin system on the BMP/Smad signaling and the PAH progression has not been well-known. Methods and Results: As in previous reports, Cav1 knockout mice exhibited PH with pulmonary vascular remodeling and right ventricular hypertrophy. Caveolae disappeared in pulmonary microvascular endothelial cells of Cav1 knockout mice. We then examined the role of Caveolin-Cavin and the association with BMP/Smad signaling in human pulmonary artery endothelial cells (hPAECs). Cav1 knockdown in hPAECs reduced BMPRII at the plasma membrane and Smad 1/5/9 phosphorylation. Cav1 knockdown also significantly increased hypoxia-induced apoptosis in hPAECs. Cav1 was associated with BMPRII at the membrane of hPAECs. In addition, Cavin-1 inhibited the interaction of BMPRII with Cav1 and reduced BMPRII localization on the membrane of hPAECs. Cavin-1 knockdown reversed BMPRII localization at the plasma membrane and Smad 1/5/9 phosphorylation induced by Cav1 knockdown. Both Cavin-1 and BMPRII were associated with the Cav1 scaffolding domain. These results suggest that Cavin-1 interacts with Cav1 and inhibits the association of Cav1 with BMPRII, resulting in modulating Smad signaling pathway. Conclusions: Cavin-1 and BMPRII are competitively associated with Cav1 at the plasma membrane and modulating BMP/Smad signal transduction in PAECs. Our findings reveal a previously undescribed mechanism via Cavin-Caveolin interaction in BMP/Smad signaling-modulated PH development.
Abstract 13975: Macrophage Specific Lipoxygenase Deletion Amplify Cardiac Repair Activating Treg in Chronic Heart Failure
Authors: Gabriel A Grilo, Charles N Serhan, jerry nadler, Vasundhara Kain, Ganesh V Halade
Journal: Circulation (2021)

Introduction: Splenic leukocytes, particularly macrophage (Mφ)-expressed lipoxygenases, facilitate the biosynthesis of resolution mediators essential for cardiac repair. Next, we asked whether deletion of 12/15 lipoxygenase (12/15LOX) in Mφ may impede resolution mediators and impair cardiac remodeling after coronary ligation in heart failure (HF). Hypothesis: To determine Mφ-specific inflammation-resolution signaling in cardiac repair and HF, we tested whether Mφ-specific deletion of 12/15LOX delays resolution of inflammation in HF. Methods: Using 12/15 flox/flox and LysMcre scheme, we generated Mφ-specific 12/15LOX (Mφ-12/15LOX -/- ) mice and LOX deletion validated in Mφ. Risk-free young adult (8-12-week-old) C57BL/6J wild-type (WT; n=43) and Mφ-12/15LOX -/- male mice (n=40) were subjected to permanent coronary artery ligation surgery (MI; myocardial infarction). Mice were monitored at day (d)1, d5 (as acute HF; AHF), and to d56 (chronic HF; CHF) post-MI, maintaining no-MI mice as d0 naïve controls. Cellular and molecular events of cardiac repair were determined in AHF and CHF. Results: Post ligation, Mφ-12/15LOX -/- mice showed increased survival (88% vs. 56%) and limited heart dysfunction compared with WT. In AHF, Mφ-12/15LOX -/- mice have increase biosynthesis of CYP2J-derived epoxyeicosatrienoic acid (EET), particularly 11,12 EET in the infarcted heart. Overall, myeloid cell profiling from both heart and spleen indicated that Mφ-12/15LOX -/- mice showed a higher number of immune cells during AHF. In addition, the detailed immune profiling revealed reparative Mφ phenotype (Ly6C low ) in Mφ-12/15LOX -/- mice with higher expression of Arg-1 in a splenocardiac manner post-MI. Mφ-12/15LOX -/- mice showed an increase in myeloid population in CHF that coordinated increase of T regs (CD4+/ Foxp3+) in spleen and injured heart compared with WT. Conclusions: Thus, deletion of 12/15 LOX in Mφ direct reparative phenotype to facilitate cardiac repair marked with biosynthesis of EETs in acute HF and activated T regs in CHF thereby improved survival. The presented study outlines the complex role of 12/15LOX in Mφ plasticity, T reg cell signaling, and indicate that resolution mediators are viable target to expedite cardiac repair in HF.
Use of High Dose Cytarabine (HiDAC) for Post-Remission or Re-Induction Therapy Is Safe and Effective in Select Older AML Patients
Authors: Jillian Lykon, Ellen Madarang, Nina Nguyen, Wenhui Li, Sunil G. Iyer, Michele Stanchina, Terrence Bradley, Justin Taylor, Namrata Sonia Chandhok, Mikkael A. Sekeres, Justin Watts
Journal: Blood (2021)
Treatment Patterns and Outcomes in Lenalidomide-Exposed Multiple Myeloma Patients in Real-World Settings: A Multi-Center Retrospective Study
Authors: Maria Eduarda Couto, Marina Borges, Maria José Bento, Rita Calisto, Marta Daniela Marques Magalhaes, Adil Ajmal, Nicolas Niklas, Kirill Dushkin, Finlay MacDougall, Andrea Wolf, Shabnam Shaid, Ivana von Metzler
Journal: Blood (2021)
Abstract 13272: Modeling Cardiotoxicity Utilizing Human Pluripotent Stem Cell-Derived Cardiomyocytes: Towards Protective Therapy for the Heart
Authors: Verena Schwach, Rolf H Slaats, Carla Cofino Fabres, Simone A ten Den, Jose Rivera-Arbelaez, Sabina van der Zanden, Jacques Neefjes, Marcelo C Ribeiro, Lu Cao, Robert Passier
Journal: Circulation (2021)

Introduction: Cardiotoxicity is one of the main adverse effects of cancer therapy and has been extensively assessed in animal models which are not predictive for drug-induced cardiotoxicity in humans. Human pluripotent stem cell (hPSC)-derived cardiomyocytes provide a reliable source of human cardiomyocytes and have already proven valuable for cardiotoxicity studies. We present here a versatile screening platform, utilizing hPSC-cardiomyocytes, for assessing different aspects of cardiotoxicity. Methods and Results: A well-known group of anticancer drugs that cause therapy induced cardiotoxicity are anthracyclines. To validate their toxicity on human cells we compared the uptake of Doxorubicin (DOXO) and two of its analogues Amrubicin (AMR) and Aclarubicin (ACLA) into cardiomyocytes and fast dividing hPSCs. We utilized high throughput time-lapse imaging of cardiomyocytes differentiated from an NKX2.5 eGFP -α-actinin mRuby2 hPSC reporter for assessment of viability and sarcomeric disarray by creating binary masks of the fluorescent area. After 5 days less than 25% of sarcomeres were still present and about 20% of cardiomyocytes survived treatment with 1 μM DOXO or ACLA. Moreover, we evaluated the cardiotoxic effect on a functional level by evaluating calcium transients and identified faster rates after DOXO or ACLA treatment. In addition to analysis in 2D monolayers, we also established a more advanced platform for creating 3D engineered heart tissues, more closely resembling the human heart, which allowed us to measure the effect of a cumulative drug dose on cardiac contraction. We quantified contractile force and kinetics every 12 h for 3 days and observed total loss of contraction 60 h after treatment with 5 or 10 μM DOXO, 75% reduction with 5 μM ACLA and no loss of contraction with 5 μM AMR.To study different damage mechanisms, we investigated apoptotic marker Annexin V, DNA damage marker pH2AX, calcium accumulation and expression of cardiac genes. Conclusion: These assays enabled us to study the cardiotoxic effect of DOXO and two analogues on hPSC-derived cardiomyocytes. Most importantly, treatment with AMR had no effect on cardiac function. Ultimately our platform for assessing cardiotoxicity will lead to a better and safer treatment of patients.
Changes in inferior vena cava area represent a more sensitive metric than changes in filling pressures during experimental manipulation of intravascular volume and tone
Authors: Juan B. Ivey‐Miranda, Friedrich Wetterling, Robert Gaul, Stephen Sheridan, Jennifer L. Asher, Veena S. Rao, Christopher Maulion, Devin Mahoney, Alexandre Mebazaa, Alastair P. Gray, Daniel Burkhoff, Martin R. Cowie, Zachary L. Cox, Javed Butler, Marat Fudim, Kenneth McDonald, Kevin Damman, Barry A. Borlaug, Jeffrey M. Testani
Journal: European Journal of Heart Failure (2021)

Remote monitoring of pulmonary artery pressure has reduced heart failure (HF) hospitalizations in chronic HF as elevation of pulmonary artery pressure provides information that can guide treatment. The venous system is characterized by high capacitance, thus substantial increases in intravascular volume can occur before filling pressures increase. The inferior vena cava (IVC) is a highly compliant venous conduit and thus a candidate for early detection of change in intravascular volume. We aimed to compare IVC cross-sectional area using a novel sensor with cardiac filling pressures during experimental manipulation of volume status, vascular tone, and cardiac function.Experiments were conducted in sheep to manipulate volume status (colloid infusion), vascular tone (nitroglycerin infusion) and cardiac function (rapid cardiac pacing). A wireless implantable IVC sensor was validated ex-vivo and in-vivo, and then used to measure the cross-sectional area of the IVC. Right- and left-sided cardiac filling pressures were obtained via right heart catheterization. The IVC sensor provided highly accurate and precise measurements of cross-sectional area in ex-vivo and in-vivo validation. IVC area changes were more sensitive than the corresponding changes in cardiac filling pressures during colloid infusion (p < 0.001), vasodilatation (p < 0.001) and cardiac dysfunction induced by rapid pacing (p ≤ 0.02).Inferior vena cava area can be remotely and accurately measured in real time with a wireless implantable sensor. Changes in IVC area are more sensitive than corresponding changes in filling pressures following experimental volume loading and fluid redistribution. Additional research is warranted to understand if remote monitoring of the IVC may have advantages over pressure-based monitors in HF.
RTID-06. TRENDS IN INTERNATIONAL INVESTMENT IN CHILDHOOD, ADOLESCENT AND YOUNG ADULT (CYA) BRAIN TUMOR RESEARCH 2006-2018, WITH A FOCUS ON DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Lynne Davies, Amy Weinstein
Journal: Neuro-Oncology (2021)

Abstract Organizations funding brain tumor research want to identify gap areas for funding individually or in collaboration and want to better understand existing project focus to maximize new project investments. The International Cancer Research Partnership and the US Coalition Against Childhood Cancer used international research portfolio data to assess the landscape of CYA brain tumor research. From 2006-2018, investment for brain tumor research increased from $13m to $73m, and as a percentage of the CYA portfolio, brain tumor research received the highest percent investment (30%) in 2018. Research into treatment had risen (from $6m to $38m) as had research into biology (from $3m to $19m) - an essential foundation for more future personalized treatments. Given the lifelong impact on survivors it was encouraging that survivorship research investment had also started to increase. While 5-year survival for CYA cancers is now over 80%, survival for Diffuse Intrinsic Pontine Glioma (DIPG) remains very low. To assess capacity for future progress, several indicators were considered. The number of new DIPG projects per year increased from an average of 3 per year (2006-2012) to 11 (2013-2018) and funding increased from $0.5m (2006) to $10m (2018). Also, by 2018, 9 projects included a training component to build future research capacity. The number of laboratories researching DIPG increased from 2 in the US (2006) to 53 institutions in 6 countries (2018). Recent years had seen increased funding for pre-clinical models essential for identifying new targets. Collaborative initiatives such as DIPG-Open and DIPG-All had been funded to collect biological samples and accelerate translation of therapeutics to the clinic. Despite evidence that 5-year survival had improved from 1% to 2%, clearly major advances need to be made in new treatments, and monitoring the funding landscape carefully to make strategic investments will be essential.
Sexually Transmitted Infections and Preterm Birth—Attempting to Pin Down Targets for Intervention From Population-Level Observational Data
Authors: Emily H. Adhikari, Scott Roberts
Journal: JAMA Network Open (2021)

Rui Gao, MD, PhD; Buyun Liu, MD, PhD; Wenhan Yang, MD, PhD; Yuxiao Wu, MS; Bo Wang, MD, PhD; Mark K. Santillan, MD, PhD; Kelli Ryckman, PhD; Donna A. Santillan, PhD; Wei Bao, MD, PhD
NIMG-15. 2-HYDROXYGLUTARATE MAGNETIC RESONANCE SPECTROSCOPY IN ADULT BRAINSTEM GLIOMA PATIENTS
Authors: Hiroaki Nagashima, Kazuhiro Tanaka, Yuichi Fujita, Mitsuru Hashiguchi, Mashahiro Maeyama, Yuichiro Somiya, Takanori Hirose, Tomoo Itoh, Takashi Sasayama
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE The onco-metabolite, 2-Hydroxyglutarate (2HG), is non-invasive biomarker for detecting isocitrate dehydrogenase (IDH) mutant glioma by MR-Spectroscopy. Especially 2HG-MRS may be useful in patients with brainstem lesions, where surgical biopsy presents high risk of neurological injury. Here, we examined the utility of 2HG-MRS for diagnosis of IDH mutant adult brainstem glioma. METHODS We conducted 3 tesla -MRS (3T-MRS) in 8 radiographically identified brainstem tumor (7 male and 1 female, median age 39). Single-voxel was localized from the T2-FLAIR using a 2HG-tailored MRS protocol (Philips, Achieva, PRESS, TE 35 ms). All patients underwent tumor biopsy using an intraoperative navigation system (Brain LABTM) or stereotactic biopsy system (Komai’s CT-stereotactic frame) before initial treatment. IDH and H3K27M status were diagnosed by IHC and DNA sequence. RESULTS 3 cases were H3K27M and 4 cases were IDH mutant (R132H 1 case, R132S 2 cases, and R132G 1 case). 1 case were neither H3K27M nor IDH mutant. H3-K27 and IDH1 mutations were mutually exclusive. All tumor located at pons. There were no significant radiological difference between H3K27M and IDH mutant in conventional MRI sequence. Pearson's chi-square test demonstrated that 2HG concentrations &amp;gt;1.5 mM were 100% sensitive and 75% specific for IDH mutant glioma (p = 0.0285). The median overall survival survival were 127 month in IDH mutant glioma (n=4) and 22.5 months in IDH wild-type glioma (n=4), respectively. CONCLUSIONS 2HG in adult brainstem glioma was detected by conventional 3T-MRS successfully. A noninvasive 2HG-MRS may be useful diagnostic modality for evaluating molecular status and prognosis in brainstem glioma noninvasively.
Minimal Residual Disease Assessment in CLL/SLL: Is It Ready for Routine Clinical Practice?
Authors: Jennifer A. Woyach
Journal: Journal of the National Comprehensive Cancer Network (2021)

Minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL) is defined as &lt;1 CLL cell per 10,000 leukocytes (0.01%; &lt;10 −4 ). Flow cytometry and next-generation sequencing have demonstrated high sensitivity in MRD detection. MRD assessment may help to determine prognosis after fixed-duration regimens; this has been established in the contexts of chemoimmunotherapy and venetoclax/antibody combinations. In the short term, MRD status does not seem to inform prognosis in patients treated with a BTK inhibitor plus venetoclax-based regimens; however, long-term data will be needed to determine whether it is beneficial in this population. Numerous trials have demonstrated that MRD may be used to guide therapy. It is unclear whether using an MRD-guided treatment strategy is better than using fixed-duration therapy; ongoing and future studies are warranted.
Abstract 13833: Cardiac Sympathetic Denervation in Patients With Ventricular Tachycardia or Electrical Storm: A 6 Months Follow-Up
Authors: Ahmad Mahmoud, Yasmeen Taha, Seri Hanayneh, Yazan Assaf, Omkar Betageri, Mohammed Elzeneini, Carl Pepine, Matthew Mckillop, Ramil Goel
Journal: Circulation (2021)

Introduction: Cardiac sympathetic denervation (CSD) is considered in the management of patients with refractory ventricular arrhythmias or storm. It has been shown to decrease the burden of ventricular arrhythmias and the ICD shocks acutely in previous studies, however, follow-up data is still limited. Hypothesis: The purpose of this study is to evaluate ventricular tachycardia (VT) recurrence within a 6-month period after CSD. Methods: We analyzed all patients who underwent CSD at the University of Florida hospital between 2011 to 2017. The primary outcome was the recurrence of sustained VT at 6 months. The burden of ICD shocks, the need for VT ablation/redo ablation, and cardiovascular-related mortality in the first 6 months were also reported. Results: A total of 29 patients with CSD were included (9 patients had left CSD and 20 patients had bilateral CSD, mean age 60.1±11.5, 86 % male, and EF 27.3±15.4% by 2D-echocardiography), 13 (44.8%) of them presented with VT storm and 15 (51.7%) had prior VT ablation. One patient had cardiovascular-related mortality by 1 month and 7 patients by 6 months. The rate of VT recurrence was 31% by 1 month and increased to 35% by 6 months. By the end of the follow-up period, 17 (58.6%) patients remained free of recurrent ICD shocks and VT ablation was needed in 12 (41.4%) patients, 6 of them were redo-ablations. We further divided patients based on the underlying heart disease including ischemic heart disease (HD) and non-ischemic HD and there was no difference in the rate of VT recurrence at 6 months (p=0.18). There was also no difference in the primary outcome between left only CSD and bilateral CSD (P=0.98). Conclusions: Our data show that CSD showed benefit in VT recurrence rate at 6 months post-procedure. Reduction and freedom of ICD shocks were noted in patients with refractory VT or electrical storm. These benefits were independent of the underlying heart disease etiology. More studies with a longer follow-up period are warranted to confirm these results and follow long-term outcomes.
Abrocitinib: First Approval
Authors: Emma D. Deeks, Sean Duggan
Journal: Drugs (2021)

Abrocitinib (Cibinqo®) is an oral small-molecule inhibitor of Janus kinase 1 (JAK1) being developed by Pfizer for the treatment of moderate-to-severe atopic dermatitis (AD). In September 2021, abrocitinib was approved in the UK and Japan for the treatment of moderate-to-severe AD in adults and adolescents 12 years and older who are candidates for systemic therapy. Abrocitinib has also received a positive CHMP opinion in the EU for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy. Regulatory applications for the drug have also been submitted for review to several other countries, including the USA and Australia. This article summarizes the milestones in the development of abrocitinib leading to this first approval for the treatment of moderate-to-severe AD.
Abstract 10130: Immediate Changes of Transesophageal Echocardiographic Findings in Percutaneous Closure of Atrial Septal Defects
Authors: Takehiko Yokoyama, Sachiko Inukai, Kenji Furusawa, Mamoru Nanasato, Masaki Takenaka
Journal: Circulation (2021)

Introduction: Atrial septal defects (ASD) are treated with percutaneous closures that subsequently increase the left ventricular volume load. This retrospective study aimed to assess the change in transesophageal ultrasound indices and to determine the search associated post-closure left diastolic index. Subjects: We enrolled 62 patients who underwent percutaneous closure of ASD in our hospital between January 2018 and November 2020. Method: Percutaneous ASD closure was performed under general anesthesia. We measured left ventricular inflow (early diastolic flow velocity, E; atrial contraction flow velocity, A; E-wave deceleration time, DT), mitral annulus velocity by tissue doppler imaging at lateral annulus (early diastolic myocardial velocity, E'; atrial contraction velocity, A'), and pulmonary venous blood flow velocity (peak systolic velocity, S; diastolic velocity, D; atrial systolic regurgitation velocity, AR; atrial systolic regurgitation time, AD) using transesophageal echocardiography (TEE). The ratio of E and E' (E/E') was calculated for and compared between before (pre) and after (post) ASD closure. Statistical analysis was performed using the EZR software. Wilcoxon's code order test was used for comparison, and multivariate correlation analysis was performed with post-occlusion E/E' as the objective variable. Statistical significance was set at p&lt;0.05. Results: Significant changes were seen in A', E', E, S, D, AD, and E/E'. Multivariate correlation analyses revealed a significant association of post E/E’ with the pre E/E’ and pre AR. Conclusion: In this study, the pulmonary venous flow velocity was found to decrease during systole and diastole following ASD closure. The DT did not change; thus, there was no change in the stiffness of the left ventricle. We concluded that the increased left ventricular volume load caused the increase in the left end-diastolic pressure.