tbuckley/cabot-search huggingface dataset:
Abstract 9710: Prevention of Doxorubicin-Induced Cardiotoxicity Through Targeted Degradation of Topoisomerase 2b
Authors: Hui-Ming Chang, Edward T Yeh
Journal: Circulation (2021)

Introduction: Doxorubicin-induced cardiotoxicity is a serious complication of cancer therapy recognized 40 years ago and remains to be a major clinical challenge today. Doxorubicin poisons topoisomerase 2a to kill cancer cells, whereas doxorubicin induces cardiotoxicity through topoisomerase 2b. When topoisomerase 2b was genetically deleted in the cardiomyocytes of adult mice, doxorubicin-induced cardiomyopathy can be prevented. Hypothesis: Pharmacological depletion of topoisomerase 2b in cardiac tissue could prevent doxorubicin-induced cardiomyopathy. Methods: Cell lines were treated with dexrazoxane (100 μM) for different time intervals with or without the proteasome inhibitor MG132 (10 μM). Cell lysates were immunoblotted with anti-topoisomerase 2a or 2b antibodies or anti-actin. Mice were injected with dexrazoxane (100 mg/kg IP) and cardiac tissues were analyzed for expression of topoisomerase 2b over time using western blot analysis. To study the effect of dexrazoxane pre-treatment on doxorubicin-induced chronic heart failure, C57BL/6 mice (n=7) were pre-treated with dexrazoxane (100 mg/kg IP) 8 hours before doxorubicin (5 mg/kg IP). Single injection of dexrazoxane (n=6), doxorubicin (n=8), or saline control (n=6) were also administered to three different cohorts of mice. This protocol was repeated weekly for 5 weeks. Pre-treatment and post-treatment cardiac MRI were obtained to evaluate the change in left ventricular ejection fraction. Results: Dexrazoxane induced a ubiquitin-dependent degradation of topoisomerase 2b, but not 2a in cell lines. In dexrazoxane-treated mice, topoisomerase 2b was not detectable 8 hours after dexrazoxane administration, but gradually returned to normal levels by 48 hours. Dexrazoxane pre-treatment 8 hours before doxorubicin prevented doxorubicin-induced reduction in ejection fraction as determined by cardiac MRI in a chronic heart failure model. Conclusions: Targeted degradation of topoisomerase 2b by dexrazoxane prevented doxorubicin-induced cardiotoxicity. Through selective degradation of topoisomerase 2b, but not 2a, doxorubicin's tumoricidal activity is preserved. This preventive strategy will be tested in a prospective clinical trial in breast cancer patients.
TAMI-02. DEPLETION OF INTRATUMORAL TUMOR-ASSOCIATED MACROPHAGES AND MICROGLIA (TAM/M) IMPROVES CHECKPOINT-INHIBITION THERAPY FOR BRAIN METASTASIS FROM LUNG CANCER
Authors: Philipp Karschnia, Tao Xu, Esther Fitzinger, Julia C Saliger, Jens Blobner, Nico Teske, Iven-Alex von Muecke-Heim, Sigrid Langer, Marcel Konhäuser, Hellen Ishikawa-Ankerhold, Niklas Thon, Jörg-Christian Tonn, Louisa von Baumgarten
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Brain metastases dramatically limit prognosis of lung cancer patients. Unlike systemic disease, brain metastases from lung cancer poorly respond to checkpoint-inhibition therapy. Targeting the immunosuppressive tumor-associated macrophages and microglia (TAM/M) and their receptor CSF1R may increase efficacy of checkpoint-inhibitors. METHODS Cranial windows were prepared in fully immunocompetent, transgenic CX3CR1GFP/wt-mice with green-fluorescent TAM/M. Intracranial injection of red-fluorescent Lewis Lung Carcinoma-cells was performed, and mice received one of the following three treatments: PD1-inhibition only (n = 8); PD1-inhibition combined with an anti-CSF1R-antibody (exhibiting limited blood-brain-barrier permeability under physiologic conditions, n = 8); or PD1-inhibition combined with a small molecular CSF1R-inhibitor (exhibiting high blood-brain-barrier permeability, n = 7). Tumor growth and TAM/M were followed by repetitive two-photon laser-scanning-microscopy over weeks. RESULTS Following intracranial injection, metastases were detected in all three treatment groups within eight days. In mice receiving PD1-inhibition only, metastases showed exponential growth which was paralleled by intra- and peritumoral accumulation of TAM/M. Treatment with an anti-CSF1R-antibody resulted in significantly lower numbers of intratumoral TAM/M given increased tumoral blood-brain-barrier permeability, but did not substantially affect peritumoral TAM/M or TAM/M localized in the healthy contralateral hemisphere. In contrast, treatment with a small molecular CSF1R-inhibitor not only reduced the number of intratumoral TAM/M, but also of peritumoral and contralateral TAM/M. Compared to PD1-inhibition only, the addition of either an anti-CSF1R-antibody or a small molecular CSF1R-inhibitor resulted in decreased tumor growth (tumor size on day 12: 8.3 mm2 (PD1-inhibition only) versus 0.9 mm2 (PD1-inhibition + anti-CSF1R-antibody) versus 2.5 mm2 (PD1-inhibition + small molecular CSF1R-inhibitor)) (p = 0.01). The beneficial effects of the small molecular CSF1R-inhibitor in reducing tumor growth were similar to those of the anti-CSF1R-antibody. CONCLUSION Targeting intratumoral TAM/M using CSF1-inhibition may increase the efficacy of checkpoint-inhibition therapy for cerebral lung cancer metastases. This approach warrants further evaluation in preclinical and clinical studies.
Abstract 10471: Prognostic Significance of Soluble Programed Cell Death Ligand-1 on Cardiovascular Outcomes in Patients with Atherosclerotic Cardiovascular Disease
Authors: Shuhei Miyazaki, Koichiro Fujisue, Kenshi Yamanaga, Eiichiro Yamamoto, Koichi Egashira, Takashi Komorita, Daisuke Sueta, Hiroki Usuku, Satoshi Araki, Seiji Takashio, Kenichi Matsushita, Kenichi Tsujita
Journal: Circulation (2021)

Background: Programmed Death-1(PD-1) and its ligand, PD-L1 regulate T cell proliferation and secretion of cytokines, leading to immunotolerance. A previous experimental study reported increased expression of PD-L1 in myocardium. Hence, PD-L1 could be associated with atherosclerotic cardiovascular disease (ASCVD). We hypothesized that serum soluble PD-L1 (sPD-L1) could be associated with cardiovascular events. We prospectively investigated the association between the serum levels of sPD-L1 and cardiovascular outcomes in patients with ASCVD. Methods: We prospectively measured sPD-L1 in patients with ASCVD admitted to Kumamoto University Hospital using a commercially available enzyme-linked immunosorbent assay kit and observed the occurrence of cardiovascular events between December 2017 and June 2019. The primary outcome was a composite of death from any cause, death from cardiovascular causes, nonfatal myocardial infarction, unstable angina pectoris, stroke, and heart failure hospitalization. We excluded patients complicated with cancer, hemodialysis, active collagen diseases, and inflammatory diseases. Results: Finally, 446 patients with ASCVD were enrolled. Median follow-up period was 322 days. A total of 153 events were recorded. Kaplan-Meier curve revealed that the higher sPD-L1 group (sPD-L1 ≧155pg/dL, median) showed significantly higher rate of cardiovascular events than the lower sPD-L1 group (19.2% vs. 28.1%, log-rank test: P =0.044). Univariate Cox proportional hazards analysis showed that creatinine, low density-lipoprotein cholesterol, B-type natriuretic peptide (BNP), and higher sPD-L1 (≧155pg/dL) were significantly associated with cardiovascular events. Multivariable Cox proportional hazards analysis by significant factors from univariate analysis identified that higher sPD-L1 [hazard ratio (HR): 1.699, 95% confidence interval (CI): 1.023-2.823, P =.041) and BNP (HR: 1.001, 95% CI: 1.000-1.001, P =0.036) were significantly and independently associated with cardiovascular events. Conclusions: The higher levels of sPD-L1 were significantly associated with near future cardiovascular events in patients with ASCVD, suggesting sPD-L1 could be a novel prognostic predictor in patients with ASCVD.
QOLP-23. EVALUATION OF FINANCIAL TOXICITY (FT) IN PEOPLE WITH RARE CENTRAL NERVOUS SYSTEM (CNS) TUMORS USING AN INNOVATIVE WEB-BASED STUDY DESIGN
Authors: Michael Timmer, Elizabeth Vera, Alvina Acquaye, Claudia Chambers, Alexa Christ, Jason Levine, Joseph Wooley, Heather Leeper, Margarita Raygada, Michael Scheurer, Kathleen Wall, Mark Gilbert, Terri Armstrong, Marta Penas-Prado
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Financial toxicity (FT) refers to the negative financial impact of cancer. Research exploring FT in patients with CNS tumors is limited to more common diagnoses or within single institutions. Total income, work interference and symptom burden are all key parameters when investigating FT in patients with rare CNS tumors. METHODS A web-based study of 210 participants’ responses to financial, clinical, symptom burden (MDASI-BT/MDASI-SP), depression and anxiety (PROMIS-Depression/Anxiety), work interference (SF-36) and general health status (EQ-5D-3L) is reported using descriptive statistics and tests of associations. RESULTS Patients were white (93%) employed (48%) females (72%), with median age of 47 (19-75). The most common diagnosis was ependymoma (80%). Original tumor location was the brain in 83 (40%) and spine in 115 (55%). Median time from tissue diagnosis was 48 months (0 – 402). Income was lower than the poverty level in 6% and lower than the median U.S. in 23%. A change in work due to their tumor was reported by 60%, with the majority stopping work (31%). One-third reported lack of access to health-care services and 10% required home care services. Difficulty walking was reported by 42% and difficulty in performing activities due to physical health by over 60%. Anxiety and depression scores aligned with the average for the U.S. population; however, 21% were taking antidepressants and 42% reported not being able to complete work or activities due to depression. Half of all patients reported moderate-severe pain, fatigue, and weakness with higher symptom burden and depression associated with change in work status (p &amp;lt; 0.003). CONCLUSION Patients with rare CNS tumors report an impact of their tumor diagnosis on activities/work patterns, with an associated higher symptom burden. Future studies exploring financial impact in patients with rare CNS tumors and targeted programs to address these outcomes are needed.
Abstract 10049: Outcomes, Trends and Predictors of Gastrointestinal Bleeding in Patients Undergoing Transcatheter Aortic Valve Implantation
Authors: Salman Zahid, Jay A Bapaye, Muhammmad Khan, Waqas Ullah, Hamza Zahid Ullah Muhammadzai, Mahesh Nepal, Muhammad Atif Khan, AAMER UBAID, Fnu Salman, Mian Tanveer Ud Din, Devesh Rai, Mohan Rao, bipul baibhav, Chadi Alraies, David L Fischman, Mahboob Alam, Sudarshan balla, Jeremiah Depta
Journal: Circulation (2021)

Introduction: Gastrointestinal bleeding remains one of the most common cause of major bleeding in patients undergoing transcatheter aortic valve implantation. Hypothesis: GI bleed is associated with worse outcomes in patients undergoing TAVI Methods: We investigated trends, outcomes and predictors of major bleeding from 2011 to 2018 using the national inpatient sample database. Results: A total of 216,023 weighted hospitalizations for TAVI were included in the analysis. Among the included hospitalizations, 2188 patients had GI bleed (1%) whereas 21,385 (99%) patients did not have GI bleed. Presence of peptic ulcer disease was found to be associated with the highest odds of having a GI bleed with an OR 10.24[95% CI, 7.93-13.22] followed closely by colorectal cancer OR 8.02[CI, 185.40-11.91]. Other comorbidities associated with higher adjusted rates of GI bleed were chronic kidney disease ([OR], 1.28[confidence interval (CI), 1.15-1.42]), congestive heart failure (OR, 201.21[CI, 1.08-1.35]), liver disease (OR, 1.82[CI, 1.52-1.2.18]), end stage renal disease (OR, 212.13[CI, 1.79-2.52]), atrial fibrillation (OR, 1.64[CI, 1.50-.77.]) and lung cancer (OR, 2.68[CI, 221.70-4.24]). Over the study period, mortality in patients with a GI bleed with TAVI decreased from 13.6% in 2011 to 11.50% in 2018 along with a decrease in mortality in TAVI without GI bleed group as well. Patients with GI bleed had increased mortality rates as compared those without GI bleed, (12.1% 10 vs 2.1%, p&lt;0.01). Conclusions: In conclusion, we report that mortality is higher in TAVI patients with a GI bleed. Presence of peptic ulcer disease, colorectal cancer or baseline comorbidities like atrial fibrillation and end stage renal disease are important predictors of this adverse event.
Abstract 13954: Family Caregivers’ Experience of Caring for Patients Implanted With Left Ventricular Assist Device: A Mixed-Method Study
Authors: Ashley J Xu, Mengchi Li, Samuel Byiringiro, Jennifer Wenzel, Cheryl Dennison
Journal: Circulation (2021)

Introduction: Informal caregivers of patients with left ventricular assist device (LVAD) juggle benefits and burdens of caregiving and experience uncertainty of LVAD trajectory. This study explored the experience of caring for patients with LVAD and factors leading to uncertainty among caregivers. Methods: This mixed-methods, descriptive study included online surveys and focus groups. Family caregivers (N=140) were recruited from Facebook communities for the online survey (demographic variables, patient factors, Uncertainty in Illness Scale, Medical Outcome Study Social Support Survey, and CAregiver Perceptions About Communication with clinical Team member measure) and a subset of these (N=20) were recruited for online focus groups. Data were summarized and quantitative / Qualitative data compared for convergence. Results: Caregivers averaged 54 years (SD=12), were female (89%) spouses (66%) who had been caregiving for less than 5 years (83%). The quantitative results regarding uncertainty and its associated variables: social support, perception of change after implant, and communications with health care providers were mirrored in the content of three of the categories that evolved from the qualitative analysis. Caregivers with lower social support reported high uncertainty in focus groups and had higher uncertainty scores. Those with higher social support reported lower uncertainty. Caregivers with higher uncertainty reported varying levels of communication with providers. Majority of caregivers reported life changed for the worse (increase burdens, lifestyle adjustments, patient care regime) after LVAD implantation regardless of their uncertainty levels. Conclusions: Caregivers' experiences varied as they adjusted to this complex life-transforming experience. Overall, the survey and focus group data were convergent. Caregivers with higher social support and better communication with health care providers may experience less uncertainty. This study underscores the need to enhance social support and communication with healthcare team to decrease uncertainty and improve the caregiver experience.
Abstract 10085: Risk Profiles and Outcomes of Patients Receiving Antibacterial Cardiovascular Implantable Electronic Device Envelopes
Authors: David Woodard, Grace Kim, Jonathan R Murrow, Kent R Nilsson
Journal: Circulation (2021)

Background: Antibacterial cardiovascular implantable electronic device (CIED) envelopes provide short-term local antibiotic delivery and can reduce implant site infection risk. Available antibacterial CIED envelopes are either fabricated from biologic material (extracellular matrix hydrated with antibiotics by the user) or from non-biologic material (synthetic mesh coated with antibiotics by the manufacturer). Objective: To compare the risk profiles and outcomes of CIED procedure patients receiving no envelope vs an antibacterial envelope. Methods: Records of consecutive CIED procedure patients at one center were reviewed through 12 months follow-up. Procedures used either no envelope, a biologic envelope pre-hydrated with vancomycin and gentamicin (BIO) [CanGaroo®, Aziyo Biologics], or a non-biologic envelope coated with minocycline and rifampin (Non-BIO) [TYRX™, Medtronic]. Results: CIED procedures were performed on 248 patients (191 with envelope, 89 BIO, 102 Non-BIO). Patients receiving envelopes were younger, had significantly more comorbid risk factors (p&lt;0.001), and received high powered devices and reoperative procedures more often (p&lt;0.001)(Table 1). BIO envelopes were used more often in higher risk patients (84% vs 78%) and reoperative patients (62% vs 38%) compared to Non-BIO envelopes. CIED implant site pocket infection rates were low (envelope 0.5%, no envelope 0%, p=0.584), with no significant difference between BIO and Non-BIO envelopes. Conclusion: Antibacterial envelopes were used more often to treat patients with multiple comorbid risk factors. Biologic envelopes were used more often in higher risk patients. There was no significant difference in CIED implant site pocket infection rates for patients receiving biologic or non-biologic antibacterial envelopes.
Kidney vascular congestion exacerbates acute kidney injury in mice
Authors: Takashi Kitani, Kengo Kidokoro, Tomohiro Nakata, Yuhei Kirita, Itaru Nakamura, Kunihiro Nakai, Aya Yagi-Tomita, Tomoharu Ida, Noriko Uehara-Watanabe, Kisho Ikeda, Noriyuki Yamashita, Benjamin D. Humphreys, Naoki Kashihara, Satoaki Matoba, Keiichi Tamagaki, Tetsuro Kusaba
Journal: Kidney International (2021)
Abstract P379: Inhibition Of O-glcnac Transferase Ogt Activates P38 Signaling In Neonatal Rat Cardiomyocytes
Authors: Kyriakos Papanicolaou, Natasha Zachara, Deepthi Ashok, Agnes Sidor, D B Foster, Brian O'Rourke
Journal: Circulation Research (2021)

The mitogen activated protein kinase (MAPK) p38 is important in cardiac hypertrophic responses and p38 inhibition has been tested as a potential therapeutic approach to heart failure. p38 is tightly regulated by upstream kinases and phosphatases. While p38 inhibitors suppress cardiac hypertrophy in vitro and in animal models, the partial efficacy of p38 inhibitors in clinical trials for heart failure illustrates the need for a deeper understanding of p38-regulatory mechanisms. O -linked N-Acetylglucosamine ( O -GlcNAc) on Ser/Thr residues is a ubiquitous intracellular modification ( O -GlcNAcylation) that participates in intracellular signaling, often occurring in counterpoint to phosphorylation. O -GlcNAcylation is catalyzed by O -GlcNAc Transferase (OGT) and removed by O -GlcNAc-Ase (OGA). Given the crucial regulation of p38 activity by phosphorylation, we hypothesized that O -GlcNAcylation regulates p38 phosphorylation during basal and hypertrophic cardiomyocyte signaling. Treating neonatal rat ventricular myocytes (NRVM) with OSMI-1 (inhibitor of OGT) significantly decreased O -GlcNAcylation (0.48 ± 0.02, P &lt;0.001 vs. vehicle), whereas treatment with Thiamet-G (inhibitor of OGA) significantly increased O -GlcNAcylation (3.0-fold increase ± 0.35, P &lt;0.05 vs. vehicle). OSMI1 treatment induced the phosphorylation of p38 at its activation site (3.9-fold increase ± 0.46, P &lt;0.001 vs. vehicle) and promoted the phosphorylation of the downstream target, heat shock protein Hsp27 (8-fold increase ± 1.3, P &lt;0.0001 vs. vehicle) and transcription factor Creb (3.3-fold increase ± 0.12, P &lt;0.001 vs. vehicle). OSMI-1 had an additive effect in inducing p38 and Creb phosphorylation following hypertrophic stimulation by phenylephrine (3.1-fold and 1.4-fold increase vs. phenylephrine respectively, P &lt;0.05). Treatment with the p38 inhibitor SB202190 abolished the phosphorylation of Hsp27 and Creb that was induced by OSMI-1. Canonical upstream activators of p38 include the MAP3Ks, TAK1 and ASK1. However, we found that treatment with ASK1 or TAK1 inhibitors (GS-444217 and Takinib, respectively) either alone, or in combination, did not negate the phosphorylation of p38 by OSMI-1. We conclude that regulation of p38 by OGT activity could occur at a level downstream of canonical MAP3Ks or through non-canonical pathways.
Abstract P446: Cyclophilin D Inhibition Rescues Cardiac Function And Electron Transport Chain Assembly And Activity In Hypoxia Exposed Neonatal Mice
Authors: Jonathan Burris, Gisela Beutner, George A Porter
Journal: Circulation Research (2021)

Introduction: Mitochondria play a critical role in cardiac myocyte physiology and differentiation. Hypoxia decreases cardiac function. Changes in embryonic heart metabolism at the level of the electron transport chain (ETC) are regulated by a chaperone protein known as cyclophilin D (CypD). Inhibition of CypD with chemicals such as cyclosporin A (CsA) and N-methyl-4-isoleucine cyclosporin (NIM811) leads to more complex mitochondrial structure and effective oxidative phosphorylation. Hypothesis: Inhibition of CypD with CsA or NIM811 will rescue the detrimental effects of hypoxia on cardiac function and on ETC assembly and activity. Methods: Mice were exposed to continuous hypoxia (12% oxygen) immediately before birth (gestational age E19.5) to postnatal day 7 (P7). Hypoxic mice received no treatment (No Tx) or intraperitoneal injections 10mg/kg of vehicle (VEH), CsA, or NIM811 from P1 to P6. Litters of mice born into room air served as controls. On P7, mice were anesthetized and underwent echocardiography and/or hearts were harvested for mitochondrial isolation. Enzymatic activity of ETC complexes was quantified using spectrophotometry and normalized to total protein. To measure physical assembly of complex I &amp; V of the ETC, high resolution clear native polyacrylamide gel electrophoresis (HCRN PAGE) followed by in-gel assays were utilized using appropriate protein loading controls. Results: Cardiac ejection fraction was decreased in hypoxic No Tx (P&lt;0.0001) and VEH (P&lt;0.0001), but was rescued by CsA or NIM811 when compared to room air controls (P&gt;0.05). Heart weight to body weight ratio was increased in No Tx and VEH groups (P&lt; 0.0001) and rescued in the CsA and NIM811 groups when compared to room air controls (P&gt;0.05). Complex I enzymatic activity was rescued with treatment with CsA and NIM811. HCRN PAGE followed by in-gel ETC complex assay demonstrated assembly of complexes I and V into dimers and tetramer in the room air, CsA, and NIM811 groups that was not seen in the No Tx and VEH groups. Conclusion: Pharmacologic inhibition of CypD reversed the effects of hypoxia on cardiac function and ETC activity and assembly in the neonatal heart. Our studies may help develop therapies to treat neonatal cardiomyopathies and the effects of hypoxia on the neonatal heart.
Abstract 12142: Intravascular Ultrasound Guided Percutaneous Coronary Intervention Improves Acute Angiographic Results & 1-year Clinical Outcomes for Patients With Chronic Total Occlusion
Authors: Jiachen Bi, Kongto Hau, Bryan P Yan
Journal: Circulation (2021)

Introduction: Intravascular ultrasound (IVUS) on long-term clinical outcomes in patients undergoing percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) is not well establishe...
Variation in Use of Immunoglobulin and Impact on Survival in Multiple Myeloma: A Report from the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR)
Authors: Khai Li Chai, Cameron Wellard, Elizabeth M. Moore, Bradley Augustson, Akshay Bapat, Hilary Anne Blacklock, Rachel Elizabeth Cooke, Cecily Forsyth, Nada Hamad, Simon J Harrison, Phoebe Joy Ho, Jay Hocking, Ian H. Kerridge, Tracy King, Georgia J McCaughan, Peter Mollee, Orla Morrissey, Nicholas E. Murphy, Hang Quach, Xuan Ni Tan, Kimberly Wong, Andrew Spencer, Erica M. Wood, Zoe McQuilten
Journal: Blood (2021)
Phase 1/2 Study Investigating CC-90011, a Potent, Selective, and Reversible Oral Inhibitor of Lysine-Specific Demethylase 1 (LSD1), Plus Concurrent Venetoclax (VEN) and Azacitidine (AZA) in Patients with Acute Myeloid Leukemia (AML)
Authors: Courtney D. DiNardo, Gautam Borthakur, Brian Ball, Harry P. Erba, Raya Mawad, Marina Kremyanskaya, James S. Blachly, Hetty E. Carraway, Ahrim Youn, Jessica Garzon, Daniel Lopes de Menezes, Patricia Martin-Regueira, C.L. Beach, Justin Watts
Journal: Blood (2021)