tbuckley/cabot-search huggingface dataset:
Abstract 12493: Comparison of Coronary Plaque Progression by Coronary Computed Tomography Angiography in Systemic Lupus Erythematosus and Rheumatoid Arthritis
Authors: Jeff Moore, Suvasini Lakshmanan, April Kinninger, Matthew Budoff, George Karpouzas
Journal: Circulation (2021)

Introduction: Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are autoimmune diseases associated with high incidence of cardiovascular disease (CVD), likely related to common underlying pathways of inflammation. Characterization of coronary atherosclerosis, particularly total plaque (TP) and total non-calcified plaque (TNCP), on Coronary Computed Tomography Angiography (CCTA) has been correlated with adverse CV events. We compared rates of coronary plaque progression by serial CCTA in SLE and RA patients. Methods: Semi-automated plaque software (Qangio, Medis) was used for quantitative coronary assessment. Analysis included 22 SLE [48.5 (13.0) years; 19 females; 64% White] and 22 age and sex- matched RA patients [49.1 (11.2) years; 19 females; 95% Hispanic]. Linear regression was used to compare log adjusted total atheroma volume ((TAV norm ) = (Plaque volume)/Vessel length * mean cohort vessel length)) for TP and TNCP between SLE and RA patients. Results: Baseline mean levels of TAV norm for TP and TNCP in RA patients vs SLE patients were 0 (0 - 7.3) mm 3 vs 21.2 (1.1 - 64.1) mm 3 (p &lt;.0001) and 0 (0 - 5.8) mm 3 vs 19.5 (1.1 - 62.2) mm 3 (p&lt;.0001), respectively. After adjustment for baseline plaque and CV risk factors, progression of TAV norm was higher in SLE than RA patients (log TAV TP volume (β: 2.271 (.530), p=.0001) and log TNCP volume (β: 2.384 (.502), p&lt;.0001) (Table 1). Patients with RA had 87% less TP and 89% less TNCP progression than those with SLE. Conclusions: These results suggest that coronary plaque progression is greater in young, adult SLE patients, compared to RA patients. These results improve the mechanistic understanding of increased CV risk in these patients. Further research to evaluate screening and targeted management strategies for CVD in this high risk cohort, especially SLE is warranted.
Abstract 6970: Extracellular Vesicles Prevent Post-Operative Atrial Fibrillation
Authors: Sandrine Parent, Venkata Ramana Vaka, Yousef Risha, Darryl R Davis
Journal: Circulation (2021)

Half of patients recovering from cardiac surgery experience a malignant form of atrial fibrillation that results from inflammation in the pericardial space surrounding the heart. Given that post-operative atrial fibrillation (POAF) increases mortality, effective measures to prevent or treat POAF are highly desirable. In this study, we built on previous work to see if extracellular vesicles (EVs) isolated from human atrial explant-derived cell conditioned media can prevent POAF. Hypothesis: Human EVs will reduce AF inducibility in a rat model of sterile pericarditis by reducing inflammation and the malignant pro-fibrillatory transformation of atrial fibroblasts. Methods and Results: Middle aged female and male Sprague-Dawley rats (6 months old) were randomized to sham operation (n=24; 12 females, 12 males) or induction of sterile pericarditis followed by intra-atrial injection of 10 8 human EVs (n=34; 17 females, 17 males) or vehicle (n=34; 17 females, 17 males). Three days later, all rats underwent invasive electrophysiological testing prior to sacrifice. As expected, pericarditis increased the probability of inducing AF (Figure Panel A). EV treatment reduced the probability of AF. Recipient sex did not alter this effect. Analysis of atrial tissue histology (H&amp;E staining) and lysate (Luminex assays for IL-2, Il-18, MCP-1 and PDGF-AB) revealed that EV treatment abrogated the pro-inflammatory effects of pericarditis. As shown in Panel B, pericarditis increased both atrial fibrosis and mass while EV treatment limited the effect of pericarditis on atrial fibrosis and mass. These effects were attributable to the anti-fibrotic effect of EV treatment on atrial fibroblast proliferation profiled using in-vitro cultures exposed to pro-fibrillatory stimuli (i.e., IL-6 and TGFβ1). Conclusion: Intramyocardial injection of EVs at the time of open chest surgery may provide a facile acellular strategy to prevent POAF by reducing inflammation and fibrosis.
A Novel Stealth Strategy That Activates Adoptively Transferred Allogeneic Immune Cells and Avoids Rejection for Off-the-Shelf Cell-Based Cancer Therapy
Authors: Alan M Williams, Ken Hayama, Yijia Pan, Brian Groff, Rina M Mbofung, Lauren Fong, Nicholas Brookhouser, Berhan Mandefro, Ramzey Abujarour, Tom Lee, Quirin Hammer, Karl-Johan Malmberg, Maksim Mamonkin, Ryan Bjordahl, Jode P Goodridge, Bahram Valamehr
Journal: Blood (2021)
Germline biallelic mutation affecting the transcription factor Helios causes pleiotropic defects of immunity
Authors: Tala Shahin, Hye Sun Kuehn, Mohamed R. Shoeb, Lisa Gawriyski, Sarah Giuliani, Peter Repiscak, Birgit Hoeger, Özlem Yüce Petronczki, Sevgi Köstel Bal, Samaneh Zoghi, Jasmin Dmytrus, Davide Seruggia, Irinka Castanon, Nima Rezaei, Markku Varjosalo, Florian Halbritter, Sergio D. Rosenzweig, Kaan Boztug
Journal: Science Immunology (2021)

A homozygous mutation in IKZF2 disrupts the interactions of Helios with epigenetic remodelers, leading to impaired T cell activation.
RADT-06. RADIOTHERAPY FOR BRAIN METASTASES FROM THYROID CANCER: A RETROSPECTIVE COHORT STUDY
Authors: Erik Blomain, Scott Berta, Nicholas Hug, Duc Giao, Antonio Meola, Michael Binkley, Nastaran Shahsavari, Kaniksha Desai, Steven Chang, Scott Soltys, Erqi Pollom
Journal: Neuro-Oncology (2021)

Abstract PURPOSE/OBJECTIVE(S) Brain metastases from thyroid carcinoma are rare. Although stereotactic radiosurgery (SRS) is a standard of care for patients with brain metastases across many histologies, the current NCCN guidelines do not support a universal role for this modality in thyroid cancer. MATERIALS AND METHODS Thyroid cancer patients with brain metastases treated with radiotherapy at our institution from 2002-2020 were studied. Cumulative risk of local failure, distant intracranial failure and radiation necrosis were calculated using a competing risk of death analysis and censored at the last imaging follow-up. Overall survival was analyzed using Kaplan-Meier method. Stratified cox regression was used to study per-lesion outcomes. RESULTS We identified 34 patients with 203 treated brain metastases. 179 (88.2%) lesions were of differentiated histology; the remainder were anaplastic histology. Four patients received whole brain radiotherapy (WBRT) while 30 patients received SRS (SFED 22, interquartile (IQ) range 20-22). Of the patients receiving WBRT, one (25%) had anaplastic histology, and the median number of lesions was 15 (as compared to 2 for SRS). Median follow up among survivors was 32.3 months and median survival was 10.8 months. There were no observed failures (local or distant intracranial) observed at 1 year in the 24 metastases with anaplastic histology, although competing risk of death was high (91.7%). The 1 year cumulative incidences of local failure and distant intracranial failures were 9.8% (95CI 5.7%-13.9%) and 35.0% (95CI 29.0%-41.0%), respectively, in differentiated tumors. 6 (10.2%) of the distant intracranial failures were new cases of leptomeningeal disease. The 1 year risk of radiation necrosis was 15.5%. Of these cases, most were Grade 2 (57.1%); 3 (42.9%) were Grade 4 (there were no Grade 1 or 3 events). CONCLUSION In the largest known cohort of thyroid cancer brain metastasis patients, radiotherapy and SRS appear to be safe and effective treatment modalities.
Abstract 9682: The Cardiac Protective Effects of Novel Synthetic Pan-Estrogen Related Receptor Agonists Slu-pp-332 and Slu-pp-915
Authors: Weiyi Xu, Cyrielle Billon, Hui Li, Eleni Nasiotis, Chen Fu, Liming Pei, Anthony Wynshaw-Boris, Thomas P Burris, Lilei Zhang
Journal: Circulation (2021)

Introduction: Estrogen receptor-related orphan receptors ERRα and ERRγ are essential regulators for cardiac metabolism. Mice lacking ERRα and ERRγ develops lethal cardiomyopathy and heart failure. Therefore, activation of ERR is a potential therapeutic intervention for HF treatment. However, no natural or synthetic ERR agonist is available to demonstrate their pharmacological effect in vivo . Hypothesis: ERR agonist can provide cardioprotection against heart failure. Methods: Two structurally distinct pan-ERR agonists, SLU-PP-332 (332) and SLU-PP-915 (915) were chemically synthesized. Transaortic constriction (TAC) was performed to induce heart failure in adult male mice. Cardiac function was assessed by echocardiography. Wheat germ agglutinin (WGA) staining was perform on cardiac muscle sections. In vitro study was performed in neonatal rat ventricular myocytes (NRVMs). Results: 332 treatment significantly improved ejection fraction and mitochondrial ultrastructure, and reduced the expression of Nppa/Nppb and cardiac fibrosis in mice after 6-week TAC. Consistently, 915 treatment also greatly improved cardiac function in vivo . However, echocardiography and WGA staining showed that 332/915 failed to prevent cardiac hypertrophy in mouse after 6-week TAC. Moreover, 332/915 did not prevent the cardiomyocyte hypertrophy as well as activation of ERK1/2 and NFAT signaling pathways in NRVMs treated with phenylephrine. Further analysis using transcriptomics and metabolomics approaches revealed that 332/915 upregulated oxidative phosphorylation and fatty acid metabolism pathway in vitro . In addition, 332/915 induced downregulation of cell cycle genes in vitro , which was partially mediated by E2F1. Finally, interrogation of ERR dependency showed that siRNA knockdown of ERRγ, but not ERRα or ERRβ, abolished most of the 332/915-induced transcriptions of metabolic genes in vitro . Conclusions: 332/915, mainly through ERRγ, elevate mitochondrial function and fatty acid metabolism leading to improved cardiac function in TAC-induced heart failure, suggesting ERR agonist holds potential as a heart failure therapeutic agent.
Abstract 14031: Effects of Custodiol-HTK and Del Nido Solutions in a Coronary-Perfused Rabbit Ventricular Wedge Model
Authors: Serge Sicouri, Maxwell Kilcoyne, Gan-Xin Yan, Tengxian Liu, Meghan Buckley, Basel Ramlawi
Journal: Circulation (2021)

Introduction: Distinct cardioplegic solutions are used in cardiac surgery for myocardial protection. Custodiol-HTK (CUS) solution consists of histidine, tryptophan, ketoglutarate and mannitol to reduce cellular edema. Del Nido (DN) is a nonglucose-based solution containing low calcium and high lidocaine concentrations, preventing intracellular Ca2+ accumulation during ischemia. Hypothesis: Using a coronary-perfused rabbit experimental model, this study compares the effects of CUS and DN on transmural electrocardiogram (ECG) and tension parameters. Methods: Twelve left ventricular (LV) wedge preparations from 12 rabbit hearts were arterially perfused with Tyrode's solution and stimulated at a cycle length of 1000 ms. Simultaneous recording of transmural ECG and tension were obtained. After exposure to normal Tyrode, the LV wedge preparation was perfused with 20 cc of CUS (n=6) or 20 cc of DN (n=6) leading to complete arrest maintained for 30 minutes. ECG and tension recordings were obtained under baseline conditions and at 5, 15, and 30 minutes after reperfusion with normal Tyrode. Differences in change from baseline ECG and tension parameters after CUS or DN were compared using a mean differences regression model. Results: Reperfusion effects of CUS and DN on ECG and tension are shown in Table 1 . After reperfusion, DN group had a significantly greater increase in QRS duration, significantly more QT shortening and more ST segment change compared to CUS group. At 5- and 15-minutes post-reperfusion, the CUS group had significantly higher tension recovery. Negative T wave were observed in 1 of 6 wedges of the CUS group and 5/6 (83.3%) wedges of the DN group. Conduction block was observed in 0/6 wedges in the CUS group and 5/6 (83.3%) wedges in the DN group. Conclusions: In a LV coronary-perfused rabbit wedge preparation, Custodiol-HTK cardioplegia led to less ischemic changes in ECG and faster tension recovery following reperfusion compared to del Nido cardioplegia.
Abstract 12484: Weekday 16:8 Time-Restricted Eating in Breast Cancer Survivors: Feasibility, Safety, and Effects on Cardiometabolic Health
Authors: Amy A Kirkham, Jordan Topolnyski, mark J Haykowsky, Ian Paterson, Carla M Prado, Anil Abraham A Joy, Normand Boule, Katherine L Ford, Pelletier B Andre, Bruna Ramos Da Silva, Edith Pituskin, Richard Thompson
Journal: Circulation (2021)

Introduction: Time-restricted eating (TRE) is a form of intermittent fasting involving ad libitum energy intake within a set time window, commonly 8 hours, followed by a water-only fast for 16 hours (i.e., 16:8 TRE). TRE is a practical approach to improve cardiometabolic health but has not been tested in cancer populations. Hypothesis: TRE is feasible (&gt;85% adherence), safe (no major adverse events), and will improve cardiometabolic health in breast cancer survivors. Methods: Women who completed chemotherapy for early-stage breast cancer 1-6 years earlier, are ≥60 years, have a BMI &gt;25 kg/m 2 , and not taking lipid or glucose-lowering medications were enrolled in a single-arm study of 16:8 TRE on weekdays for 8 weeks. Participants could eat ad libitum between 12-8 pm on weekdays and all weekend. No other dietary or physical activity instructions were given. Adherence was collected by twice daily text messages that asked participants to respond with the times that they started/stopped eating. The Framingham 10-year cardiovascular disease (CVD) risk score and heart age, and ectopic adipose tissue (3T magnetic resonance imaging) were assessed before and after 8 weeks of TRE. Results: Fifteen participants (66±4 years, 31±4 kg/m 2 ) have completed the study. Participants responded to 99% of text messages and adhered to the 16-hour fast a median of 98% of days (range 93-100%). Reported symptoms were minor and transient. At baseline, 73% of participants were at ‘intermediate’ (10-19%) CVD risk, and pharmacological treatment was indicated. Among those at intermediate risk, 8 weeks of TRE decreased the absolute CVD risk by a median of 2% and heart age by 6 years, and reversed the need for pharmacological treatment (i.e., reclassification to ‘low’ risk) or metabolic syndrome in 45%. In all participants, visceral adipose tissue decreased by a median of 6% (p=0.018) and triglycerides by 17% (p=0.008). There were no significant changes in hemoglobin A1c, or ectopic adipose tissue in the liver or thigh. Conclusions: Eight weeks of weekday 16:8 TRE is highly feasible, safe, and reduces CVD risk among older breast cancer survivors with overweight/obesity at moderate CVD risk. Improvements in glucose control and liver/thigh ectopic adipose tissue may require a longer intervention.
Recovery of Gonadal Hormone Level Is a Potential Marker for the Response and Prognosis in POEMS Syndrome Patients Treated with Bortezomib Based Combined Chemotherapy
Authors: Fang Fang, Guoxiang Wang, Ronghua Hu, Wuhan Hui, Hong Zhao, Yixian Guo, Bingxin Ji, Li Su, Wanling Sun
Journal: Blood (2021)
Abstract 9749: High-Avidity Binding Drives Nucleation of Amyloidogenic Transthyretin Monomer in Cardiac Amyloidosis
Authors: Li Gao, Xinfang Xie, Pan Liu, Jing Jin
Journal: Circulation (2021)

Amyloidosis involves stepwise growth of fibrils assembled from soluble precursor proteins. Mutations of plasma carrier protein transthyretin (TTR) are associated with hereditary transthyretin amyloidosis (ATTR). TTR naturally folds into a stable tetramer for its function, whereas conditions and mutations that foster aberrant monomer formation facilitate TTR oligomeric aggregation and subsequent fibril extension. We investigated the dynamics of early assembly of oligomers by wild-type TTR, in comparison to its TTR V30M and TTR V122I disease mutants. We selected buffer conditions for monitoring time-dependent redistribution among monomer, dimer, tetramer, and oligomer contents in the presence and absence of multimeric TTR seeds. The seeds were artificially constructed recombinant multimers that contained 20-40 TTR subunits via engineered biotin-streptavidin interactions. As expected, these multimer seeds rapidly nucleated TTR monomers and dimers into larger complexes, while having no effect on tetramers. In vivo , streptavidin-induced multimers formed ATTR-like deposits in the heart and the kidney following i.v. injection in mice. While all three variants prominently deposited in the kidney glomerulus, only TTR V30M resulted in extensive deposition in the heart. The cardiac TTR deposits varied in size and shape and were localized to the intermyofibrillar space along the capillaries. These results are consistent with the notion of monomeric TTR to engage high-avidity interactions with tissue amyloids. Our multimeric induction approach therefore provides a new model for studying the initiation of TTR deposition in the heart.
NCOG-36. LONG-TERM SURVIVAL AND COGNITIVE FUNCTION FOLLOW UP OF PRIMARY CNS LYMPHOMA TREATED WITH R-MVP FOLLOWED BY HIGH DOSE CHEMOTHERAPY WITH AUTOLOGOUS STEM CELL TRANSPLANT CONSOLIDATION
Authors: Kate Therkelsen, Christian Grommes
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Primary central nervous system lymphoma (PCNSL) is a rare central nervous system malignancy, and long-term follow up studies are uncommon. First line therapy is based on high-dose methotrexate and different consolidation therapy options. This is a long-term follow up study of PCNSL patients enrolled in a prospective trial using R-MPV chemotherapy regimen followed by high dose chemotherapy and autologous stem cell rescue to determine long-term survival and cognitive effects. METHODS From June 2005 to September 2011, 32 newly diagnosed immunocompentent PCNSL were enrolled. Patients received 5-7 doses of rituximab (500mg/m2), methotrexate (3.5 gm/m2), procarbazine (100mg/m2), and vincristine (1.4mg/m2) (R-MVP). Consolidation therapy consisted of high dose chemotherapy (HDC) with thiotepa (250 mg/m2), busulfan (3.2 mg/kg), and cyclophosphamide (60 mg/kg), followed by autologous stem cell rescue (ASCT) in those with partial or complete response to R-MVP. Long-term follow-up status including disease status, cognitive status (KPS, NANO score), and leukoencephalopathy (modified Fazkas Scale) were collected. RESULTS 26 of 36 underwent HDC and ACST. Of those, 3 died due to treatment related effects; 2 died of disease progression within two years after ASCT. After a median follow-up of 10.5 years, none of the remaining 21 patients progressed. At the time of last follow up, the median KPS was 90, compared to 80 at time of ASCT. The median NANO score and leukoencephalopathy score post ASCT and at follow-up did not change. Of note, 2 of 4 patients with a partial or complete response to R-MVP that elected not to proceed with HDC-ASCT consolidation, experienced progression at a mean of 52 months. CONCLUSION Long-term follow up demonstrates that treatment was tolerated well with stable leukoencephalopathy on MRI and good performance status. Disease recurrence 2 years after HDC with ASCT consolidation was not observed.
Defining the Biochemical Role of Sialic Acid-Binding Immunoglobulin-like Lectin-6 in Adhesion and Migration in Chronic Lymphocytic Leukemia
Authors: Jessica Nunes, Ann Ventura, Kevan Zapolnik, Eileen Hu, Liwen Zhang, Xiaokui Mo, John C. Byrd, Christoph Rader, Raj Muthusamy
Journal: Blood (2021)
Abstract 10170: Mode of Death After Heart Failure Hospitalization in Elderly Patients
Authors: Ryo Nakamaru, Yasuyuki Shiraishi, Shun Kohsaka, Takashi Kohno, Ayumi Goda, Makoto Takei, Yuji Nagatomo, Toshikazu D Tanaka, Shintaro Nakano, Keiichi Fukuda, Tsutomu Yoshikawa
Journal: Circulation (2021)

Introduction: Mode of death in heart failure (HF) patients varies by age. This study aimed to assess associations between cardiovascular (CV) and non-CV mortality with age among patients discharged after HF hospitalization using the competing risk analysis. Methods: From 2006 to 2017, 3558 consecutive patients enrolled in a prospective multicenter registry in Japan (the West Tokyo Heart Failure registry) were analyzed. The patients were categorized based on age and LVEF as follows: 1) &lt;65 years (younger; LVEF ≥50% [n=182] and LVEF&lt;50% [n=575]); 2) 65-84 years (elderly; LVEF ≥50% [n=894] and LVEF&lt;50% [n=1159]); and 3) ≥85 years (very elderly; LVEF ≥50% [n=429] and LVEF&lt;50% [n=319]). We evaluated the cumulative incidence of all-cause death and each mode of death after discharge. A Cox proportional hazards modeling was used with the Fine-Gray competing method. Results: During the median follow-up of 2.0 years, the incidence of all-cause death increased in parallel with increasing age categories. The Fine-Gray model demonstrated that LVEF was independently associated with risk of CV death (CVD) (adjusted subdistribution hazards ratio, 1.03; 95% confidence interval, 1.03-1.04, p&lt;0.01). An enrichment in the proportional risk of CVD vs. non-CVD was also observed in patients with LVEF &lt;50% even with increasing age categories: LVEF&lt;50% (younger: 65.0%, elderly: 64.2%, very elderly: 55.6%) and LVEF ≥50% (younger: 50.0%, elderly: 41.2%, very elderly: 38.2%) (Figure). Conclusions: Mortality after HF hospitalization remains substantial in the contemporary era, particularly among elderly patients. Of note, the proportion of non-CVD increased with age, albeit CVDs still accounted for over half of deaths in patients with LVEF &lt;50% in the patients within the oldest category.
EXTH-25. ENHANCING GLIOBLASTOMA CELL STRESS RESPONSE TO IMPROVE GAMMA DELTA T-CELL IMMUNOTHERAPY
Authors: Amber Jones, Kate Rochlin, Lawrence Lamb, Anita Hjelmeland
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is an aggressive cancer that has been largely intractable to novel therapies, however, enhancing the efficacy of immunotherapy could potentially overcome immunosuppression and potentially improve patient outcomes. The cellular stress induced by Temozolomide (TMZ) increases innate immune ligands, which could be exploited to promote immune recognition. TMZ-induced DNA damage can activate the stress response pathway, increasing the expression of NKG2D ligands (NKG2DL) on tumor cells. This leads to an increase in NKG2DL recognition by NKG2D receptors on both natural killer and cytotoxic T-cells to elicit a cytotoxic effect. The lymphodepleting effect of TMZ, however, can limit the ability of these cells to recognize and kill tumor cells. TMZ was shown to induce NKG2DL in gliomas both in vitro and in vivo, providing the basis for clinical trials of TMZ in combination with genetically engineered TMZ-resistant gamma delta T-cells (NCT04165941). To further promote immune recognition, we sought to augment the TMZ-induced stress response by exploring the combination of DNA alkylation with either PARP (Niraparib) or ATM Kinase inhibition (AZD1390). Combinatorial therapy significantly, but heterogeneously, increased differential subsets of NKG2DL genes in comparison to TMZ alone in GBM cells isolated from patient derived xenografts (PDX): 1) MICA and MICB were increased at least 10-fold in D456 (proneural) cells; 2) ULBP1 and ULBP2 were increased at least 2-fold in JX39 (classical) cells; and 3) minimal increases in NKG2DLs were observed in JX22 (mesenchymal) cells. Repression of NKG2DLs by hypoxia/low glucose was also heterogeneous, being observed in two of three GBM models tested. We are currently determining whether these combinatorial treatments improve gamma delta T-cell cytotoxicity against GBM cells and in vivo tumor models. Taken together, our data suggest that enhancing cell stress responses induced by chemotherapies may permit novel immunotherapy therapeutic interventions for brain tumor patients.