tbuckley/cabot-search huggingface dataset:
IMMU-12. TUMOR CELL IDO ENHANCES IMMUNE SUPPRESSION AND DECREASES SURVIVAL INDEPENDENT OF TRYPTOPHAN METABOLISM IN GLIOBLASTOMA
Authors: Lijie Zhai, April Bell, Erik Ladomersky, Kristen Lauing, Lakshmi Bollu, Brenda Nuygen, Matthew Genet, Miri Kim, Xinlei Mi, Masha Kocherginski, Jennifer Wu, Matthew Schipma, Brian Wray, John Griffiths, Richard Unwin, Simon Clark, Rajesh Acharya, Riyue bao, Craig Horbinski, Rimas Lukas, Gary Schiltz, Derek Wainwright
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is an immune checkpoint that’s characterized as a potent immunosuppressive mediator through its ability to metabolize tryptophan and wild-type IDH patient-resected glioblastoma (GBM) expresses IDO in ≥ 95% of cases. Recent findings from our group led us to investigate the alternative hypothesis that IDO possesses immunosuppressive effects that are independent of its associated metabolic activity. METHODS Murine GBM cell lines that overexpress either wild-type or enzyme-null IDO were created for in vivo characterization of IDO enzyme-independent immunosuppressive function. Microarray was conducted to identify human IDO expression-correlated genes, which were further investigated in human GBM cell lines, patient GBM tissues and plasma, as well as the TCGA database. Ex vivo cell co-culture assays and syngeneic mouse orthotopic GBM models were employed to study immunosuppressive mechanisms. RESULTS Here, we demonstrate that non-enzymic IDO activity decreases survival in experimental animals and increases the expression of immunosuppressive complement factor H (CFH) in human GBM. CFH mRNA levels positively correlate with those of IDO and many other immunosuppressive genes in patient resected GBM and can be applied as a prognostic marker in both lower grade gliomas and GBM. Similar to IDO, the increased expression of CFH in patient-resected glioma was positively correlated with an increased signature for regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs). High expression of CFH in tumor cells increases intratumoral Tregs levels and decreases overall survival in mice with GBM, while inducing tumor associated macrophage cell differentiation. CONCLUSIONS Here, we demonstrated that glioblastoma (GBM) cell IDO promotes the accumulation of intratumoral FoxP3+ regulatory T cells (Tregs) and tumor progression while decreasing overall survival - independent of IDO enzyme activity. Our study reveals a targetable non-metabolic IDO-dependent mechanism for future therapeutic intervention in patients with GBM.
Abstract 12293: Intercalated Disk Nanostructure and Molecular Organization Underlie Conduction Differences Between Atria and Ventricles
Authors: Heather L Struckman, Nicolae Moise, Izabella Dunlap, Zhenhui Chen, Seth Weinberg, Rengasayee Veeraraghavan
Journal: Circulation (2021)

The intercalated disc (ID) is a complex, heterogeneous structure that affords electrical (gap junctions; GJ) and mechanical (adherence junctions [AJ], desmosomes [Des]) coupling between cardiomyocytes. Electrogenic proteins underlying the action potential upstroke (cardiac sodium channels [Na V 1.5], inward-rectifier potassium channels [K ir 2.1] and sodium potassium ATPase [NKA]) enriched within ID nanodomains are emerging as vital machinery for cardiac impulse propagation. ID structure is thus a critical determinant of cardiac conduction. We used indirect correlative light and electron microscopy ( iCLEM ) to assess ID ultrastructure (transmission electron microscopy; TEM) and molecular organization (confocal, STORM super resolution microscopy) in mouse atria and ventricles. TEM uncovered structural differences between atrial and ventricular IDs from the micro- through nano-scales including key factors that may underlie faster atrial conduction: larger interplicate regions and more numerous GJs with associated perinexi. Confocal microscopy revealed significant ID enrichment of Na V 1.5, K ir 2.1 and NKA in both atrial and ventricular myocytes. All three displayed more intense immunosignals in atrial myocytes, suggestive of greater expression relative to ventricle. STORM defined the distribution of Na V 1.5, K ir 2.1, NKA within the ID relative to AJ, Des, and GJ: In the ventricle, Na V 1.5 associated most closely with GJ (median intercluster distance: 110 nm), K ir 2.1 with Des (163 nm), and NKA with both GJ (150 nm) and AJ (135 nm). Next, the % of each electrogenic protein localized within 100 nm from AJ, Des, and GJ were calculated: 47% of Na V 1.5 around GJs, 35% of K ir 2.1 around Des and 36% and 39% of NKA near GJ and AJ respectively were the most prominent subpopulations. Protein organization within atria ID was broadly similar with some notable differences: Na V 1.5 was shifted closer to MJs relative to GJs with K ir 2.1 showing the opposite pattern. These data provide the first ever comprehensive quantitative picture of ID structure and molecular organization. We are now incorporating these data into our recently published modeling pipeline to generate realistic 3D finite-element meshes of IDs to uncover the structural underpinnings of conduction.
TAMI-78. STEM CELL IMMUNOTHERAPY MODULATES IMMUNOREGULATORY PATHWAYS IN THE TUMOR MICROENVIRONMENT
Authors: Tyler Wildes, Bayli DiVita Dean, Joseph Dean, Laura Falceto Font, Catherine Flores
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION A major obstacle in efficacious therapeutics against high-grade gliomas has been an inability to overcome powerful regulatory mechanisms within the TME that hamper immune activation. Fortunately, immunotherapy has enabled the enhancement of immune activation within the TME through adoptive immunotherapy and checkpoint inhibition. We found that co-transfer of hematopoietic stem cells (HSCs) with either adoptive immunotherapy or PD-1 blockade significantly improves therapeutic outcomes by manipulating the cellular components that make up the TME in high-grade gliomas. HSC co-transfer with immunotherapy leads to increased in situ downregulation of multiple immune regulatory pathways, activation of tumor-reactive T cells, and significant reduction in the frequency of MDCs and TAMs within the TME. METHODS C57BL/6 mice with orthotopic KR158B-gliomas received either adoptive immunotherapy using activated tumor-reactive T cells or αPD-1, either with or without HSC co-transfer. After treatment of late-stage tumors, brains were sectioned and digital spatial profiling (NanoString GeoMx) of the TME was conducted in situ. Briefly, tumor-bearing brain sections were stained for nuclei, CD3, CD45, and GFP (HSC-derived cells); regions of interest (ROIs) containing 200 nuclei were selected and processed for whole genome sequencing. Areas rich in immune cells within the TME were chosen as ROIs and compared between groups. Results were corroborated with flowcytometry and PCR. RESULTS Mice that received HSCs with either adoptive cellular therapy or αPD-1 had reductions in expression of multiple regulatory markers in the TME including iNOS, TGFβ, and PD-L1. This was accompanied by reductions in the frequencies of MDSCs and TAMs. An increased relative abundance of activated CD8+ T cells within the TME was also observed. Interestingly, we found that HSC-derived cells provided rich amounts of dendritic cells at the TME when co-transferred with immunotherapy. Host-derived myeloid cells were significantly displaced from the TME in mice receiving HSC plus adoptive cellular therapy or αPD-1.
Intensive Lifestyle Management Improves Steatosis and Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease
Authors: Sander Lefere, Ellen Dupont, Ann De Guchtenaere, Stephanie Van Biervliet, Saskia Vande Velde, Xavier Verhelst, Lindsey Devisscher, Hans Van Vlierberghe, Anja Geerts, Ruth De Bruyne
Journal: Clinical Gastroenterology and Hepatology (2021)
Abstract 11415: Extent of Leaflet Coaptation Governs the Biomechanics of Mitral Valve Neochordae Used for Posterior Leaflet Prolapse
Authors: Dongyang Xu, Kirthana Sreerangathama Suresh, Hirschel Nambiar, Qi He, Muralidhar Padala
Journal: Circulation (2021)

Introduction: Reducing peak forces and stresses on the neochordae used to repair mitral valve prolapse, can inhibit their late failure, and increase repair durability. Restoring a larger shelf of leaflet coaptation at the time of repair, could reduce neochordae stresses and aid durability. Hypothesis: In this study, we hypothesized that using a slightly smaller annuloplasty ring can yield a higher systolic coaptation length, which in turn could reduce the neochordal forces/stresses. Methods: Pig MV (n=7) were excised and studied in a pulsatile left heart simulator ( Fig. A ), with P2 prolapse induced by transecting the marginal chordae ( Fig B1,2 ). Repair was performed with force transducer instrumented Goretex PTFE suture loops (6-0) ( Figure C1,2 ), and annuloplasty with a custom adjustable ring that could be reduced from 36mm to 30mm in 2mm increments ( Fig D1,2 ). Regurgitant fraction, leaflet coaptation, and temporal neochordae force traces were measured. Results: P2 prolapse increased MR compared to baseline (10.5 ± 7.7% vs 0%, p=0.0001), which was reduced by neochordoplasty and annuloplasty ( Fig. E ). Leaflet coaptation length increased from 0mm to 11.3 ± 3.8mm with neochordae alone, and further increased with annuloplasty to 12.7 ± 3.6mm with 34mm, 14.8 ± 4.4mm with 32mm and 15.7 ± 3.9mm with 30mm ( Fig. F ). With increasing coaptation, the peak neochordae forces reduced ( Fig G, H ), demonstrating a negative correlation between parameters ( Fig I ). Conclusions: Neochordal forces can be reduced by increasing the coaptation length with slight downsizing of the mitral annulus. An operative strategy achieving larger coaptation can yield a biomechanically optimal repair configuration, potentially improving durability.
Abstract 11839: Outcomes of Stroke and Bleeding by Class of Anticoagulant Use for Non-Valvular Atrial Fibrillation in Patients With Active Cancer
Authors: Ashley Patel, Muzamil Khawaja, Christopher R Chen, Henry Zheng, Jacob Morgan, Jessica Kaczmarek, Feng Gao, Kaveh Karimzad, Juhee Song, Juan Lopez-Mattei, Cezar Iliescu, Anita M Deswal, Nicolas L Palaskas
Journal: Circulation (2021)

Introduction: The choice of anticoagulant for patients with non-valvular atrial fibrillation (AF) in the setting of active cancer has not been well studied given only a minority of patients with cancer included in clinical trials. Hypothesis: Cancer patients will have similar rates of stroke (CVA), gastrointestinal bleeding (GIB), and intracranial hemorrhage (ICH) when treated with direct oral anticoagulants (DOAC) compared to warfarin (VKA) for AF. Methods: A retrospective study was performed at MD Anderson Cancer Center on patients with cancer and AF being treated with VKA or DOAC. The outcomes assessed were overall mortality, CVA, GIB, or ICH and patients were censored at 5 years. 1:1 propensity score matching was conducted to select comparable patients receiving VKA versus DOAC. Multivariable Cox proportional hazards regression models were fitted for each outcome. Results: A total of 1133 patients were included in the dataset with mean age of 72 years, 42% women, and 74% received DOAC (57% received apixaban). At 5 year follow up, mortality occurred in 145, CVA in 59, GIB in 59, and ICH in 6 patients. The baseline risk scores were higher for those on VKA compared to DOAC (CHADSVASC 3.5±1.6 vs 3.3±1.7 p=0.04, HASBLED 2.0 ± 1.1 vs 1.8 ± 1.0 p&lt;0.01). After propensity score matching 210 patients were included in each anticoagulant group. Survival analysis showed higher GIB free survival in the DOAC group however no difference was observed for composite GIB, CVA, or ICH (Figure). On multivariate analysis the risk of GIB was higher in the VKA group (HR 3.1, 95% CI 1.3-7.3); however, risk of mortality (HR 1.1, 95% CI 0.7-1.8), CVA (HR 0.9, 95% CI 0.4-1.8), ICH (HR 0.3, 95% CI 0.0-2.2), and composite of GIB, CVA, or ICH (HR 1.3, 95% CI 0.8-2.3) were not different comparing VKA to the DOAC propensity matched group. Conclusion: Patients with active cancer have higher risk of GIB but similar overall survival and risk for composite stroke and bleeding when treated with VKA compared to DOAC for AF.
Abstract 10921: The Relationship Between Lipoprotein(a) and Cardiovascular Events in Chronic Kidney Disease Patients Hospitalized for Acute Coronary Syndrome
Authors: Qing Li, Chen Yinong, Luyao Yu, longyang Zhu, jingang Zheng, Yihong Sun
Journal: Circulation (2021)

Introduction: Patients with chronic kidney disease (CKD) have the high risk of residual cardiovascular events after statin therapy, hence whether elevated lipoprotein(a) [Lp(a)] levels leading to worse outcomes is unclear. Hypothesis: High Lp(a) levels are associated with higher risk of major adverse clinical events (MACE) in patients with CKD and acute coronary syndrome (ACS). Methods: Patients with CKD (estimated glomerular filtration rate &lt; 60mL/min/1.73m 2 ) hospitalized for ACS were enrolled in China-Japan Friendship Hospital from January 2015 to December 2019. Patients were divided into 2 groups according to median levels of Lp(a). The MACE were a composite endpoint of cardiac death, non-fatal myocardial infarction, and non-fatal ischemia stroke. Multivariate Cox regression analysis and restricted cubic spline curve were performed to explore the relationship between Lp(a) levels and MACE. Results: A total of 434 ACS patients with CKD were enrolled, with 37.8% were women. The median Lp(a) concentration was 16.7mg/dL. During a median follow-up of 2.8 years, patients had higher risk of MACE (45.2% vs. 14.7%, log rank p &lt; 0.001) in the high Lp(a) group than the low Lp(a) group. The relationship between Lp(a) and MACE appeared to be nonlinear. Multivariable Cox regression analysis showed that high Lp(a) value was an independent predictor of MACE compared with low Lp(a) value (HR = 3.33, 95% CI 2.20-5.05, p &lt; 0.001). The receiver operating characteristic curve analysis showed that adding Lp(a) concentration to original risk model improved the prognostic model, with area under the curve increasing from 0.69 to 0.74. Conclusions: In ACS patients with CKD, high Lp(a) concentrations predict the risk of cardiac death, non-fatal myocardial ischemia and non-fatal ischemia stroke at 2-years follow-up.
Abstract 11421: The M2 Gene is a Determinant of Reovirus-Induced Myocarditis
Authors: Marcelle Dina Zita, Matthew B Phillips, Johnasha D Stuart, Anthony J Snyder, Gopinath Venugopal, Asangi R Kumarapeli, Pranav Danthi, Tiffany Weinkopff, Karl W Boehme
Journal: Circulation (2021)

Although a broad range of viruses can cause myocarditis, the mechanisms that underlie virus-induced cardiac inflammatory disease are poorly understood. Here, we use mammalian orthoreovirus (reovirus) to examine mechanisms of viral myocarditis. We found that the M2 gene is a determinant of reovirus myocarditis in neonatal mice. The M2 gene encodes viral outer capsid protein μ1, which mediates host membrane penetration during viral entry. A recombinant reovirus in which the M2 gene from strain T3D was substituted into an otherwise strain T1L genetic background (T1L/T3DM2) caused significantly more myocarditis than the parental T1L strain. T1L was non-lethal in wild-type mice, whereas greater than 90% of mice succumbed to T1L/T3DM2. T1L/T3DM2 produced higher viral loads at the site of inoculation and disseminated with more rapid kinetics than T1L. T1L/T3DM2 also produced higher peak viral titers compared to T1L, most notably in the heart where T1L/T3DM2 viral loads were approximately 50-fold higher than T1L. Hearts from T1L-infected animals contained small purulent lesions, consistent with previous reports that T1L is mildly myocarditic. In contrast, hearts from T1L/T3DM2-infected mice were grossly abnormal, with extensive pericardial inflammatory infiltrate. Histological analysis revealed that T1L/T3DM2-infected hearts had larger and more frequent heart lesions containing necrotic cardiomyocytes with pyknotic debris than animals infected with T1L. T1L/T3DM2 also induced more lymphocyte and histiocyte infiltration than T1L. More cells with activated caspase-3 were found in hearts infected with T1L/T3DM2. Flow cytometry profiling of cardiac immune cells revealed that T1L/T3DM2 induced significantly more lymphoid cell (CD4 + and CD8 + T cells) and inflammatory monocyte infiltration than T1L. Together, our findings indicate that the M2 gene, and by extension the μ1 protein, promotes reovirus replication in the heart, leading to increased cardiac inflammation and enhanced myocarditis.
The iron revolution: Keeping abreast of the developments in iron therapy
Authors: Michael Auerbach, Iain C. Macdougall, George M. Rodgers, Tom Deloughery, Toby Richards
Journal: American Journal of Hematology (2021)

A recent review of iron homeostasis published in the Journal of Clinical Investigation1 (JCI) elegantly reviewed the role of iron homeostasis in mammalian physiology. Unfortunately, this was counter-balanced by a disappointing failure of the authors to acknowledge the recent revolution in iron therapy with newer therapies of intravenous iron transforming the management of a number of disabling conditions. Iron deficiency is the commonest nutritional deficiency worldwide, affecting over two billion people, and is the commonest cause of anemia. It ranks as a World Health Organization top five cause of disability and causes an average of 8 years living with disability. The last decade has seen a pivotal change in our understanding of iron metabolism and the introduction of new treatments which offer a potential cure to iron deficiency in one treatment; indeed, a revolution which will support the WHO target to cut the global incidence of anemia by half by 2025.2 There are no conflicts of interest to declare. Data sharing not applicable - no new data generated.
A Clinical Decision Aid to Support Personalized Treatment Selection for Patients with Clinical T1 Renal Masses: Results from a Multi-institutional Competing-risks Analysis
Authors: Sarah P Psutka, Roman Gulati, Michael A S Jewett, Kamel Fadaak, Antonio Finelli, Laura Legere, Todd M Morgan, Phillip M Pierorazio, Mohamad E Allaf, Jeph Herrin, Christine M Lohse, R Houston Thompson, Stephen A Boorjian, Thomas D Atwell, Grant D Schmit, Brian A Costello, Nilay D Shah, Bradley C Leibovich
Journal: European Urology (2021)
Abstract 12629: Intravascular Dual Targeted NIRF Molecular Imaging Integrated With OCT for Calcifying Inflammatory Activity in the Plaque
Authors: Dong Kang, Yong Geun Lim, Yeon Hoon Kim, Joon Woo Song, Ye Hee Park, Ryeong Hyun Kim, JIN HYUK KIM, Hyun Jung Kim, Hyeong Soo Nam, Wang-Yuhl Oh, Kyeongsoon Park, Hongki Yoo, Jin Won Kim
Journal: Circulation (2021)

Background/Objectives: Spotty calcification linked with macrophage activity is a major target for high-risk plaque but the biological interconncetion remains questionable. To address this issue, we newly developed intravascular multimodal imaging strategy by fully integration of OCT with dual-targeted near-infrared fluorescence (NIRF) molecular imaging using customized osteogenic activity and macrophage targetable probes. Methods/Results: We newly integrated intravascular OCT structural imaging with dual-targeted NIRF imaging. Scale-up novel NIRF emitting probe targeting osteogenic activity was fabricated by chemically coupling alendronate ligand and Cy5.5 to the ends of azide-PEG-NHS ester (Al-Cy5.5). Based on biodistribution, OCT/dual-NIRF in vivo imaging of rabbit aortoiliac atheroma was acquired 72 hrs after intravenous injection of Al-Cy5.5 (5.0 mg/kg) and macrophage mannose receptor targeted Cy7-emitting probe (7.5 mg/kg). NIRF signals of Cy5.5 and Cy7 were highly enhanced in spotty calcification and inflammatory sites of the plaque, respectively (Figure) (p&lt;0.01). Fluorescence microscopy and immunostainings from the corresponding sections well corroborated the in vivo findings. Intriguingly, an interconnection of osteogenic activity (TRAP stain) with macrophages was more prominent in superficial spotty calcification rather than outer dense calcification (Figure) (p&lt;0.01). Conclusions: Our intravascular OCT/dual-NIRF imaging was feasible to simultaneously image osteogenic activity and macrophages in the coronary-sized atheroma. This novel imaging strategy is expected to expand the understanding for the biological behavior of calcifying inflamed activity in the high-risk plaques existing on cap microcalcification.
Abstract 8889: Predictors of 30-Day Readmission in Nonagenarians Presenting With Acute Diastolic Heart Failure: Nationwide Analysis
Authors: Ahmed Maraey, Hadeer Elsharnoby, Ahmed Elzanaty, Ahmed Younes, Mahmoud Khalil, Mahmoud Salem, Nabila Dawoud
Journal: Circulation (2021)

Background: Acute diastolic heart failure (DHF) is a common but poorly studied diagnosis in hospitalized nonagenarians. Objective: To identify predictors of 30-day readmission in nonagenarians hospitalized with acute DHF. Methods: We queried National Readmission Database (NRD) of years 2016-2018 for patients aged 90 or above admitted with acute or acute on chronic DHF. ICD-10 was used to identify diagnoses. We excluded patients discharged in December and those who died in index admission. Univariate regression was performed on each variable. Variables with p value of &lt; 0.2 were included in our multivariate regression model (figure 1). Results: From a total of 45393 index admissions, 43646 (96.2%) survived to discharge. A total of 7437 (16.4%) patients had a 30-day readmission. Mean cost of readmission was 43265 USD per patient. Significant predictors of 30-day readmission were chronic ischemic heart disease (OR=1.11, 95%CI [1.01-1.22], P=0.023), chronic kidney disease stage 3 or above (OR=1.19, 95%CI [1.07-1.34], P=0.002), complicated diabetes (OR=1.22, 95%CI [1.07-1.38], P=0.003), and length of stay (LOS) &gt; 2 days (OR=1.20, 95% CI [1.09-1.32], P=0.000). Female sex (OR=0.90, 95% CI [0.83-0.99], P=0.030) and palliative care visit (OR=0.27, 95% CI [0.21-0.34], P=0.000) were associated with lower odds of readmission. Conclusion: In nonagenarians hospitalized with acute DHF, 30-day readmission is common and costly. Chronic comorbidities and LOS &gt;2 days were predictors of readmission. Palliative care visit was strongly associated with lower risk of readmission. Further strategies need to be developed to improve the quality of care and prevent readmission in this age group.
Elimination of fluorescent protein immunogenicity permits modeling of metastasis in immune-competent settings
Authors: Candice A. Grzelak, Erica T. Goddard, Emma E. Lederer, Kamya Rajaram, Jinxiang Dai, Ryann E. Shor, Andrea R. Lim, Jeanna Kim, Slobodan Beronja, Alister P.W. Funnell, Cyrus M. Ghajar
Journal: Cancer Cell (2021)