tbuckley/cabot-search huggingface dataset:
Abstract 10622: Z Scores in Pediatric Cardiac Magnetic Resonance: Reclassification of Smaller, Younger Hearts with Novel Calculator
Authors: Nyshidha Gurijala, Yue-hin Loke, Russell Cross, Karin Hamann, Laura Olivieri
Journal: Circulation (2021)

Introduction: The use of z scores to describe growth of normal structures is necessary in the management of pediatric cardiac disorders, particularly in babies and toddlers. Z score calculators for cardiac magnetic resonance (CMR) have traditionally relied on a convenience sample given complexity of the test. A recently published, novel z score calculator from prospectively-imaged, awake, healthy children ages 0-12 years may add value to assessments of ventricular size compared to traditional calculators. Hypothesis: A novel z score calculator (“Olivieri et al”) with robust prediction in younger, smaller children may reclassify right and left ventricular end diastolic volumes and mass (RVEDV, LVEDV, LVM) compared to the traditional calculator (“Buechel et al”). Methods: A retrospective cohort of subjects less than 12 years of age who underwent clinical CMR imaging on a 1.5T scanner (n=96; median age 5.5 years (IQR 3.7-7.6 years); 42% female) was studied. Z scores were calculated using both novel and traditional models for RVEDV, LVEDV and LVM. Subjects were categorized into the agreement group (both calculators agree) or disagreement groups, where novel calculator reclassified to normal (z&lt; ± 2) or abnormal (z&gt; ±2). Reclassified subject characteristics were compared with ANOVA and t-test. Results: Novel and traditional z scores agreed for 77%, 58% and 62% of cases for RVEDV, LVEDV and LVM, respectively. Amongst disagreements, subjects reclassified from abnormal to normal by the novel calculator had significantly lower age, BSA and RV size (Table 1). Reclassified subjects showed no association with specific diagnoses. Conclusion: The novel z score calculator reclassifies younger, smaller children away from severe z scores into more normal z scores. Ventricular volume assessment is highly relevant to critical decision-making in the first years of life in borderline lesions.
AACR Project GENIE: Powering Precision Medicine through an International Consortium
Authors: Fabrice André, Monica Arnedos, Alexander S. Baras, José Baselga, Philippe L. Bedard, Michael F. Berger, Mariska Bierkens, Fabien Calvo, Ethan Cerami, Debyani Chakravarty, Kristen K. Dang, Nancy E. Davidson, Catherine Del Vecchio Fitz, Semih Dogan, Raymond N. DuBois, Matthew D. Ducar, P. Andrew Futreal, Jianjiong Gao, Francisco Garcia, Stu Gardos, Christopher D. Gocke, Benjamin E. Gross, Justin Guinney, Zachary J. Heins, Stephanie Hintzen, Hugo Horlings, Jan Hudeček, David M. Hyman, Suzanne Kamel-Reid, Cyriac Kandoth, Walter Kinyua, Priti Kumari, Ritika Kundra, Marc Ladanyi, Céline Lefebvre, Michele L. LeNoue-Newton, Eva M. Lepisto, Mia A. Levy, Neal I. Lindeman, James Lindsay, David Liu, Zhibin Lu, Laura E. MacConaill, Ian Maurer, David S. Maxwell, Gerrit A. Meijer, Funda Meric-Bernstam, Christine M. Micheel, Clinton Miller, Gordon Mills, Nathanael D. Moore, Petra M. Nederlof, Larsson Omberg, John A. Orechia, Ben Ho Park, Trevor J. Pugh, Brendan Reardon, Barrett J. Rollins, Mark J. Routbort, Charles L. Sawyers, Deborah Schrag, Nikolaus Schultz, Kenna R Mills Shaw, Priyanka Shivdasani, Lillian L. Siu, David B. Solit, Gabe S. Sonke, Jean Charles Soria, Parin Sripakdeevong, Natalie H. Stickle, Thomas P. Stricker, Shawn M. Sweeney, Barry S. Taylor, Jelle J. ten Hoeve, Stacy B. Thomas, Eliezer M. Van Allen, Laura J. Van 'T Veer, Tony van de Velde, Harm van Tinteren, Victor E. Velculescu, Carl Virtanen, Emile E. Voest, Lucy L. Wang, Chetna Wathoo, Stuart Watt, Celeste Yu, Thomas V. Yu, Emily Yu, Ahmet Zehir, Hongxin Zhang
Journal: Cancer Discovery (2017)

The AACR Project GENIE is an international data-sharing consortium focused on generating an evidence base for precision cancer medicine by integrating clinical-grade cancer genomic data with clinical outcome data for tens of thousands of cancer patients treated at multiple institutions worldwide. In conjunction with the first public data release from approximately 19,000 samples, we describe the goals, structure, and data standards of the consortium and report conclusions from high-level analysis of the initial phase of genomic data. We also provide examples of the clinical utility of GENIE data, such as an estimate of clinical actionability across multiple cancer types (>30%) and prediction of accrual rates to the NCI-MATCH trial that accurately reflect recently reported actual match rates. The GENIE database is expected to grow to >100,000 samples within 5 years and should serve as a powerful tool for precision cancer medicine.
Risk of adverse events and reported clinical relapse after COVID-19 vaccination in patients with IBD
Authors: Rosanna Cannatelli, Francesca Ferretti, Stefania Carmagnola, Irene Maria Bambina Bergna, Maria Camilla Monico, Giovanni Maconi, Sandro Ardizzone
Journal: Gut (2021)

Chemical, Biological, Radiological, Nuclear and Explosive/Environmental/Endemic Disease (CBRNE<sup>3</sup>) incidents encompass a wide spectrum of events from natural events/disasters to industrial accidents through to deliberate military release and nuclear war. The UK military operates globally and in environments that are often austere. The very nature of these environments means that CBRNE<sup>3</sup> incidents are a very real risk, and a CBRNE<sup>3</sup> incident in a well-developed society could ultimately create an austere environment. Responding to such an event in an austere environment poses challenges. The very nature of the environment may be problematic. It may be very remote with limited or no access by road and/or air. It may have limited resources such as water and infrastructure required to manage the event. Extremes of temperature and weather may pose a risk to casualties and responders alike. Specialist teams and equipment may be required, but the host or partner nations may not have suitable capability and these resources may take time to mobilise from the home base. The volume of equipment and material needed in the response may overwhelm logistical chains which may not be robust enough to withstand the initial incident. Proper planning and preparedness is crucial to operating in and managing a CBRNE<sup>3</sup> incident in an austere environment. Recognition of the potential threat by intelligence gathering and recognition by personnel on the ground are essential. This requires an appropriate awareness at all levels of command and appropriate prior training, including interoperability training with partner forces. Ultimately, robust planning and training is key to managing CBRNE<sup>3</sup> incidents in an austere environment.
TAMI-26. INVESTIGATING TUMOR MICROENVIRONMENT METABOLIC DEPENDENCIES IN GLIOBLASTOMA
Authors: Jenna Minami, Nicholas Bayley, Christopher Tse, Danielle Morrow, Henan Zhu, William Yong, Linda Liau, Timothy Cloughesy, Thomas Graeber, David Nathanson
Journal: Neuro-Oncology (2021)

Abstract Metabolic reprogramming is a hallmark of cancer. Malignant cells must acquire metabolic adaptations in response to a multitude of intrinsic and extrinsic factors to fuel neoplastic progression. Mutations or changes in metabolic gene expression can impose nutrient dependencies in tumors, and even in the absence of metabolic defects, cancer cells can become auxotrophic for particular nutrients or metabolic byproducts generated by other cells in the tumor microenvironment (TME). Altered metabolism in GBM is becoming an increasingly promising area of research to identify novel therapeutic targets and biomarkers, as metabolic rewiring can occur across numerous genotypes. The unique features of the brain TME pose a difficult challenge when studying GBM and other primary brain cancers – currently, the availability of nutrients in the brain, as well as how they influence or are influenced by tumor metabolism, are not well understood. Our group has identified a subgroup of gliomas, hereafter termed TME-dependent, which can only form tumors in the brain TME. While genetically heterogeneous, these tumors share transcriptional identities linked to oligodendrocyte precursor cell (OPC) and neuronal lineages. Systematic molecular profiling of over 75 patient tumors and their matched cell culture and brain orthotopic xenograft derived models revealed that TME-dependent tumors display lipid metabolic signatures linked to signaling and interactions with surrounding neurons and glial cells. Collectively, these data emphasize the metabolic heterogeneity within GBM, and reveal a subset of gliomas that lack metabolic plasticity in fatty acid biosynthetic programs, indicating a potential brain-microenvironment specific metabolic dependency linked to transcriptional identity that can be targeted for therapy.
Individualized AML Induction with Venetoclax Based Therapy in Unfit Treatment Naïve Patients Aged ≤ 60 Years: A Real World Perspective from India
Authors: Mohd Rizwan Mohamad Anwar Shaikh, Pallavi Mehta, Sumeet Prakash Mirgh, Rohan Halder, Narendra Agrawal, Vishvdeep Khushoo, Rayaz Ahmed, Bhaarat Folbs, Divya Pratihast, Nitin Bansal, Dinesh Bhurani
Journal: Blood (2021)
Abstract P514: The Role Of Sweet And Umami Taste Receptors In The Heart
Authors: Maria Papadaki, Sara Osorio- Valencia, Jonathan A Kirk
Journal: Circulation Research (2021)

The tongue can distinguish between five different tastes via the taste receptors, which are G-protein coupled receptors (GPCRs). There are two classes of taste receptors, the TAS1 (T1) and TAS2 (T2) families, and the T1R1-T1R3 dimer senses the umami taste and T1R2-T1R3 senses the sweet taste. Recently, the taste receptors have also been found in the brain, lungs, intestine and pancreas, where they sense changes in the nutrient environment and respond through GPCR signalling. Given the importance of glucose and amino acid metabolism in the heart, we hypothesized that the sweet and umami taste receptors have an important function in the heart. Using a variety of technologies and disease states, we have identified that T1R1, T1R2 and T1R3 are expressed in the heart. More specifically, mass spectrometry of a dog model of dyssynchrony has shown the presence of T1R1, T1R3 and T1R2. RNA seq of human patients who received a Left Ventricular Assist device and those who did not also revealed the presence of T1R1 and T1R3. The expression of these proteins was also confirmed using Western blot. We further showed T1R2 and T1R3 protein is localized in the plasma membrane of the cardiomyocytes by immunofluorescence (colocalized with Na/K ATPase) and PM enrichment. When we compared the taste receptor protein levels in dilated cardiomyopathy (DCM) compared to donor heart tissue, we found that T1R2 was overexpressed in DCM, showing that taste receptors may be important in nutrient sensing in disease. Furthermore, when neonatal rat ventricular myocytes were treated with sweet and umami agonists (aspartame for the sweet taste receptor and monosodium glutamate for the umami receptor), they had increased calcium transients as shown by an increase in peak calcium. Cardiomyocytes treated with aspartame also showed a decrease in time to relax. We hypothesize that in the heart, sweet and umami receptors induce positive inotropy upon a change in nutrient environment.
Abstract P341: Juvenile Exposure To Doxorubicin Differentially Alters The Cardiac Response To Angiotensin II And Isoproterenol In Adult Mice
Authors: Marianne K Grant, Beshay N Zordoky
Journal: Circulation Research (2021)

Hypertension is the most significant risk factor for heart failure in doxorubicin (DOX)-treated childhood cancer survivors. We previously developed a two-hit mouse model of juvenile DOX-induced latent cardiotoxicity that is exacerbated by adult-onset angiotensin II (ANGII)-induced hypertension. Nevertheless, it is still not known how juvenile exposure to DOX would predispose the heart to other cardiovascular pathologic stimuli that do not cause hypertension. The objective of this work was to compare the effects of ANGII to those of isoproterenol (ISO) in adult C57BL6/N mice pre-exposed to DOX as juveniles. Five-week-old male mice were administered a low dose of DOX (4 mg/kg/week) or saline for 3 weeks and then allowed to recover for 5 weeks. Thereafter, mice were either infused with ANGII (1.4 mg/kg/day) or injected with ISO (10 mg/kg/day) for 14 days. Juvenile exposure to DOX abrogated the hypertrophic response to both ANGII and ISO, while it failed to correct ANGII- and ISO-induced upregulation in the hypertrophic markers ANP and BNP. ANGII, but not ISO, worsened cardiac function in DOX-exposed mice as measured by echocardiography. Cardiac fibrosis was also exacerbated by ANGII, but not ISO, in DOX-exposed mice as evident by Masson’s trichrome staining and upregulation of the inflammatory and fibrotic markers, Cox-2, Col1a1, Col3a1 , and galectin-3 . In conclusion, the current work demonstrates that ANGII causes more severe deterioration in cardiac function and adverse cardiac remodeling in DOX-exposed mice when compared to ISO. The comparison between DOX/ANGII and DOX/ISO models is critical to understanding why hypertension is the most significant risk factor for heart failure in DOX-treated childhood cancer survivors and thereby devising effective therapeutic strategies against this significant clinical problem.
Abstract 402: Defining Diverse Disease Pathomechanisms Across Thick And Thin Filament Hypertrophic Cardiomyopathy Variants.
Authors: Christopher Toepfer, Yiangos Psaras, Francesca Margara, Manuel Schmid, Violetta Steeples, Julia D Marsiglia, Amanda Garfinkel, Giuliana Repetti, Bueno-Orovio Alfonso, Blanca Rodriguez, Jonathan Seidman, Christine E Seidman
Journal: Circulation Research (2021)

Hypertrophic cardiomyopathy (HCM) affects as many as ~1 in 500 individuals, and is often typified by hyperdynamic contraction and poor cellular relaxation. HCM can be caused by mutations in a variety of key contractile proteins of the sarcomere. A large proportion of these variants are found in MYBPC3, MYH7, TNNT2, and TNNI3. These genes encode proteins that control cardiac muscle contraction at the thick (MYBPC3 and MYH7) and thin filaments (TNNT2 and TNNI3) of the sarcomere. In this study we use human induced pluripotent stem cell derived cardiomyocytes to model HCM across all of these genes. We do this to define key mechanistic differences between thick and thin filament HCM. We define sarcomeric contractility (SarcTrack) calcium transients (CalTrack) and myosin states using the mant-ATP assay. We use the parametric data from these experimental studies in iPSC-CMs to model possible disease mechanisms in silico. Our experimental analysis highlights that both thick and thin filament HCM variants cause cellular hypercontractility, with slowed cellular relaxation. We find that thick filament HCM variants drive cellular HCM phenotypes by destabilising the myosin interacting heads motif (IHM), showing a marked reduction in the super relaxed state of myosin. Counterintuitively thin filament based HCM variants show a reduction in DRX myosin. When applying Mavacamten the allosteric myosin ATPase inhibitor to our thin and thick filament HCM variant iPSC-CMs we find a dichotomy of cellular responses. The thick filament variants studied all show a clear resolution of cellular HCM. However, not all cellular phenotypes of thin filament HCM are corrected by Mavacamten treatment, although there is benefit. We conclude that causal mechanisms of thick filament HCM are well corrected at the molecular and cellular level by Mavacamten, but these causal mechanisms in thin filament based HCM are not suitably corrected. We highlight key mechanistic pharmacological targets for thin filament variants that could add cellular benefit to HCM phenotype resolution.
Abstract 14246: Septic Shock and Myocardial Infarction
Authors: Ishan kamat, Salik Nazir, Juan C Plana, Prathit Kulkarni, VIJAY NAMBI, Biykem Bozkurt, Hani Jneid
Journal: Circulation (2021)

Introduction: Septic shock (SS) is a life-threatening host response to infection, contributing to significant mortality, morbidity, and cost burden in the United States. Although the inflammatory link between SS and myocardial infarction (MI) has been established, outcomes of patients who concomitantly develop types 1 or 2 MI have not been directly studied. Purpose: To examine patient profiles and the associations of type 1 and type 2 MI with hospital-related clinical outcomes in patients admitted with SS. Methods: The National Readmission Database 2018 was queried to identify patients whose hospital discharge diagnoses were either SS without MI, SS with type 1 MI, or SS with type 2 MI. Complex-sample multivariable logistic and linear regression models were used to determine the associations of these conditions with clinical outcomes including in-hospital mortality, length of stay, discharge to nursing facility, 30-day all-cause readmission and hospital cost. Results: A total of 354,528 patients with SS were included in this study. Among them, 11,519 (3.2%) had type 1 MI, and 13,970 (3.9%) had type 2 MI. Compared to SS without MI, SS with type 1 MI was more likely to be associated with significantly higher in-hospital mortality (adjusted odds ratio [aOR] 1.67, 95% confidence interval [CI] 1.57-1.77), hospital cost (adjusted parameter estimate [aPE] 4,571, 95% CI 3,020-6,122), and discharge to nursing facility (aOR 1.13, 95% CI, 1.05-1.22). In contrast, SS with type 2 MI was associated with similar in-hospital mortality, discharge to nursing facility, and higher hospital cost (aPE 1,798, 95% CI, 549-3,047) compared to SS without MI. Type 1 MI was associated with higher in-hospital mortality (aOR 1.74, 95% CI, 1.60-1.90, p&lt;0.001) than type 2 MI. Conclusions: In hospitalized patients with SS, the development of type 1 MI is associated with higher mortality and resource utilization in the United States, whereas type 2 MI was only associated with higher resource utilization.
TAMI-32. CORRELATION BETWEEN RADIOSENSITIVITY INDEX AND M2 MACROPHAGE PROPORTION IN TUMOR MICROENVIRONMENT OF GLIOBLASTOMA
Authors: Bum-Sup Jang, In Ah Kim
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Tumor-associated macrophages (TAMs) Macrophage are predominant in glioblastoma tumor microenvironment (TME), supporting for neoplastic cell expansion and invasion. We investigated the relationship between radiosensitivity of glioblastoma and M1/M2 macrophage profiles in bulk and single cell RNA sequencing datasets. METHODS We used radiosensitivity index (RSI) gene signature and estimated RSI score based on the ranking of genes by expression level. Two large glioma datasets – The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) – were employed to identify whether RSI is clinically predictive of overall survival following radiation therapy. To analyze the association between M1/M2 macrophages and RSI within spatial context, the Ivy Glioblastoma Atlas Project dataset was investigated and single cell RNA sequencing dataset (GSE84465) was analyzed as well. Macrophages were profiled using a deconvolution algorithm, CIBERSORTx. RESULTS The RSI-high group having radioresistant tumors showed worse overall survival than the RSI-low group in both the TCGA (HR=1.87, 95% CI=1.06-3.29, P=0.031) and the CGGA (HR=1.61, 95% CI=1.04-2.50, P=0.031) glioblastoma population. In the Ivy Glioblastoma Atlas Project dataset, radiosensitive tumor having lower RSI was significantly more found in more vascular region including hyperplastic and microvascular region (coefficient=-0.07, P=0.001), meanwhile, radioresistant tumor was significantly clustered in necrotic region including perinecrotic and pseudopalisading regions (coefficient=0.07, P&amp;lt; 0.001). The proportion of M1/M2 macrophage and RSI score showed an inverse relationship (coefficient=-0.23, P=0.015), indicating that radioresistant glioblastomas are related with TME having more M2 than M1 macrophage. In single cell RNA sequencing dataset composed of immune and tumor cells collected from four patients, mean RSI of neoplastic cells was positively correlated with high proportion of M2 macrophages. CONCLUSION RSI can predict radiation response in terms of overall survival in glioblastoma patients. High proportion of M2 macrophage may play an important role in TME of radioresistant glioblastoma.
Abstract P314: TGFβ2-Mediated Cardiac Fibroblast Activation Is Dependent On BET Bromodomain Proteins
Authors: Andrew Antolic, Zhe Jiao, Talha Ijaz, Ria Gupta, Michael A Burke
Journal: Circulation Research (2021)

Heart failure is a common and morbid disease frequently caused by dilated cardiomyopathy (DCM). Fibrotic remodeling is a key feature of DCM. Stress signaling pathways trigger transdifferentiation of quiescent cardiac fibroblasts into myofibroblasts (MF). Bromodomain and extra-terminal (BET) epigenetic reader proteins are stress-responsive distal signaling integrators that drive fibrosis. Here, we explored the role of BETs on distinct inflammatory pathways in ex vivo cultured cardiac fibroblasts. The Langendorff hanging heart procedure was used to isolate and culture primary non-myocytes from wild type hearts, which are almost exclusively fibroblasts. Cells were stimulated with TGFβ2 to trigger MF transdifferentiation. Prior to TGFβ2 treatment, fibroblasts were treated with 1 of the following: vehicle, the BET inhibitor JQ1, or siRNA targeting either Smad3 or Rela . MF-specific gene expression was assessed by Q-PCR. α-smooth muscle actin (αSMA) levels were assessed by immunocytochemistry (ICC) and immunoblotting. NFκB transcriptional activity was evaluated using a dual luciferase reporter assay. TGFβ2 activated MF-specific gene expression ( Acta2 , 9.0-fold; Col3a1 , 3.6-fold; Ctgf, 10.1-fold; Postn , 12.8-fold; p&lt;0.05 for all vs. vehicle), and increased αSMA levels (1.5-fold by ICC and immunoblotting; p&lt;0.05 vs. vehicle) in cultured primary cardiac fibroblasts. This was ablated by JQ1 and Smad3 siRNA. By contrast, Rela siRNA alone induced MF-specific gene expression ( Acta2 , 6.9-fold; Col3a1 , 7.0-fold; Ctgf, 3.7-fold; Postn , 11.2-fold; p&lt;0.05 for all vs. vehicle), and increased αSMA staining by ICC (3.4-fold; p&lt;0.05) but not protein (1.3-fold; p=NS). TGFβ2 further potentiated MF-specific gene expression ( Acta2 , 17.1-fold; Col3a1 , 7.1-fold; Ctgf, 13.2-fold; Postn , 42.5-fold; p&lt;0.05 for all vs. vehicle) and αSMA protein (1.7-fold; p&lt;0.05) in fibroblasts treated with Rela siRNA. NFκB transcriptional activity was reduced by TGFβ2 (-2.9-fold; p&lt;0.05) and with JQ1 pre-treatment (-2.7-fold; p&lt;0.05). These data define a critical role for BETs in TGFβ2-mediated gene transcription in cardiac fibroblasts. Surprisingly, NFκB does not appear to be a key activator of TGFβ2-stimulated fibroblast transdifferentiation.