tbuckley/cabot-search huggingface dataset:
Abstract P194: Proteomic Analysis of Cardiac Troponin I And T in Older Adults Without Cardiovascular Disease
Authors: Olive Tang, Josef Coresh, Jingsha Chen, Adrienne Tin, Kunihiro Matsushita, Eric Boerwinkle, Bing Yu, Xiaoming Jia, Ron C Hoogeveen, James S Pankow, Christie M Ballantyne, Elizabeth Selvin
Journal: Circulation (2020)

Background: Minute elevations in cardiac troponins detected with high sensitivity assays are associated with cardiovascular disease (CVD) and mortality. The biology underlying these associations is uncertain. We identified plasma proteins associated with cardiac troponins and assessed the relation of troponin-associated proteins with CVD and all-cause mortality in adults without prevalent CVD. Methods: We included 3451 adults (62% female, 18% black, mean age: 75 years) in ARIC at Visit 5 (2011-2013). High sensitivity assays were used to measure troponins (hs-cTnI [Abbott], hs-cTnT [Roche]). We used linear regression to model the association of log2-transformed troponin and plasma proteins (SomaLogic aptamer assay). Upstream regulators of the troponin-associated proteins were identified using Ingenuity Pathway Analysis. Elastic net was used to extract troponin-associated protein signatures for principal component analysis and Cox models of CVD and all-cause mortality (median follow-up: 6 years). Results: Of the 4326 plasma proteins, there were 281 significantly (p&lt;1.16e-5) associated with hs-cTnI and 576 with hs-cTnT (adjusted for age and sex). In models adjusted for CVD risk factors, there were 99 proteins associated with hs-cTnI and 118 associated with hs-cTnT (Figure), with 65 in common; the top upstream regulator associated with both hs-cTnI (p = 0.001) and hs-cTnT (p=0.006) was myocardin (MYOCD), a transcriptional activator in smooth and cardiac muscles. The first principal component derived from the troponin-associated proteins was significantly associated with both all-cause and CVD mortality. In models with both troponins and the first principal component, hs-cTnI, but not hs-cTnT, remained significantly associated with both outcomes (Table). Conclusions: Hs-cTnI and hs-cTnT have overlapping, but distinct, proteomic signatures. The underlying proteomic signature explains most of the mortality risk associated with hs-cTnT, but not hs-cTnI.
Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8+ T cells in autoimmunity and cancer
Authors: Jared Liu, Hsin-Wen Chang, Zhi-Ming Huang, Mio Nakamura, Sahil Sekhon, Richard Ahn, Priscila Munoz-Sandoval, Shrishti Bhattarai, Kristen M. Beck, Isabelle M. Sanchez, Eric Yang, Mariela Pauli, Sarah T. Arron, Wai-Ping Fung-Leung, Ernesto Munoz, Xuejun Liu, Tina Bhutani, Jeffrey North, Anne M. Fourie, Michael D. Rosenblum, Wilson Liao
Journal: Journal of Allergy and Clinical Immunology (2020)
Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial
Authors: David C Wheeler, Bergur V Stefánsson, Niels Jongs, Glenn M Chertow, Tom Greene, Fan Fan Hou, John J V McMurray, Ricardo Correa-Rotter, Peter Rossing, Robert D Toto, C David Sjöström, Anna Maria Langkilde, Hiddo J L Heerspink
Journal: The Lancet Diabetes & Endocrinology (2020)
Endothelial Klf2-Foxp1-TGFβ signal mediates the inhibitory effects of simvastatin on maladaptive cardiac remodeling
Authors: Hongda Li, Yanfang Wang, Jiwen Liu, Xiaoli Chen, Yunhao Duan, Xiaoyu Wang, Yajing Shen, Yashu Kuang, Tao Zhuang, Brain Tomlinson, Paul Chan, Zuoren Yu, Yu Cheng, Lin Zhang, Zhongmin Liu, Yuzhen Zhang, Zhenlin Zhao, Qi Zhang, Jie Liu
Journal: Theranostics (2020)

Aims: Pathological cardiac fibrosis and hypertrophy are common features of left ventricular remodeling that often progress to heart failure (HF). Endothelial cells (ECs) are the most abundant non-myocyte cells in adult mouse heart. Simvastatin, a strong inducer of Krüppel-like Factor 2 (Klf2) in ECs, ameliorates pressure overload induced maladaptive cardiac remodeling and dysfunction. This study aims to explore the detailed molecular mechanisms of the anti-remodeling effects of simvastatin. Methods and Results: RGD-magnetic-nanoparticles were used to endothelial specific delivery of siRNA and we found absence of simvastatin's protective effect on pressure overload induced maladaptive cardiac remodeling and dysfunction after in vivo inhibition of EC-Klf2. Mechanism studies showed that EC-Klf2 inhibition reversed the simvastatin-mediated reduction of fibroblast proliferation and myofibroblast formation, as well as cardiomyocyte size and cardiac hypertrophic genes, which suggested that EC-Klf2 might mediate the anti-fibrotic and anti-hypertrophy effects of simvastatin. Similar effects were observed after Klf2 inhibition in cultured ECs. Moreover, Klf2 regulated its direct target gene TGFβ1 in ECs and mediated the protective effects of simvastatin, and inhibition of EC-Klf2 increased the expression of EC-TGFβ1 leading to simvastatin losing its protective effects. Also, EC-Klf2 was found to regulate EC-Foxp1 and loss of EC-Foxp1 attenuated the protective effects of simvastatin similar to EC-Klf2 inhibition. Conclusions: We conclude that cardiac microvasculature ECs are important in the modulation of pressure overload induced maladaptive cardiac remodeling and dysfunction, and the endothelial Klf2-TGFβ1 or Klf2-Foxp1-TGFβ1 pathway mediates the preventive effects of simvastatin. This study demonstrates a novel mechanism of the non-cholesterol lowering effects of simvastatin for HF prevention.
Outcomes of Hepatitis C Virus Treatment with Ledipasvir/Sofosbuvir in Mongolian Population: Successes and Challenges Facing Scale-up of Care
Authors: Seong Hee Kang, Moon Young Kim
Journal: Clinical and Molecular Hepatology (2020)

See the Original "Efficacy and safety of ledipasvir/sofosbuvir in 5,028 Mongolian patients infected with genotype 1 hepatitis C virus: A multicenter study" on page 125.
BIOM-28. IDENTIFICATION OF SOLUBLE AXL AS A POTENTIAL NON-INVASIVE SERUM BIOMARKER FOR GLIOBLASTOMA
Authors: Parvez Akhtar, Daniel Raymond, Melanie Fukui, Samuel Zwernik, Robert Winn, Amber LaCrosse, Brittany Last, Natalie Polinske, Richard Rovin
Journal: Neuro-Oncology (2020)

Abstract AXL, a member of the TAM family of tyrosine kinases, engages cellular pathways that promote a cancer phenotype. In glioblastoma, increasing AXL expression is associated with worse prognosis. The extracellular domain of AXL is cleaved by the sheddases ADAM10 and ADAM17, releasing soluble AXL (sAXL), which is detectable in blood and tumor related fluid collections. In this study we use ELISA to measure serum sAXL levels in 23 patients with newly diagnosed GBM pre- and post- operatively and every 3 months during treatment. Relative AXL expression was assessed in tumor tissue obtained from 13 patients via western blotting. Additionally, we used T1-weighted MRI scans to interpolate pre-operative tumor volume for all patients enrolled in the study. We found that serum sAXL concentrations were elevated in 84 GBM serum samples (35.77 ±1.25 ng/mL) compared to 40 healthy volunteer samples (30.16 ±1.88 ng/mL). When normalized to total serum albumin the difference between GBM and healthy controls was statistically significant (t(df)=5.647(122), p= 0.0132). In the 19 patients with paired samples, the pre- and post- operative sAXL levels were not significantly different. Using the Pearson method, we did not find a significant correlation between tumor volume and sAXL level. However, in patients with sAXL levels above the healthy population average, there was a moderate negative correlation between sAXL and pre-operative tumor volume (r= -0.58; p= 0.23). Interestingly, there was a strong correlation between sAXL level and tumor expression of AXL in patients with high preoperative sAXL levels (r= 0.85; p= 0.03). Though sAXL shed from brain tumors is detectable in the serum of GBM patients, in this small series of patients, it does not correlate with tumor volume. That said, we feel a larger study correlating sAXL level with improved volumetric MRI determination of viable GBM is warranted.
Effect of a Culturally Adapted Behavioral Intervention for Latino Adults on Weight Loss Over 2 Years
Authors: Lisa G. Rosas, Nan Lv, Lan Xiao, Megan A. Lewis, Elizabeth M. J. Venditti, Patricia Zavella, Kristen Azar, Jun Ma
Journal: JAMA Network Open (2020)

Identifying effective weight loss interventions for Latino adults at risk of diabetes is of critical public health importance.To determine whether a culturally adapted behavioral intervention for Latino adults was more effective than usual care for weight loss over 24 months.In this randomized clinical trial, Latino adults with a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 24 or greater and a high risk for type 2 diabetes were recruited in primary care practices in the San Francisco, California, area, randomized to receive the Vida Sana intervention or usual care, and followed up for 24 months. The study was conducted from November 2015 to May 2019, and data were analyzed from July 2019 to Septmeber 2020.The treatment group received Vida Sana, a culturally adapted lifestyle intervention that included a family-based orientation session and 22 group sessions over 12 months. Participants were encouraged to use a wearable activity tracker and mobile applications to track their physical activity and dietary intake. Participants received monthly email messages for an additional 12 months. The control group received usual care.The primary outcome was weight loss at 24 months. Secondary outcomes included weight loss at 12 months and achieving at least 5% weight loss at 12 and 24 months. Associations of baseline characteristics and intervention adherence with weight loss outcomes were also examined.Among 191 participants (mean [SD] age, 50.2 [12.2] years; 118 [61.8%] women; 107 participants [57.2%] of Mexican origin; mean [SD] baseline BMI, 32.4 [5.7]) randomized, 92 participants were randomized to the intervention and 99 participants were randomized to usual care. Of these, 185 participants (96.9%) completed 24-month follow-up. Mean (SD) weight loss did not differ significantly by group at 24 months (intervention: -1.1 [5.7] kg; control: -1.1 [7.1] kg; P = .93). However, mean (SD) weight loss was significantly greater in the intervention group (-2.6 [6.0] kg) than the control group (-0.3 [4.2] kg) at 12 months (mean difference, -2.1 [95% CI, -3.6 to -0.7] kg; P = .005). Intervention participants were more likely to achieve at least 5% weight loss than control participants at 12 months (22 participants [25.9%] vs 9 participants [9.2%]; P = .003), and participants who achieved at least 5% weight loss attended more intervention sessions than those who did not (mean [SD], 16.6 [7.6] sessions vs 12.4 [7.5] sessions; P = .03).These findings suggest that among Latino adults with high diabetes risk, a culturally adapted behavioral lifestyle intervention was effective for weight loss over 12 months but not 24 months.ClinicalTrials.gov Identifier: NCT02459691.
Epithelioid Hemangioma of Vertebra Mimicking Metastasis on FDG PET/CT in a Patient With Renal Cell Cancer
Authors: Fumi Yanagisawa, Yasuo Amano, Yuko Omori, Ryo Takagi, Xiaoyan Tang
Journal: Clinical Nuclear Medicine (2020)

Abstract Vertebral epithelioid hemangioma is a rare vascular tumor composed of the many vessels lined by distinct epithelioid endothelial cells. We present the case of a patient with renal cell cancer (RCC) and suspicious vertebral metastasis presenting with back pain, who was later found to have epithelioid hemangioma. FDG PET/CT demonstrated uptake of FDG not only in RCC, but also in the sixth thoracic vertebral body. The SUVmax of the vertebra was more than twice as high as RCC. This report indicates importance of quantitative assessment of FDG uptake, as well as combined use of MRI.
THER-07. INHIBITION OF THE RAS SIGNALING ENHANCES VIRAL ONCOLYSIS IN MALIGNANT GLIOMAS
Authors: Yoshiki Arakawa, Makoto Yamaguchi, Masahiro Tanji, Yohei Mineharu, Susumu Miyamoto
Journal: Neuro-Oncology (2020)

Abstract Pediatric malignant glioma indicates rapid proliferation, widely infiltrative properties and resistance to various therapies, and carries a very poor prognosis. There are methods of using virus within novel therapies under development against malignant neoplasms, which have been studied for many years already. We examined the treatment with sunitinib or GW5074 to our experimental model of vaccinia virus therapy for malignant glioma, and then evaluated changes in the tumoricidal activity, the viral infectivity, and the impact on the Ras signaling pathway. Glioma cells (U251MG, LN229, LN18, rat C6) infected with vaccinia virus was fatal, in its course of death, apoptosis and autophagy were induced. The activity of Ras signaling in vaccinia-infected cells heightened in the early stage and declined in the late stage Inhibition of the Ras signaling pathway at the early stage of viral infection prevented vaccinia virus replication, while viral oncolysis was not inhibited when the pathway was blocked after sufficient viral spread. Glioma cells infected with vaccinia virus are led to cell death. Vaccinia virus regulates Ras or other survival signaling pathways in the infected cells. It enhances the signaling in the early stage (viral replicative period), however suppresses in the later stage (virus-releasing stage). Inhibition of the Ras signaling pathway at the early stage of viral infection prevents vaccinia virus from replicating, while viral oncolysis appears to be accelerated when the pathway was blocked after sufficient viral reproduction.
Abstract 14843: Electrocardiographic Manifestations of Immune Checkpoint Inhibitor Associated Myocarditis
Authors: John R Power, Joachim Alexandre, Arrush Choudhary, benay ozbay, Nicolas L Palaskas, Lorenz H Lehmann, Daniel Finke, Jennifer Cautela, Franck Thuny, Yuichi Tamura, Salim S Hayek, Tariq U Azam, Aarti Asnani, Tyler Mehegan, Mandar A Aras, Alan H Baik, Lauren Gilstrap, Michal Laufer-Perl, Dimitri Arangalage, Steven Ewer, Matthew Martini, Joseph Nowatzke, Olusola A Orimoloye, Douglas M Brinkley, Wouter C Meijers, Charlotte Fenioux, Stephane EDERHY, Javid J Moslehi, Joe-elie Salem
Journal: Circulation (2020)

Introduction: Immune checkpoint inhibitor (ICI)-myocarditis is a new syndrome with estimated 50% mortality. Similar to acute cellular rejection (ACR), it is pathologically characterized by lymphocytic infiltration. We aimed to characterize the electrocardiograph features of ICI-myocarditis, compare them to ACR, and evaluate their association with adverse outcome. Methods: Presenting ECG of 130 cases of ICI-myocarditis were collected from a multicenter network spanning 12 countries and compared to 50 cases of ACR. ECG were quantified and interpreted by two blinded cardiologists. 53 patients with ICI-myocarditis had baseline ECG available for comparison via paired univariate analysis. Cox models correcting for age and sex determined association with a composite outcome of life-threatening arrhythmia or myocarditis-related death. Results: ICI-myocarditis patients had average age of 68(58-76), were 61.2% male, and 64.8% had prior cardiovascular disease. QRS prolongation (26% vs 13%, p=0.008), conduction disorders (67% vs 44%, p=0.007) such as left bundle branch block (LBBB) (18% vs 4% p=0.008), ST/T wave changes (50% vs 24%, p=0.004), and PVCs (16% vs 6%, p=0.020) were more prevalent on presenting ECG compared to baseline. ICI-myocarditis showed more PVCs (16% vs 2%, p=0.011) and less ST/T wave changes (41% vs 66%, p=0.002) when compared to ACR. On multivariate analysis, the combined outcome of life-threatening arrhythmia or myocarditis-related death was associated with pathological Q waves (HR=3.60 (1.78-7.27) p&lt;0.001), QRS prolongation (HR=3.35 [1.00-11.21] p=0.05), LBBB (HR=2.24 [1.13-4.45] p=0.021), and supraventricular arrhythmia (HR=2.03 [1.05-3.91] p=0.035) on presenting EKG. Conclusions: ICI-myocarditis manifests as new conduction delays, ST/T-wave changes, and PVCs. QRS prolongation, LBBB, pathological Q waves, and supraventricular arrhythmias were associated with subsequent adverse outcomes.
HGG-20. DIAGNOSTIC AND BIOLOGICAL ROLE OF METHYLATION PATTERNS IN REPLICATION REPAIR DEFICIENT HIGH GRADE GLIOMAS
Authors: Andrew Dodgshun, Kohei Fukuoka, Melissa Edwards, Vanessa Bianchi, Alexandra Sexton-Oates, Valerie Larouche, Vanan Magimairajan, Scott Lindhorst, Michal Yalon, Gary Mason, Bruce Crooks, Shlomi Constantini, Maura Massimino, Stefano Chiaravalli, Jagadeesh Ramdas, Warren Mason, Ashraf Shamvil, Roula Farah, An Van Damme, Enrico Opocher, Syed Ahmer Hamid, David Ziegler, David Samuel, Kristina A Cole, Patrick Tomboc, Duncan Stearns, Gregory Thomas, Alexander Lossos, Michael Sullivan, Jordan R Hansford, David Jones, Alan Mackay, Chris Jones, Vijay Ramaswamy, Cynthia Hawkins, Eric Bouffet, Uri Tabori
Journal: Neuro-Oncology (2020)

Abstract Replication repair deficiency (RRD) is an important driving mechanism of pediatric high grade glioma (pHGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although pHGG present specific patterns of DNA methylation corresponding to driving oncogenic processes, methylation patterns have not been well studied in RRD tumors. We analyzed 52 RRD pHGG using either 450k or 850k methylation arrays. These arrays were compared with 234 PHGG driven by other genetic or epigenetic mechanisms and 10 additional pHGG samples known to be hypermutant. RRD pHGG displayed a methylation pattern corresponding to specific secondary mutations such as IDH1 and H3K27M. Strikingly, RRD pHGG lacking these known secondary mutations largely clustered together with a poorly described group previously labelled Wild type-C. Most of the hypermutant tumors clustered in a similar location suggesting undiagnosed RRD may be a driving force for tumors clustering in this location. Analysis of methylation patterns revealed that RRD pHGG displayed a unique CpG Island Demethylator Phenotype in contrast to the Methylator Phenotype described in other cancers. This effect was most concentrated at gene promotors. Prominent demethylation was observed in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism and cellular organization. These data suggest that methylation profiles may provide diagnostic information for the detection of RRD pHGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide novel impact of hypermutation and RRD on the cancer epigenome.
IMMU-13. EFFICACY OF CXCR6 BLOCKADE AS A POTENTIATOR OF ANTI-PD-1 THERAPY FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Ayush Pant, Laura Saleh, Kisha Patel, Ravi Medikonda, Michael Lim
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is an aggressive primary tumor of the brain with a dismal prognosis for patients. Despite the standard of care treatment, median survival is 12–15 months. The blockade of inhibitory checkpoints such as PD-1 and CTLA-4 has become the mainstay immunotherapy to treat solid tumors but it lacks efficacy in treating GBM patients. Emergence of alternative checkpoints on T cells as a mechanism of acquired resistance is considered one of the major hurdles for the success of anti-PD-1 therapy in GBM. Using an orthotopic mouse model of GBM, we have seen that cytotoxic T cells infiltrating the tumor show a preponderance of the chemokine receptor CXCR6 on exhausted cells. Furthermore, ablating CXCR6 along with anti-PD-1 therapy greatly improved anti-tumor immune response. Whereas PBS treated and CXCR6 KO mice had no long-term survivors 40 days post-tumor implantation, 90% of anti-PD-1 treated CXCR6 KO mice were long-term survivors, compared with 12% among anti-PD-1 treated wildtype mice. This supports our hypothesis that blockade of CXCR6 licenses anti-PD-1 blockade by alleviating acquired resistance to anti-PD-1 therapy. We have observed CXCR6 expression on exhausted T cells of GBM patients, making it a promising target for dual therapy with anti-PD-1 in clinical trials.
NURS-12. MAKING SURVIVORS HEALTHIER: A MULTIDISCIPLINARY APPROACH TO HYPOTHALAMIC OBESITY
Authors: Molly Hemenway, Kathleen Dorris, Amy Rydin, Thomas Inge, Megan Kelsey, Todd Hankinson, Suzanne Paul, Matthew Haemer, Jaime Moore
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Pediatric survivors of hypothalamic/suprasellar tumors have significant morbidities that greatly impact their quality of life. Management of hypothalamic obesity has traditionally fallen between multiple subspecialties without a timely and comprehensive approach. METHODS A multidisciplinary group of key players from neuro-oncology, endocrinology, nutrition, neurosurgery, and bariatric surgery were identified. Through this collaboration, a clinical algorithm for early identification of and intervention for hypothalamic obesity was developed. The goal of the quality improvement process is to increase the number of encounters with a registered dietitian (RD) with earlier and more consistent referrals to a specialized, multidisciplinary weight management program [Lifestyle Medicine; (LM)] for counseling and pharmacologic interventions. Indications for referral to LM were BMI &amp;gt;95th percentile, crossing &amp;gt;2 BMI percentiles on growth curve and/or hyperphagia symptoms. A retrospective review of pediatric patients who have suprasellar/ hypothalamic tumors was also conducted. Data collected included demographics, tumor type, BMI, RD visit, and LM clinic referral/visit. RESULTS Fifty patients were identified for analysis six months following clinical algorithm institution. Thirty-three (66%) patients had craniopharyngioma, 15 (30%) had low-grade gliomas, and two (4%) had germ cell tumors. Thirty-three (66%) patients were noted to be obese (defined as BMI &amp;gt;95th percentile) at review. The median BMI of the entire cohort was 93rd (range, 1st-137th) percentile. Thirty-four (68%) patients had been seen by an RD. Twenty-seven (82%) of the obese patients had been referred to LM. CONCLUSIONS The development and implementation of the process for hypothalamic obesity prevention and intervention will be discussed.
NCOG-68. COMPARING COGNITIVE PROFILES OF PERSONS WITH BRAIN AND NON-BRAIN METASTATIC CANCER
Authors: Gabrielle Willhelm, Victor Del Bene, Stephen Aita, Meredith Gammon, Adam Gerstenecker, John Fiveash, Dario Marotta, Kristen Triebel
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Cognitive impairment in primary cancer and brain metastatic (BM) cancer has been well-documented. However, to date, there are no neuropsychological studies comparing the cognitive profiles of people with BM and non-brain metastatic cancer (NBM). The present study addressed this gap in the literature by comparing the cognitive profiles of participants with BM and NBM. METHOD The study sample consisted of 61 BM, 40 NBM, and 37 healthy control (HC) participants. All participants completed the same neuropsychological battery, including tests of processing speed, attention, working memory, expressive language, auditory-verbal memory, and executive functioning. RESULTS Both clinical groups showed reduced processing speed, verbal learning/memory, and executive functions. BM participants performed below HC participants across all neuropsychological tests, while NBM participants performed below control participants on tests of processing speed and executive functioning. The clinical groups differed in semantic verbal fluency (NBM &amp;gt; BM). Fifty-seven percent of BM participants had ≥ 3 impaired scores (i.e., ≤ 5th percentile), and 25% of NBM participants had the same level of cognitive impairment. CONCLUSION Over half of BM participants were cognitively impaired on at least three neuropsychological tests, and 25% of NBM participants also demonstrated this same level of cognitive impairment. In the BM group, the elevated rate of cognitive dysfunction is likely due to the greater neurologic disease burden posed by brain metastases, while in the NBM group, the cognitive deficits are possibly due to systemic illness and treatment effects.