tbuckley/cabot-search huggingface dataset:
Abstract P427: Inhibition Of PP2A By Insulin Impairs Beta-Adrenergic Receptor Function
Authors: Anita Sahu, Sromona D Mukherjee, Conner P Witherow, Kate Stenson, John Tesmer, Maradumane L Mohan, Sathyamangla V Naga Prasad
Journal: Circulation Research (2021)

Insulin impairs β2-adrenergic receptor (β2AR) function via trans-phosphorylation through G protein-coupled receptor kinase 2 (GRK2). However, less is known about dephosphorylation mechanisms mediated by protein phosphatase 2A (PP2A) during this insulin-β2AR cross-talk. Pharmacologic or genetic inhibition of phosphoinositide 3-kinase γ (PI3Kγ) unexpectedly resulted in significant reduction of insulin-mediated β2AR phosphorylation. Interestingly, β2AR-associated phosphatase activity was inhibited by insulin but was reversed by knock-down of PI3Kγ showing negative regulation of PP2A by PI3Kγ. Co-immunoprecipitation and surface plasmon resonance studies using purified proteins showed that GRK2 and PI3Kγ form a complex and could be recruited to β2ARs as GRK2 interacts with insulin receptor substrate (IRS) following insulin treatment. Further, co-immunoprecipitation studies showed that PI3Kγ directly interacted with both IRS-1 and IRS-2 but only IRS-2 interaction with PI3Kγ significantly increased following insulin stimulation. These results indicated that PI3Kγ could also be directly recruited to the receptor complex by IRS-2. Consistently, β-blocker pretreatment did not reduce insulin-mediated β2AR phosphorylation indicating agonist- and Gβγ-independent non-canonical regulation of receptor function. Mechanistically, PI3Kγ inhibits PP2A activity at the βAR complex by phosphorylating an intracellular inhibitor of PP2A (I2PP2A). Knock-down or CRISPR ablation of endogenous I2PP2A unlocked PP2A inhibition mediating β2AR dephosphorylation showing an unappreciated acute regulation of PP2A in mediating insulin-β2AR cross-talk.
Abstract 12364: Dysfunction of N-terminal Acetylation Causes Multiple Electrical Abnormalities Leading to Long QT Syndrome and Dilated Cardiomyopathy
Authors: Daisuke Yoshinaga, Rui Feng, Jasmine Feng, David Walker, Sofia de la Serna Buzon, Bridget Boss, Sheila Upton, Tarsha Ward, Jonathan Seidman, Vassilios J Bezzerides
Journal: Circulation (2021)

Introduction: NAA10-related syndrome, also known as Ogden syndrome, is characterized by long QT syndrome (LQTS), cardiomyopathy, hypotonia, and neurodevelopmental delay. NAA10 complexes with the regulatory subunit NAA15 to make the post-translationally modifying N-terminal acetyltransferase, NatA. Despite the association of LQTS and NAA10 mutations, the mechanism is unknown. Hypothesis: NAA10 dysfunction affects the function of cardiac ion channels or related proteins causing LQTS. Methods: Target sequencing of large kindred with multiple family members who had LQTS and sudden death revealed a segregating mutation in NAA10 (c.10C&gt;A; p.R4S). Somatic cell reprogramming was used to create an induced pluripotent stem cell (iPSC) line from a gene-positive male patient with LQTS and dilated cardiomyopathy, (pNAA10 R4S ). We also genome-edited the mutation into a control iPSC line (eNAA10 R4S ). The iPSC lines were differentiated into cardiomyocytes (iPSC-CMs) for electrophysiologic characterization. Results: Action potential duration (APD) of wild-type (WT) and mutant iPSC-CMs was evaluated using patch-clamp and dynamic-clamp electrophysiology. There was significant APD prolongation in NAA10 R4S -iPSC-CMs and eNAA10 R4S -iPSC-CMs as compared to WT iPSC-CMs (448.1 ± 102.2 ms and 392.3 ± 20.8 ms, vs 73.1 ± 12.1 ms; p&lt;0.05). We then investigated potential derangements in the underlying sodium (I Na ), potassium (I K ) and calcium (I CaL ) currents. Voltage-clamp measurements demonstrated increased peak I Na in mutant iPSC-CMs lines (pNAA10 R4S : -72.2 ± 11.1 pA/pF and eNAA10 R4S : -77.4 ± 15.3 pA/pF vs. WT: -44.4 ± 7.9 pA/pF, N&gt;12, p&lt;0.05) However, there were no changes in voltage-dependent activation or inactivation. Similarly peak I CaL was also increased (-10.2 ± 1.7 pA/pF, vs -7.0 ± 1.2 pA/pF (N= 5 and 3, respectively)) compared to control iPSC-CMs without any changes in Ca 2+ channel biophysics. There were no significant differences in measured I K . Conclusion: We demonstrate that the NAA10 mutation cause APD prolongation by increasing I Na and I CaL current densities leading to QT prolongation and arrhythmia. This data indicated a novel role for N-terminal acetylation in cardiac ion channel regulation leading to cardiovascular disorders.
NCMP-19. RADIATION-INDUCED CRANIAL NEUROPATHY PRESENTING AS PROGRESSIVE BULBAR SYNDROME
Authors: Carlos Eduardo Silva Correia, Xi Chen
Journal: Neuro-Oncology (2021)

Abstract Neuropathy is a well-known complication of radiation, especially when administered in proximity to the brachial plexus (BC), with symptoms usually appearing years after radiation. Pain is a less prominent feature when compared to neoplastic infiltration, with numbness and weakness being a more common and disabling complaint. Radiation-induced neuropathies tend to reach clinical stabilization after several months with por response to treatment. This is a case report of a 59 year-old Malaysian man who was diagnosed with nasopharyngeal carcinoma in 2002 treated with radiation to the nasopharynx in China. He has no evidence of disease to this date. In 2016 he started to develop progressive bulbar symptoms, such as hoarseness, hypophonia, and dysphagia. Symptoms worsened over the subsequent 18 months after presentation with clinical stabilization thereafter. Following the initial bulbar symptoms, he also developed bilateral hearing loss, atrophy of bilateral sternocleidomastoid muscles, significant tongue atrophy with fasciculations and tongue deviation. His clinical picture was consistent with bulbar amyotrophic lateral sclerosis. MRI brain and total spine did not show any intraparenchymal or nerve disease. An electromyography test was performed, which showed myokymia of the tongue and trapezius consistent with radiation-induced cranial neuropathy (CN). He received steroids without any clinical improvement, followed by hyperbaric oxygen with minimal improvement of his dysphagia, hoarseness and hypophonia. On last follow up his symptoms continued to be stable. Radiation to nasopharynx can cause radiation-induced CN with similar electromyographic findings to radiation-induced brachial plexopathy, such as myokymia. Symptoms can appear more than 10 years from radiotherapy, with progression over several months followed by clinical stabilization. Treatment with steroids, bevacizumab or hyperbaric oxygen only provide minimal benefit on this population.
Interim Results of a Phase II Study of Dasatinib and Prednisone As an Oral, Chemo-Free Induction and Consolidation Regimen for Adults with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Authors: Mixue Xie, Ying Lu, Guifang Ouyang, Liming Zhang, Huixian Hu, Ting Shi, Xueying Li, Xiujing Ye, Jie Jin, Hong-Hu Zhu
Journal: Blood (2021)
Evaluation of in vitro/in vivo correlations for three fentanyl transdermal delivery systems using in vitro skin permeation testing and human pharmacokinetic studies under the influence of transient heat application
Authors: Soo Hyeon Shin, Mingming Yu, Dana C. Hammell, Priyanka Ghosh, Sam G. Raney, Hazem E. Hassan, Audra L. Stinchcomb
Journal: Journal of Controlled Release (2021)
Abstract MP230: Nuclear Rupture In A Mouse Model Of <i>Lmna</i> -related Cardiomyopathy Causes Cytoplasmic Exposure Of The Proinflammatory Signaling Protein Hmgb1
Authors: Kohta Ikegami, Alexis Stutzman, Sachie Ikegami, Omar Almakki, Sunny Liu, Ozanna Burnicka-turek, Ivan Moskowitz
Journal: Circulation Research (2021)

Cardiomyopathies caused by mutations in LMNA, encoding nuclear Lamin A/C, are highly malignant and prevalent. How LMNA mutations cause cardiomyopathies remains unknown. We characterized cellular, molecular, and pathological evolution of mouse models of LMNA -related cardiomyopathy and provide evidence for a model in which nuclear rupture generates nuclear-localized proinflammatory signaling as a candidate molecular mechanism underlying disease pathogenesis. We observed that cardiomyocyte-specific, tamoxifen-inducible deletion of Lmna in adult mice ( Lmna CMKO ) caused a gradual reduction of Lamin A/C protein at the nuclear lamina, reflecting the slow turnover of Lamin A/C. A modest reduction of Lamin A/C in Lmna CMKO was sufficient to cause extensive fibrosis, reduced ejection fraction, and chamber dilation by 3 weeks after Lmna gene deletion. Lmna CMKO cardiomyocytes exhibited localized rupture of the nuclear envelope 2 weeks prior to the development of fibrosis and reduction of ejection fraction. Nuclear rupture in Lmna CMKO was immediately followed by an extensive upregulation of pro-inflammatory gene expression programs. We hypothesized that nuclear rupture might expose nuclear DNA to the cytoplasm thereby activating the pro-inflammatory cGas-STING cytosolic DNA sensing pathway. However, we did not observe localization of the cytosolic DNA sensor cGas to cytoplasmic DNA protruded from the ruptured nuclei in Lmna CMKO cardiomyocytes. Instead, we found that HMGB1, a potent proinflammatory protein normally sequestered in the nucleus, was released from the ruptured nuclei in Lmna CMKO cardiomyocytes. Mass spectrometry identified a strong interaction between Lamin A/C and HMGB1 in normal human fibroblast cells. Our data suggested that Lamin A/C tethers HMGB1 to the nuclear periphery by direct interaction and that reduction of Lamin A/C unleashes HMGB1 to the cytoplasm upon nuclear rupture. Future work will examine the hypothesis that cytoplasmic HMGB1 triggers pathogenic sterile inflammation leading to dilated cardiomyopathies in Lmna CMKO mice. In conclusion, we identified the nuclear rupture-induced cytoplasmic release of HMGB1 as a candidate mechanism underlying LMNA -related cardiomyopathies.
Abstract 12416: Modeling Diabetic Endothelial Cell Dysfunction With Induced Pluripotent Stem Cells
Authors: Beatrix Kovacs, Rayyan Gorashi, Bin Jiang
Journal: Circulation (2021)

Introduction: Diabetes is one of the major risk factors for cardiovascular diseases (CVDs), which is mediated by vascular endothelial dysfunction. Currently, there is no in vitro disease model of endothelial cell (EC) dysfunction in diabetic patients, which hinders mechanistic understanding and therapeutic discovery. The goal of this study is to develop a comprehensive model of diabetic EC dysfunction using patient-derived induced pluripotent stem cells (iPSCs) and recapitulating the diabetic microenvironment. Methods: Our model utilizes iPSC derived ECs from the following sources: healthy subjects and diabetic patients with underlying CVDs (n=3). To simulate in situ conditions of diabetes, we used the following treatment for 5 days: hyperglycemia (25 mM glucose); high urea (9 mM); and inflammatory stimulation with tumor necrosis factor alpha (TNF-α, 8 pg/ml). EC dysfunction was assessed through oxidative stress, inflammation, permeability, and thrombosis. Immunofluorescence identified localization for surface adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), endothelial selectin (E-sel), and platelet selectin (P-sel). Enzyme-linked immunosorbent assay (ELISA) quantitatively measured expression of these surface adhesion molecules. Results: Overall, the qualitative effect of the diabetic microenvironment resulted in increased expression of ICAM-1, E-sel, and P-sel. After TNF-α treatment, we observed a stronger increase in expression of P-sel in healthy subject-derived cells than diabetic patient-derived cells. This indicates a possible pre-conditioned tolerance of pro-inflammatory conditions. Ongoing experimentation will provide results for quantitative expression of ICAM-1, E-sel, and P-sel after treatment with the diabetic microenvironment. Conclusion: The development of a robust in vitro model of diabetic endothelial dysfunction, similar to the onset of type 2 diabetes, will allow for high-throughput testing of pharmacological agents to ultimately treat the disease’s effects within the vascular bed. The widespread implications of type 2 diabetes on the vascular bed further amplify the significance of this study in the development of pharmacological agents to treat the disease.
Abstract 10528: Exaggerated Inspiratory Muscle Metaboreflex in Heart Failure with Preserved Ejection Fraction
Authors: Joshua R Smith, Shane M Hammer, Eric J Bruhn, Barry A Borlaug, Thomas P Olson
Journal: Circulation (2021)

Introduction: Heart failure patients with preserved ejection fraction (HFpEF) may exhibit inspiratory muscle dysfunction potentially contributing to exercise intolerance. Activation of neural afferents in response to inspiratory muscle contraction (metaboreflex) elicits increases in mean arterial pressure (MAP) and leg vascular resistance (LVR) through enhanced sympathetic outflow leading to decreases in leg blood flow (LBF) in healthy humans. It is unknown if HFpEF patients exhibit exaggerated cardiovascular responses to inspiratory muscle metaboreflex activation. Hypothesis: We hypothesize that patients with HFpEF will exhibit a greater increase in MAP and LVR with a decrease in LBF during inspiratory muscle metaboreflex activation than controls. Methods: HFpEF patients (n=15, 10M/5W, 69±10 yrs; 33±4 kg/m2) and controls (n=14; 10M/4W; 70±8 yrs; 28±4 kg/m2) performed inspiratory resistive breathing tasks (IRBT) at 2% and 60% of their maximal inspiratory pressure. During the IRBTs, the breathing frequency was 20 breaths/min with a 50% duty cycle. At rest and during the IRBTs, MAP was measured by photoplethysmography, venous norepinephrine was measured, LBF was measured by near-infrared spectroscopy and indocyanine green dye injections, and LVR was calculated. Results: During the 2% IRBT, there were no differences between groups in the changes from rest in MAP (HFpEF: 2±4 vs. CTL: 3±4 mmHg) or LBF (HFpEF: 1±14 vs. CTL: 1±12%) (both, p&gt;0.05). During the 60% IRBT, venous norepinephrine increased from rest in HFpEF and controls (p&lt;0.05), while no differences existed between groups (p&gt;0.05). During the 60% IRBT, HFpEF patients, compared to controls, exhibited a greater increase from rest in MAP (HFpEF: 16±7 vs. CTL: 10±6 mmHg) and LVR (HFpEF: 76±45 vs. CTL: 32±19%) coupled with a greater decrease in LBF (HFpEF: -32±14 vs. CTL: -17±9%) (all, p&lt;0.05). Conclusions: These data indicate that patients with HFpEF exhibit exaggerated cardiovascular responses with inspiratory muscle metaboreflex activation compared to healthy individuals. These findings have important implications for the integrative physiology of exercise in HFpEF patients.
Arc-Shaped Furrow on the Forehead Extending From Linear Alopecia on the Vertex
Authors: Il-Jae Lee, Seok-Kweon Yun, Kyung-Hwa Nam
Journal: JAMA Dermatology (2021)

A man in his 50s presented with a depressed skin groove on his forehead and linear hair loss. Examination revealed 2 long curved alopecic patches on the left side of the vertex and frontal scalp area extending to the left eyebrow. What is your diagnosis?
Abstract 12550: Overexposed? Evaluating the Need for Serial Surveillance Imaging Following Elective Aortic Hemiarch Replacement
Authors: Cenea Kemp, Christian V Ghincea, Anna K Gergen, Zihan Feng, Leighton McCabe, Vishal Krishnan, Jessica Y Rove, Joseph Cleveland, David Fullerton, Jay Pal, Muhammad Aftab, T Brett Reece
Journal: Circulation (2021)

Introduction: The optimal timing for imaging following ascending aortic replacement is unknown. Protocols currently differ based on institution. For the last 3 years, our institution has surveilled patients at 3 months, yearly for 3 years, and at 5 years following the operation. Hypothesis: We hypothesize surveillance CT scans performed at 3 months will identify any pathologies related to the ascending aortic repair that will require re-intervention; additional imaging may be superfluous. Methods: Using our single institution-maintained database, 311 patients who underwent an elective aortic hemiarch repair between February of 2010 and March of 2021 were identified. The timing for and stability of surveillance imaging was reviewed, paying special attention to pathology associated with the repair. Results: Of the 311 patients who underwent elective aortic hemiarch repair, 217 completed surveillance imaging. 187 patients had their initial imaging around 3 months following the operation, 85 patients completed imaging around one year, and 54 patients were imaged 2-8 years post-operatively with some patients undergoing multiple scans during this period. Nine patients required re-intervention; of these 9, four patients demonstrated pathology, on CT scan, associated with the actual ascending arch repair. Two patients developed a pseudoaneurysm (PSA), one at the distal aspect of the repair and one at the left ventricular outflow tract. The other two patients had degeneration of known distal aortic aneurysms. The two PSAs were intervened upon within the first 3 months and the degenerating aneurysms were intervened upon at 1 and 2.5 years post-operatively. Conclusions: These data support surveillance imaging completed at 3 months following ascending aortic replacement is sufficient to identify pathology related to the repair. While other indications may dictate ongoing surveillance, for most patients, the need for further imaging is potentially zero.
PATH-38. APC MUTATION AS A DRIVER ONCOGENE IN NON-CTNNB1 MUTANT ADAMANTINOMATOUS CRANIOPHARYNGIOMAS
Authors: Christopher Hong, Zeynep Erson-Omay, S Bulent Omay
Journal: Neuro-Oncology (2021)

Abstract Craniopharyngiomas arise from the embryonic remnants of Rathke’s pouch in the craniopharyngeal duct. Their invasive capacity and geographic proximity to the optic apparatus, pituitary gland and stalk, third ventricle, and the hypothalamus can cause progressive visual, hormonal, and neurological deficits and transform these lesions into behaviorally malignant tumors. The classic subtypes of craniopharyngiomas, adamantinomatous and papillary, have conventionally been approached similarly in regards to therapeutic strategies. However, recent exome sequencing studies have revealed mutually exclusive pathways for their genetic origins. Recurrent mutations in BRAF (V600E), a regulator of MAP kinase/ERK signaling pathway have been observed in 95% of papillary craniopharyngiomas and may be amenable to targeted therapies with BRAF inhibitors. However, CTNNB1 mutations are observed in only 75%–96% of adamantinomatous craniopharyngiomas, revealing a gap in the classic genetic-histological correlation. We describe a 74-year-old male who underwent resection of a craniopharyngioma with suprasellar and third ventricular involvement. The pathology demonstrated adamantinomatous craniopharyngioma with aberrant nuclear beta-catenin activity on immunohistochemistry. Whole-exome sequencing, performed in accordance with an institutional review board-approved protocol on the tumor and blood, revealed wildtype CTNNB1 but notably two somatic stop-codon mutations in APC (rs786201856:c.C793T:p.R265X and rs587779780:c.1159T:p.R387X), considered pathogenic variants in other reported cancer types. Loss of APC leads to constitutive activation of the Wnt signaling pathway, similar to the observed downstream effects of activating CTNNB1 mutations in adamantinomatous craniopharyngioma. Our case suggests that craniopharyngiomas may arise from somatic loss of APC, which previously was only described in a handful of individuals with familial adenomatous polyposis, harboring germline APC mutations. This report adds new insight into the pathogenesis of adamantinomatous craniopharyngiomas, particularly those that are otherwise wildtype for CTNNB1. Based on accumulating evidence, we propose that along with BRAF and CTNNB1, APC should also be routinely checked in cranipharyngiomas, especially if the former two have been negative.
Abstract 11761: Association of Mitochondrial DNA Copy Number With Risk of Progression of Kidney Disease in the Chronic Renal Insufficiency Cohort (CRIC) Study
Authors: William J He, Tanika N Kelly, Changwei Li, Varun S Rao, Zhijie Huang, L L Hamm, Jiang He, Morgan Grams, Dan E Arking, Lawrence J Appel, Casey M Rebholz
Journal: Circulation (2021)

Introduction: Mitochondrial DNA copy number (mtDNA-CN) is a biomarker of mitochondrial function that has been associated with chronic kidney disease (CKD) and all-cause mortality in several community-based studies. However, there has been little research on mtDNA-CN and progression of CKD. Hypothesis: We hypothesized that higher mtDNA-CN will be associated with lower risk for CKD progression in a cohort of CKD patients. Methods: A total of 2,943 Chronic Renal Insufficiency Cohort (CRIC) study participants had mtDNA-CN calculated from probe intensities of mitochondrial single nucleotide polymorphisms (SNP) genotyped on the Illumina HumanOmni 1-Quad Array. To correct for batch effects, DNA quality, DNA quantity, and latent confounding factors, mtDNA-CN was regressed on 15 principal components generated from autosomal SNP probe intensity signals. mtDNA-CN residuals were then standardized to a mean of 0 and standard deviation of 1 and used in this analysis. CKD progression was defined as incident end-stage renal disease (ESRD) or halving of eGFR from baseline. Cox proportional hazards models were used to calculate hazard ratios for mtDNA-CN and risk of CKD progression. Results and Conclusions: Compared to patients in the lowest mtDNA-CN tertile, those in the middle tertile [HR=0.78, 95% CI: (0.68, 0.91)] and highest tertile [HR=0.78, 95% CI: (0.67, 0.91)] had a statistically significantly lower risk for CKD progression after adjustment for established risk factors (Table). Similar results were seen in race- and sex-stratified analyses (Table). These findings suggest that mtDNA-CN may have potential clinical utility in improving CKD risk classification. Furthermore, mitochondrial dysfunction has been hypothesized to contribute to renal disease through podocyte injury, tubular epithelial cell damage, and endothelial dysfunction. Future research on the mechanisms underlying mtDNA-CN and CKD progression may lead to novel strategies for CKD management.