tbuckley/cabot-search huggingface dataset:
Abstract 11673: What Predicts the Use of Cardiovascular Screeners in Primary Care Among Women Veterans With Depression?
Authors: B Bean-mayberry, Catherine Chanfreau, Kimberly Clair, Claire Than, Catherine Amanda Schweizer, Tannaz Moin, Erin Finley, Alison Hamilton, Melissa Farmer
Journal: Circulation (2021)

Introduction: One in three American women die of cardiovascular (CV) disease annually, and women Veterans suffer higher risk, especially those with mental health burden. To improve CV risk identification, we implemented a CV risk screener template in 5 VA primary care clinics. Objective: To examine factors associated with CV screening in a cohort of women with depression. Methods: The cohort included all women with at least one primary care visit during the study period (12/2016-03/2020) with a depression diagnosis. We used t-tests/chi-square to compare CV screener completion vs not, and modeled completion with logistic regression including demographics, CV risk conditions, utilization, and PTSD adjusting for site-level clustering. Results: Among 6009 women, 2090 (35%) had diagnosed depression in the past two years and 582 (28% with depression) had a completed screener. For women with depression, screener completion was more likely for women who were older (48 vs. 45 years), White (46% vs. 36%), obese (49% vs. 39%), diagnosed with hyperlipidemia (39% vs. 33%), hypertension (36% vs. 27%), or diabetes (16% vs. 12%), had more primary care visits (3 vs 1) and without PTSD (46% vs. 54%; p&lt;0.01 for each comparison). In the full logistic model, obese women had greater odds (OR 1.8, 95%CI 1.3-2.3), whereas women with PTSD had lower odds (OR 0.7, 95% CI 0.5-0.8) of screener completion. Conclusions: Women Veterans have a high prevalence of depression and other mental health conditions putting them at higher risk for CV disease. Our sample of women with depression had more traditional CV risks, yet, obesity and PTSD were the driving factors of the CV screening within primary care. Since PTSD is a significant predictor in ischemic heart disease in women Veterans, mechanisms to leverage CV screening and intervention in this population are paramount so that providers and patients do not miss opportunities for risk reduction.
ITVT-04. Management of intraoperative technological advances [intraoperative MRI, neuronavigation system using PET, and 5-aminolevulinic acid (5-ALA)–induced fluorescence image-guided surgery] for glioblastoma
Authors: Keisuke Miyake, Daisuke Ogawa, Tetsuhiro Hatakeyama
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE The maximum resection of Glioblastoma (GBM) is the standard therapy and is expected to improve prognosis. Image-guided surgery using a neuronavigation system is the standard technique for glioma. However, due to the brain shift during surgery, intraoperative technologies, such as 5-ALA fluorescence and intraoperative MRI (IoMRI), are employed. Radiotracers are used during positron emission tomography (PET) for metabolic imaging and assist the evaluation of glioma metabolism. We compared the effectiveness of these intraoperative technologies. METHODS Between January 2016 and May 2021, 52 patients with gliomas underwent IoMRI. 21 patients were selected for 5-ALA fluorescence-guided resection of GBM and underwent multiple PET studies (MET, FLT, and FMISO). We graded fluorescence level as strong, vague, or none. Following tumor resection, we identified the fluorescence level and evaluated the residual volume of gadolinium-enhanced T1WI (T1-Gd) on IoMRI and at each PET study. After calculating the extent of resection (EOR) for T1-Gd, we compared the residual volume on T1-Gd for IoMRI and each PET study, between EOR ≥ 93% and EOR &amp;lt; 93%. RESULTS We detected strong 5-ALA fluorescence during induction and before tumor resection in all 21 (100%) patients with a newly-diagnosed and histopathologically-confirmed GBM. Following tumor resection, we noted an EOR ≥ 93% for T1-Gd in 12 cases (vague, 4; none, 8) and an EOR &amp;lt; 93% for T1-Gd in 9 cases (vague, 5; none, 4). The compared median residual volume (mL) with no fluorescence between EOR ≥ 93% and EOR &amp;lt; 93% for T1-Gd were T1-Gd (0.22, 0.74), MET (0.29, 3.31), FLT (0.24, 1.77), and FMISO (0.22, 1.02). CONCLUSIONS GBM cells are difficult to distinguish in cases without 5-ALA fluorescence. For cases without 5-ALA fluorescence, we were able to maximize the resection of GBM by extracting the area of MET accumulation.
Abstract 10763: Atrial Fibrillation and Supraventricular Ectopy in Relation to Brain Morphology and Subclinical Vascular Brain Injury: The Multi-Ethnic Study of Atherosclerosis
Authors: Thomas R Austin, Paul Jensen, Ilya Nasrallah, Mohamad Habes, Tanweer Rashid, Lin Yee Y Chen, Philip Greenland, Timothy M Hughes, Wendy Post, Steven Shea, Karol E Watson, Colleen Sitlani, James S Floyd, Richard Kronmal, W T Longstreth, Nick Bryan, Susan Heckbert
Journal: Circulation (2021)

Introduction: Atrial fibrillation (AF) increases stroke risk and is associated with accelerated cognitive decline. Information is mixed about the relationship of AF and other supraventricular (SV) arrhythmias with brain changes on magnetic resonance imaging (MRI). Hypothesis: Prevalent AF and SV ectopy are associated with reduced gray matter (GM) volume and subclinical vascular brain injury. Methods: In the Multi-Ethnic Study of Atherosclerosis (MESA), participants completed Zio Patch monitoring and brain MRI. Prevalent AF was estimated from ambulatory monitoring, hospital surveillance, Medicare claims, and MESA electrocardiogram (ECG). For secondary analyses, AF was categorized into continuous - AF during 100% of monitoring - and intermittent - prevalent AF with &lt;100% AF during monitoring. Brain MRI measures included GM volume, white matter (WM) lesion volume, WM fractional anisotropy, and presence of cerebral microbleeds (CMBs). Linear and Poisson regression analyses were adjusted for cardiovascular risk factors and socioeconomic status. Results: In MESA, 967 participants without a history of stroke or transient ischemic attack (TIA) completed &gt;24 hours of ECG monitoring (median, 14.0 days) and completed brain MRI a median 17 months later. Mean (standard deviation) age was 72 (8) years; 53% were women. A total of 116 participants had prevalent AF, of whom 20 had continuous AF. Compared with no AF, prevalent AF was associated with lower WM FA (-0.22 standard deviations, 95% CI: -0.39, -0.04) and higher prevalence of CMBs (prevalence ratio: 1.46, 95% CI: 1.18, 1.80). In secondary analyses, compared with no AF, continuous but not intermittent AF was associated with lower GM volume (-18.6 mL, 95% CI: -31.4, -5.8). Rates of premature atrial contractions and runs of SV tachycardia were not significantly associated with brain MRI measures. Conclusions: In a multi-ethnic sample free of a history of stroke or TIA, prevalent AF was associated with lower WM FA, a measure of WM injury, and presence of CMBs. These results highlight the importance of AF prevention for brain health. Further analysis of subclinical infarcts is needed in this sample, and study in other settings is needed to confirm whether greater AF burden is associated with reduced GM volume.
EXTH-27. MOLECULAR CHARACTERIZATION AND PRECLINICAL DEVELOPMENT OF NOVEL SMALL MOLECULE INHIBITOR SPECIFIC FOR WILD-TYPE IDH1 FOR FERROPTOSIS INDUCTION IN GLIOBLASTOMA
Authors: Kevin Murnan, Serena Tommasini-Ghelfi, Lisa Hurley, Corey Dussold, Daniel Wahl, Alexander Stegh
Journal: Neuro-Oncology (2021)

Abstract Increased de novo synthesis, mobilization and uptake of fatty acids are required to provide sufficient lipids for membrane biogenesis in support of rapid tumor cell division and growth. In addition to their structural roles as components of the plasma membrane, fatty acid-derived lipids regulate ferroptotic cell death, a type of programmed cell death, when oxidized by iron-dependent lipoxygenase enzymes. De novo lipogenesis and the defense against oxidative lipid damage require large amounts of cytosolic NADPH. Our group has recently found that HGG up-regulate wild-type Isocitrate dehydrogenase 1 (referred to hereafter as ‘wt-IDH1high HGG’) to generate large quantities of cytosolic NADPH. RNAi-mediated knockdown of wt-IDH1, alone and in combination with radiation therapy (RT), slows the growth of patient-derived HGG xenografts, while overexpression of wt-IDH1 promotes intracranial HGG growth. Isotope tracer and liquid chromatography-based lipidomic studies indicated that wt-IDH1 supports the de novo biosynthesis of mono-unsaturated fatty acids (MUFAs) and promotes the incorporation of monounsaturated phospholipids into the plasma membrane, while displacing polyunsaturated fatty acid (PUFA) phospholipids. In addition, enhanced NADPH production in wt-IDH1high HGG increases glutathione (GSH) level, reduces reactive oxygen species (ROS), activates the phospholipid peroxidase glutathione peroxidase 4 (GPX4)-driven lipid repair pathway, and dampens the accumulation of PUFA-containing lipid peroxides, known executioners of ferroptosis. To pharmacologically target wt-IDH1,we have used and characterized wt-IDH1i-13, a first-in-class competitive α,β-unsaturated enone (AbbVie). wt-IDH1i-13 potently inhibits wt-IDH1 enzymatic activity, by covalently binding to the NADP+ binding pocket. Our data indicate that wt-IDH1i-13 promotes ferroptosis, which can be rescued by pre-treatment of cells with the peroxyl scavenger and ferroptosis inhibitor ferrostatin. wt-IDH1i-13 is brain-penetrant, and similar to genetic ablation, reduces progression and extends the survival of wt-IDH1high HGG bearing mice, alone and in combination with RT. These studies credential to wt-IDH1i-13 as a novel therapeutic modality for the treatment of wt-IDH1 gliomas.
The potential of gene therapy for recessive dystrophic epidermolysis bullosa*
Authors: K.S. Subramaniam, M.N. Antoniou, J.A. McGrath, S.M. Lwin
Journal: British Journal of Dermatology (2021)

Epidermolysis bullosa (EB) encompasses a heterogeneous group of inherited skin fragility disorders, with mutations in genes encoding the basement membrane zone (BMZ) proteins that normally ensure dermal-epidermal integrity. Of the four main EB types, recessive dystrophic EB (RDEB), especially the severe variant, represents one of the most debilitating clinical entities, with recurrent mucocutaneous blistering and ulceration leading to chronic wounds, infections, inflammation, scarring and ultimately cutaneous squamous cell carcinoma, which leads to premature death. Improved understanding of the molecular genetics of EB over the past three decades and advances in biotechnology have led to rapid progress in developing gene and cell-based regenerative therapies for EB. In particular, RDEB is at the vanguard of advances in human clinical trials of advanced therapeutics. Furthermore, the past decade has witnessed the emergence of a real collective, global effort involving academia and industry, supported by international EB patient organizations such as the Dystrophic Epidermolysis Bullosa Research Association (DEBRA), among others, to develop clinically relevant and marketable targeted therapeutics for EB. Thus, there is an increasing need for the practising dermatologist to become familiar with the concept of gene therapy, fundamental differences between various approaches, and their human applications. This review explains the principles of different approaches of gene therapy, summarizes its journey, and discusses its current and future impact in RDEB.
Abstract 13320: APOO Knockout Elevates Plasma Cholesterol Levels Independent of LDLR and Accelerates Atherosclerosis in Mice
Authors: Jin Chen, Xin Guo, Jiarui Hu, yang yang, Donglu Qin, Xiaoyu Tang, Jie Kuang, Daoquan Peng, Bilian Yu
Journal: Circulation (2021)

Introduction: Apolipoprotein O (APOO), also known as MIC26, was first discovered through a functional genomics study aimed at identifying genes differentially regulated in the heart by obesity. While its physiologic role is incompletely understood, recent studies implicate a critical intracellular role for APOO in regulating lipid metabolism. The overall objective of the present study was to determine whether genetic deletion of APOO in mice would affect cholesterol metabolism and accelerate atherosclerosis. Methods and Results: Hepatic Apoo expression was induced in response to hyperlipidemia but was inhibited after simvastatin treatment. Using a novel APOO global knockout ( Apoo -/- ) model and liver-specific APOO knockout ( Alb Cre Apoo fl/f l ) model, we report here that APOO deletion elevates hepatic and plasma cholesterol levels. Then, we bred Apoo -/- mouse onto both the Ldlr and Apoe KO hyperlipidemic mouse models. Female Apoo -/- Apoe -/- mice and Apoo -/- Ldlr -/- mice in both sexes displayed markedly elevated plasma cholesterol levels and more severe atherosclerotic lesions as compared to their littermate controls, implying the effect of APOO on cholesterol metabolism independent of LDLR and APOE. We demonstrate that APOO reduces cholesterol excretion through bile and feces. In addition, APOO deficiency led to hepatic triglycerides accumulation and decreased phospholipid unsaturation by inhibiting the expression of CYB5R3, which is responsible for hepatic fatty acid desaturation and elongation. Conclusions: These data represent the first in vivo experimental validation of the association of APOO with plasma cholesterol metabolism independent of LDLR. These results demonstrate that APOO deficiency led to the decreased CRB5R3 expression and fatty acid unsaturation, which responsible for the decrease of cholesterol excretion and elevated plasma cholesterol levels.
Abstract 12342: Depression and Anxiety Disorders in Peripheral Artery Disease Admissions: Associations With Post-Revascularization Amputation and Resource Utilization
Authors: Kristie M Harris, Carlos Mena-hurtado, Matthew M Burg, Kim G Smolderen
Journal: Circulation (2021)

Introduction: It is unknown whether depression or anxiety disorders may complicate the clinical pathway during a peripheral artery disease (PAD) admission, especially in the context of a revascularization. We therefore examined their co-occurrence in PAD admissions over time and association with amputation, length of stay (LOS), and costs among those undergoing a revascularization. Methods: In the 2011-2017 National Inpatient Sample, annual ICD-defined depression and anxiety disorder rates were calculated in primary PAD admissions, and trends evaluated with the Cochran-Mantel-Haenszel test. Excluding CLI ICD codes, PAD admissions with endovascular and surgical revascularizations were identified. In those, hierarchical multivariable logistic regression models examined the association of depression and anxiety with major amputation. Median LOS and cost by depression or anxiety were compared with the Wilcoxon rank sum test. Results: From 2011-2017, there were 1,415,888 PAD admissions (mean age=67 years; 41% female). Depression increased from 12 to 14% and anxiety from 6 to 13% (P trend &lt;.0001) over time. In admissions with endovascular revascularization (n=293,209), depression and anxiety were associated with higher odds of amputation, longer LOS (3.2 vs. 2.3; 3.3 vs. 2.3 days), and higher cost ($75,046 vs. $70,385; $77,369 vs. $70,194; all p &lt;.0001). In surgical revascularizations (n=298,810), depression was associated with higher odds of amputation (Fig. 1), and depression and anxiety were associated with longer LOS (both 3.7 vs. 3.2 days) and higher cost ($58,976 vs. $56,566; $59,925 vs. $56,513; all p &lt;.0001). Conclusions: Depression and anxiety codes as part of a PAD admission increased over time, with depression rates twice that of community dwelling adults. Concomitant depression and anxiety disorders are associated with adverse outcomes following revascularization, including major amputation, longer hospitalization, and increased costs.
Opioids: US court finds major pharmacy chains guilty of contributing to crisis
Authors: Janice Hopkins Tanne
Journal: BMJ (2021)

Three of the US’s largest pharmacy chains have been found guilty of contributing to the nation’s opioid crisis by allowing millions of prescription opioid pills to enter the black market, leading to thousands of deaths from overdoses.

CVS, Walmart, and Walgreens were judged responsible for playing a part in the opioid crisis. All three are huge enterprises. CVS is the largest pharmacy chain in the US, with nearly 10 000 stores. Walgreens is a close second with 9277 pharmacies, and Walmart has about 4700 stores.

The decision on 23 November came in a jury trial in the US District Court for the Northern District of Ohio in Cleveland. It was the first court decision against pharmacies and may set a precedent …
IMMU-42. OPTIMIZING IMMUNOTHERAPY FOR GLIOMA USING CYTOKINE-ACTIVATED NATURAL KILLER CELLS
Authors: Amber Kerstetter-Fogle, Folashade Otegbeye, David Soler, Peggy Harris, Alankrita Raghavan, Andrew Sloan
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most common primary central nervous system malignancy associated with a 12-15 month survival after surgery and radio-chemotherapy. Utilizing adoptive cellular immunotherapy using natural killer (NK) cells has developed over the past two decades for a variety of hematologic malignancies. This approach in solid malignancies is limited by questions of cell dose versus tumor burden, insufficient tumor infiltration, and a tumor microenvironment that suppresses NK cell function. METHODS We isolated NK cells from healthy volunteers and activated them using IL-2, -15, -12, -18, then perform cytotoxic assays in the presence of glioma stem cells. We also tested the efficacy of the NK cells with intracranial delivery in a pre-clinical murine model of glioma. We tested various concentrations of IL-2 and IL-15 on the cytokine culture platform. RESULTS In this study, we demonstrate human NK cells, activated using a cytokine cocktail of interleukins-2, -15, -12, and -18, exert strong cytotoxic events against glioma cell lines. To further examine the efficacy of activated NK cells in vitro, we utilized intracranially xenografted glioma lines and demonstrated a survival benefit with tumor bed injections of these cytokine-activated NK cells (p=0.0089). We were able to confirm that NK cells cultured with low doses (200u IL2; 50ng/ml IL15) of both cytokines are just as effective as higher doses. This is important, as in vivoexhaustion of NK cells stimulated with high doses of either cytokine has been well validated. We also found that low-dose irradiation (4Gy) of glioma cells prior to co-culture with cytokine-activated NK cells promoted increased targeted glioma cell killing within 4 hours(32% cell killing). CONCLUSIONS These findings suggest that in a clinical study, injection of cytokine-activated NK cells into the glioblastoma tumor bed could be used as adjuvant treatment following either stereotactic radiation or surgical resection.
Abstract 10172: Mitochondrial Connexin43 Can be Involved in the Occurrence of Arrhythmias
Authors: Wakako Satoh, Kazunori Kumasaka, Chiyohiko Shindoh, Haruka Sato, Masahito Miura
Journal: Circulation (2021)

Background: Connexin43 (Cx43) forms gap junctions in cardiac ventricles and exits as hemichannels in the inner mitochondrial membrane (mCx43). Objective: To examine whether mCx43 is involved in the occurrence of arrhythmias with modulation of mitochondrial K ATP channels (mK ATP ). Methods: To generate cardiac-specific Cx43-deficient ( Cx43 -/- ) mice, Cx43 flox/flox mice were crossed with α-myosin heavy chain -cre +/- mice. The resulting offspring, Cx43 -/- -mice and their littermates ( Cx43 +/+ -mice) were used. Trabeculae were obtained from right ventricles. Force was measured with a strain gauge, Ca 2+ within the mitochondria (Ca m ) with rhod-2, intracellular Ca 2+ (Ca i ) with microinjected fura-2 (22°C). The minimal extracellular Ca 2+ concentration (Cao min ), at which arrhythmias were induced by electrical stimulation, was determined. Using isolated single ventricular myocytes, mitochondrial membrane potential (ΔΨ m ) was estimated with tetramethylrhodamine methylester (TMRM), ROS production with 2’,7’-dichlorofluorescein (DCF), and Ca 2+ spark frequency with fluo-4 and confocal microscopy. Results: Cx43 -/- -mice showed sudden death within 8 weeks (p&lt;0.01). Cx43 was present in the inner mitochondrial membrane in Cx43 +/+ -mice but not in Cx43 -/- -mice. Developed force and Ca i transients by 0.5 Hz electrical stimulation showed no difference between Cx43 -/- - and Cx43 +/+ -mice (n=7). The Cao min in Cx43 -/- -mice was lower than that in Cx43 +/+ -mice (n=5, p&lt;0.01) and was increased by diazoxide (DZX, n=4, p&lt;0.05), suggesting that arrhythmia susceptibility is increased in Cx43 -/- -mice and is suppressed by DZX. Ca 2+ spark frequency and DCF oxidation rate in Cx43 -/- -mice were higher (p&lt;0.01) and were decreased by DZX (p&lt;0.01). TMRM fluorescence was decreased in Cx43 -/- -mice, and it was increased by DZX (p&lt;0.01) and was decreased by 5-hydroxydecanoic acid (p&lt;0.01). Rhod-2 signal was increased at 4 - 6 mM extracellular Ca 2+ in Cx43 -/- -mice but not in Cx43 +/+ -mice. Conclusions: Cx43 deficiency depolarizes ΔΨ m and increases Ca m at higher Ca o , ROS production, Ca 2+ spark frequency, and arrhythmia susceptibility. These changes in Cx43 -/- -mice are suppressed by DZX. Thus, mCx43 can be involved in the occurrence of arrhythmias with modulation of mK ATP .
Abstract 12007: RNA Sequencing Analysis Reveals A Novel Pathway Associated With The Exacerbation Of Covid-19
Authors: Mami Ikemachi, Kazuya Miyagawa
Journal: Circulation (2021)

Introduction: The severity of Coronavirus disease 2019 (COVID-19) depends on the host immune cell response and dysregulation. Most COVID-19 patients had mild disease, however, 15-30 % of patients developed severe disease which could result in severe acute respiratory failure and death. Risk factors associated with severe disease such as age, smoking and comorbidities are well known, while molecular signatures to predict the disease progression are still emerging. Hypothesis: Severe COVID-19 have a unique gene expression profile in peripheral blood mononuclear cells (PBMCs) at early stage of disease compared to mild disease. Methods: We used RNA sequencing analysis and pathway analysis in PBMCs collected from COVID-19 patients at a median 4 days after the onset. Subsequent clinical course was evaluated by WHO definition (meet any of oxygen saturation &lt; 90 %, respiratory rate &gt; 30 breaths / min and signs of severe respiratory distress or not), and based on the severity, PBMCs obtained from mild (n=6) and severe (n=6) groups were analyzed. Results: At the sample collection, there was no significant difference in clinical characteristics between groups, but laboratory tests exhibited higher C-reactive protein and lactate dehydrogenase levels in severe group compared to mild group (Table). We identified 148 differentially expressed genes (DEGs, FDR &lt; 0.05) that are enriched for a pathway, HDACs deacetylate histone, as the top pathway using Metascape. This includes 15 genes in HIST1 cluster that has not only antimicrobial but also cytotoxic and blood coagulation effect once the proteins are released into circulation, which could result in acute lung injury. Conclusions: Our results suggest that the upregulation of HIST1 cluster genes expression in PBMCs at early stage of COVID-19 could predict the subsequent disease exacerbation. These findings may also link to the pathophysiology of COVID-19 in the context of histone protein mediated lung injury and respiratory failure.