tbuckley/cabot-search huggingface dataset:
Accumulation of M1G adduct in nucleotide excision repair deficient mice after carbon tetrachloride, but not trichloroethylene exposure
Authors: Yo-Chan Jeong, James A. Swenberg
Journal: Cancer Research (2005)

3053  The objective of this research is to test the role of nucleotide excision repair (NER) in the genotoxicity of pyrimido[1,2-a]purin-10(3H)-one (M1G) in animal. M1G is a secondary DNA damage product arising from primary ROS damage to membrane lipids or deoxyribose. In addition to exogenous or endogenous ROS inducing chemical exposures, individual differences in DNA repair of DNA adducts may contribute to elevated levels of adducts in genomic DNA. To investigate the effect of NER deficiency on the background level of M1G, DNA was isolated from liver, brain and kidney tissues collected from age- and gender-matched wild type or XPA null C57BL mice. The XPA null mice, a model for the human disease xeroderma pigmentosum, were obtained from Dr. Harry van Steeg, National Institute of Public Health and the Environment (Bilthoven, The Netherlands). M1G was analyzed by LC-MS/MS after selective labeling of the adduct with pentafluorobenzyl hydroxylamine. The levels of M1G in liver and brain showed no significant difference between wild type and XPA null mice. Surprisingly, kidneys of XPA null mice showed significantly lower numbers of M1G compared to that of wild type mice, suggesting that the molecular pathways involved in M1G repair may be different in different tissues. The effect of NER deficiency on the accumulation of M1G was further investigated by the treatment of mice with a single oral dose of either carbon tetrachloride (CCl4) or trichloroethylene (TCE) administered at 1600 mg/kg body weight, which is about 1/3 of the LD50. While both chemicals, one day after treatment, resulted in significant liver toxicity, those chemicals had no significant effect on the number of M1G adducts in liver, brain, and kidney of wild type mice. However, CCl4 treatment of XPA null mice resulted in significantly higher (p
Abstract 14882: Outcomes of Heart Failure in Hypoplastic Left Heart Syndrome and the Impact of Recovery
Authors: Aine Lynch, Aamir Jeewa, Sunghoon Minn, Katelyn Arathoon, Jenna Ashkanase, Osami Honjo, Alejandro Floh, Emilie M Jean-st-michel
Journal: Circulation (2020)

Introduction: Survival for children with hypoplastic left heart syndrome (HLHS) and right ventricular (RV) dysfunction (dysfxn) remain poor. We describe outcomes of HLHS patients with RV dysfxn and the long-term impact of interval normalization. Methods: The SickKids Heart Failure (HF) Database is a retrospective cohort of HF patients from 2001 to 2017. We included patients with HLHS and at least mild RV dysfxn on echocardiogram lasting &gt;30 days, or death or transplant within 30 days of onset of dysfxn. We defined normalization as normal RV function (fxn) lasting &gt; 30 days after dysfxn onset. The primary endpoint was death or transplant. Descriptive statistics and time to event analysis were used. Results: We identified 99 patients with a median (IQR) age at onset of dysfxn of 2.6 (1 - 5.3) months. Of these, 51 (52%) had normalization of RV fxn for a median (IQR) duration of 3.5 (0.8 - 9.1) years and 28 (55%) had multiple periods of normal fxn. Of those who normalized, 4 (8%) normalized within a few months post Glenn procedure and 6 (13%) had normal fxn at last follow up. Patients with and without normalization had similar frequency of severe dysfxn (41 vs 52%, p=0.6). Normalization of RV fxn correlated with improved transplant free survival (78 % vs. 14 %, p&lt;0.001, Figure 1C) independent of surgical stage (p=0.03, figure 1D). Table 1 shows risk factors independently associated with transplant-free survival, including angiotensin converting enzyme inhibition. Conclusions: HLHS patients with RV dysfxn have poor transplant-free survival, especially those at interstage, but outcomes improve in those with persistent normalization of fxn. Factors predicting normalization need further study
Regulation of CEACAM5 and Therapeutic Efficacy of an Anti-CEACAM5–SN38 Antibody–drug Conjugate in Neuroendocrine Prostate Cancer
Authors: Diana C. DeLucia, Thomas M. Cardillo, Lisa Ang, Mark P. Labrecque, Ailin Zhang, James E. Hopkins, Navonil De Sarkar, Ilsa Coleman, Rui M. Gil da Costa, Eva Corey, Lawrence D. True, Michael C. Haffner, Michael T. Schweizer, Colm Morrissey, Peter S. Nelson, John K. Lee
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Neuroendocrine prostate cancer (NEPC) is an aggressive form of castration-resistant prostate cancer (CRPC) for which effective therapies are lacking. We previously identified carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a promising NEPC cell surface antigen. Here we investigated the scope of CEACAM5 expression in end-stage prostate cancer, the basis for CEACAM5 enrichment in NEPC, and the therapeutic potential of the CEACAM5 antibody–drug conjugate labetuzumab govitecan in prostate cancer. Experimental Design: The expression of CEACAM5 and other clinically relevant antigens was characterized by multiplex immunofluorescence of a tissue microarray comprising metastatic tumors from 34 lethal metastatic CRPC (mCRPC) cases. A genetically defined neuroendocrine transdifferentiation assay of prostate cancer was developed to evaluate mechanisms of CEACAM5 regulation in NEPC. The specificity and efficacy of labetuzumab govitecan was determined in CEACAM5+ prostate cancer cell lines and patient-derived xenografts models. Results: CEACAM5 expression was enriched in NEPC compared with other mCRPC subtypes and minimally overlapped with prostate-specific membrane antigen, prostate stem cell antigen, and trophoblast cell surface antigen 2 expression. We focused on a correlation between the expression of the pioneer transcription factor ASCL1 and CEACAM5 to determine that ASCL1 can drive neuroendocrine reprogramming of prostate cancer which is associated with increased chromatin accessibility of the CEACAM5 core promoter and CEACAM5 expression. Labetuzumab govitecan induced DNA damage in CEACAM5+ prostate cancer cell lines and marked antitumor responses in CEACAM5+ CRPC xenograft models including chemotherapy-resistant NEPC. Conclusions: Our findings provide insights into the scope and regulation of CEACAM5 expression in prostate cancer and strong support for clinical studies of labetuzumab govitecan for NEPC.
Abstract 13806: Catheter Ablation Improves Quasar-Arterial Spin Labeling Based Regional Brain Perfusion in the Posterior Cingulate Cortex and Auditory-verbal Memory Function in Elderly Patients With Atrial Fibrillation
Authors: Yasuko Tatewaki, Tatsushi Mutoh, Hirokazu Sato, Ryo Enoki, Akiko Kobayashi, Michiho Muranaka, Shuzo Yamamoto, Tetsuo Yagi, Yasuyuki Taki
Journal: Circulation (2020)

Introduction: Recent epidemiological studies suggest that atrial fibrillation (AF) is a risk factor for cognitive decline and dementia in elderly population, which may be attributable to reduced stroke volume and related brain hypoperfusion as a potential cause. Catheter ablation therapy is an option for radical cure of AF. Although several researchers mentioned the possibility to improve cognition after the intervention, specific topographic features of the brain perfusion have not been well investigated. Hypothesis: To visualize hemodynamic alteration in regional cerebra blood flow (rCBF) associated with catheter ablation therapy using noninvasive MRI voxel-based analysis method and to clarify the relationship between AF and cognitive decline. Methods: Eight patients with persistent AF (2 male, average age 63.4±7.3) underwent noninvasive brain MRI perfusion imaging with a novel dynamic model-free arterial spin-labeling (ASL) technique (quantitative STAR labeling of arterial regions [QUASAR]) and cognitive tests including Mini-Mental State Exam (MMSE) and Ray Auditory Verbal Learning Test (RAVLT) before and after 6-months of intervention. QUASAR-ASL images were spatially normalized with SPM 12 applied by partial volume correction, followed by comparison of rCBF of each brain areas with voxel-based paired-t test. Results: After the ablation therapy, QUASAR-ASL showed significantly increased rCBF in the left posterior cingulate gyrus (PCC) (FWE, P &lt; 0.05, MNI coordinates = -9 -45 5, Figure), which was accompanied by improved scores of the RAVLT ( P &lt; 0.001). Conclusions: The PCC is a critical part of the limbic system initially affected focal energy metabolism by Alzheimer’s disease. Improved rCBF in left PCC in patients with AF after catheter ablation therapy, as demonstrated by QUASAR-ASL method, may prevent episodic memory decline related to the auditory-verbal cognitive function.
Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches
Authors: Torsten Schöneberg, Ines Liebscher
Journal: Pharmacological Reviews (2020)

There are approximately 800 annotated G protein-coupled receptor (GPCR) genes, making these membrane receptors members of the most abundant gene family in the human genome. Besides being involved in manifold physiologic functions and serving as important pharmacotherapeutic targets, mutations in 55 GPCR genes cause about 66 inherited monogenic diseases in humans. Alterations of nine GPCR genes are causatively involved in inherited digenic diseases. In addition to classic gain- and loss-of-function variants, other aspects, such as biased signaling, trans-signaling, ectopic expression, allele variants of GPCRs, pseudogenes, gene fusion, and gene dosage, contribute to the repertoire of GPCR dysfunctions. However, the spectrum of alterations and GPCR involvement is probably much larger because an additional 91 GPCR genes contain homozygous or hemizygous loss-of-function mutations in human individuals with currently unidentified phenotypes. This review highlights the complexity of genomic alteration of GPCR genes as well as their functional consequences and discusses derived therapeutic approaches. SIGNIFICANCE STATEMENT: With the advent of new transgenic and sequencing technologies, the number of monogenic diseases related to G protein-coupled receptor (GPCR) mutants has significantly increased, and our understanding of the functional impact of certain kinds of mutations has substantially improved. Besides the classical gain- and loss-of-function alterations, additional aspects, such as biased signaling, trans-signaling, ectopic expression, allele variants of GPCRs, uniparental disomy, pseudogenes, gene fusion, and gene dosage, need to be elaborated in light of GPCR dysfunctions and possible therapeutic strategies.
Electroconvulsive Therapy in Mania: A Review of 80 Years of Clinical Experience
Authors: Alby Elias, Naveen Thomas, Harold A. Sackeim
Journal: American Journal of Psychiatry (2020)

Resistance to pharmacological agents is commonly encountered in the treatment of acute episodes of mania. In contemporary practice guidelines, electroconvulsive therapy (ECT), once a widely used standalone intervention for mania, is no longer considered a first-line treatment. Stigma, logistics, and ethical factors constrain ECT administration in this condition and lead to its underutilization. However, the past three decades have produced promising research regarding the use of ECT in mania. Randomized controlled trials, albeit in limited numbers, the adoption of ultrabrief ECT, examination of the safety and efficacy of combining ECT with pharmacological agents, including lithium, and use of ECT as a maintenance strategy have enhanced our understanding of how and when to utilize this intervention in mania. In this comprehensive review, the authors summarize the evidence regarding the efficacy and safety of ECT in mania, including related syndromes, such as delirious mania and mixed affective states. The impact of technical parameters, particularly the choice of treatment frequency, electrode placements, and pulse width, are discussed in the light of recent evidence.
Abstract 12650: A Faster and Safe Way for Dose Escalation of Sotalol Therapy in Patients With Atrial Fibrillation or Flutter
Authors: John C Somberg, Alexander A Vinks, Min Dong, janos molnar
Journal: Circulation (2020)

Sotalol is frequently employed to prevent the recurrence of highly symptomatic atrial fibrillation or flutter, but recurrence is not unusual and may require dose escalation. Sotalol can cause QTc prolongation proportional to blood concentration and at times may cause Torsade de Pointes ventricular tachycardia (TdP). Because the risk of TdP, dose escalation of oral sotalol therapy is mandated by FDA to be in-hospital for a minimum of 3 days under ECG monitoring with facilities and personnel able to provide cardiac resuscitation. With oral administration (bid), 3 days are needed to reach the new maximal steady-state blood concentrations (Cmax ss) and thus maximal QTc . Three hospital days in a telemetry bed is costly of time and resources. IV sotalol makes it possible to reduce the escalation time from 3 days to 1 day. The IV to oral dose escalation has been developed by model informed drug development. Serum sotalol concentrations and corresponding QTc were obtained from a bioequivalence study in healthy volunteers who received a single dose of oral and IV sotalol. NONMEM software package was used for population pharmacokinetic modeling and simulation. First Order Conditional Estimation method with Interaction (FOCE-INTER) was used for computation. We chose to administer IV sotalol over 1 hour to obtain the new Cmax ss target in a timeframe convenient for medical staff to supervise. Simulation for dose escalation from 80 to 120 mg bid is shown in the Figure; 75 mg IV sotalol is administered over 1 hour followed by 120 mg oral sotalol at 5 hours from start of infusion, then a second oral dose of 120 mg at 12 hours. One can target escalation from 120 to 160 mg by loading 90 mg IV over 1 hr followed by 160 mg oral dosing. Sotalol concentration will peak in 2-4 hours following each oral administration, thus in 21 hour there will be 3 sotalol peak concentrations. This permits evaluation of QTc response and risk of TdP all within a 1 day admission.
Abstract 14286: Significance of Nutritional Status in Patients With Chronic Limb Threatening Ischemia
Authors: Kuniyasu Ikeoka, Stephen Kimura, Siddhartha Dash, Tarek Hammad, Jun Li, Mehdi Shishehbor
Journal: Circulation (2020)

Introduction: The nutrition status plays a key role in the pathogenesis of frailty, and is strongly associated with the prognosis of patients with chronic limb-threatening ischemia (CLTI). The Geriatric Nutritional Risk Index (GNRI) is a widely used, simple, and well established nutritional status screening method. The association between the GNRI and wound healing in patients with CLTI has not been established. Hypothesis: We assessed the hypothesis that GNRI is associated with wound healing in patients with CLTI. Methods: We conducted a single-center retrospective analysis for 172 consecutive CLTI patients who were admitted to our hospital from August 2017 to April 2019 (age 70±14 years; men 62.2%). The GNRI on admission was calculated as follows: [14.89 х albumin (g/dL)] + [41.7 х (bodyweight/ideal body weight)]. According to the GNRI values, 4 grades of nutrition-related risk are defined as major risk (GNRI:&lt;82), moderate risk (GNRI: 82 to &lt;92), low risk (GNRI: 92 to 98), and no risk (GNRI: &gt;98). The amputation-free survival (AFS) and the cumulative wound healing rate are calculated by the log-rank test. The receiver operating characteristic curve was used to obtain a cutoff value for wound heal. Cox proportional hazards regression analysis was performed to explore the independent association between the GNRI and wound heal. Results: The follow-up period was 12±6.7 months. The 1-year AFS in no risk, low risk, moderate risk, and major risk groups were 90%, 74%, 66%, and 62%, respectively ( P =0.045). GNRI was significantly associated with WIfI wound score (W1, 95±8.8; W2, 87±8.0; W3, 84±9.3, P &lt;0.001). The 1-year cumulative wound healing rate in no risk, low risk, moderate risk, and major risk groups were 56%, 45%, 37%, and 32%, respectively ( P =0.036). GNRI=95 was selected as cutoff value with maximum discriminative power for wound healing (sensitivity 70%, specificity 60%; Area under the curve, 0.67; 95% confidence interval, 0.59-0.76). GNRI&gt;95 was an independent predictor of wound healing (Hazard ratio, 1.9; 95% confidence interval, 1.0-3.7; P =0.046). Conclusions: The GNRI was significantly associated with AFS and wound healing in patients with CLTI. GNRI=95 is a novel cutoff value to predict wound healing during follow-up.
VEGF-B Promotes Endocardium-Derived Coronary Vessel Development and Cardiac Regeneration
Authors: Markus Räsänen, Ibrahim Sultan, Jennifer Paech, Karthik Amudhala Hemanthakumar, Wei Yu, Liqun He, Juan Tang, Ying Sun, Ruslan Hlushchuk, Xiuzheng Huan, Emma Armstrong, Oleksiy-Zakhar Khoma, Eero Mervaala, Valentin Djonov, Christer Betsholtz, Bin Zhou, Riikka Kivelä, Kari Alitalo
Journal: Circulation (2020)

Recent discoveries have indicated that, in the developing heart, sinus venosus and endocardium provide major sources of endothelium for coronary vessel growth that supports the expanding myocardium. Here we set out to study the origin of the coronary vessels that develop in response to vascular endothelial growth factor B (VEGF-B) in the heart and the effect of VEGF-B on recovery from myocardial infarction.We used mice and rats expressing a VEGF-B transgene, VEGF-B-gene-deleted mice and rats, apelin-CreERT, and natriuretic peptide receptor 3-CreERT recombinase-mediated genetic cell lineage tracing and viral vector-mediated VEGF-B gene transfer in adult mice. Left anterior descending coronary vessel ligation was performed, and 5-ethynyl-2'-deoxyuridine-mediated proliferating cell cycle labeling; flow cytometry; histological, immunohistochemical, and biochemical methods; single-cell RNA sequencing and subsequent bioinformatic analysis; microcomputed tomography; and fluorescent- and tracer-mediated vascular perfusion imaging analyses were used to study the development and function of the VEGF-B-induced vessels in the heart.We show that cardiomyocyte overexpression of VEGF-B in mice and rats during development promotes the growth of novel vessels that originate directly from the cardiac ventricles and maintain connection with the coronary vessels in subendocardial myocardium. In adult mice, endothelial proliferation induced by VEGF-B gene transfer was located predominantly in the subendocardial coronary vessels. Furthermore, VEGF-B gene transduction before or concomitantly with ligation of the left anterior descending coronary artery promoted endocardium-derived vessel development into the myocardium and improved cardiac tissue remodeling and cardiac function.The myocardial VEGF-B transgene promotes the formation of endocardium-derived coronary vessels during development, endothelial proliferation in subendocardial myocardium in adult mice, and structural and functional rescue of cardiac tissue after myocardial infarction. VEGF-B could provide a new therapeutic strategy for cardiac neovascularization after coronary occlusion to rescue the most vulnerable myocardial tissue.
Digital Droplet PCR: Next Generation KIT D816V Testing As Advanced Tool for Diagnosis and Prognostication in Mastocytosis
Authors: Greiner Georg, Michael Gurbisz, Franz Ratzinger, Nadine Witzeneder, Ingrid Simonitsch-Klupp, Gerlinde Mitterbauer-Hohendanner, Matthias Mayerhofer, Leonhard Muellauer, Wolfgang R. Sperr, Peter Valent, Gregor Hoermann
Journal: Blood (2017)
Abstract 14977: St-elevation Myocardial Infarction in Multi Vessel Coronary Artery Disease- What to Do? Network Meta-analysis of Revascularization Strategies
Authors: Alexander Ivanov, Bharat Ravishankar, Rishi Thaker, rachit marwaha, Issa Kutkut
Journal: Circulation (2020)

Background: Primary Percutaneous Coronary Intervention (PCI) is the preferred treatment for patients presenting with ST-elevation myocardial infarction (STEMI). Despite multiple randomized clinical trials (RCT) best revascularization strategy (RS) in patients with STEMI and multivessel disease (MVD) remains unknown. We aimed to use network meta-analysis to compare currently used approaches. Methods: We searched for RCT comparing RSs in patients with MVD undergoing PCI for STEMI. We identified and compared RCT with arms evaluating at least two of the following approaches: culprit only revascularization (CoR), complete revascularization during initial intervention (CR) and staged procedure with culprit vessel revascularization followed by non culprit significant lesions intervention during the initial hospitalization. Our primary outcome was all-cause mortality. We combined direct and indirect data to perform a network meta-analysis. Results: A total of 7,779 patients from 13 RCT were included in this analysis (Fig. 1). Overall, this is an unbalanced network with only 1 arm comparing CR and SR. Complete revascularization during initial procedure was associated with a significant reduction in mortality with RR 0.47 (0.34; 0.65), p&lt;0.01, when compared to culprit only approach. There was a higher risk of mortality associated with SR, when compared to CR, with RR 1.9 (1.29; 2.82), p&lt;0.01. There was no mortality risk difference between CoR and SR, RR 0.89 (0.72,1.11), p&gt;0.5 (Fig. 2). There was no evidence of a model inconsistency in an overall comparison, p&gt;0.21. There was a design by treatment interaction in SR vs CoR comparison, p&lt;0.01. Conclusion: Complete revascularization during primary PCI in patients presenting with STEMI and MVD was associated with significant mortality reduction when compared to culprit only lesion revascularization. There may be design by treatment interaction limiting comparison of staged and culprit only strategies.