tbuckley/cabot-search huggingface dataset:
Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain
Authors: Muhammad Saad Yousuf, Stephanie I. Shiers, James J. Sahn, Theodore J. Price
Journal: Pharmacological Reviews (2020)

Dysfunction in regulation of mRNA translation is an increasingly recognized characteristic of many diseases and disorders, including cancer, diabetes, autoimmunity, neurodegeneration, and chronic pain. Approximately 50 million adults in the United States experience chronic pain. This economic burden is greater than annual costs associated with heart disease, cancer, and diabetes combined. Treatment options for chronic pain are inadequately efficacious and riddled with adverse side effects. There is thus an urgent unmet need for novel approaches to treating chronic pain. Sensitization of neurons along the nociceptive pathway causes chronic pain states driving symptoms that include spontaneous pain and mechanical and thermal hypersensitivity. More than a decade of preclinical research demonstrates that translational mechanisms regulate the changes in gene expression that are required for ongoing sensitization of nociceptive sensory neurons. This review will describe how key translation regulation signaling pathways, including the integrated stress response, mammalian target of rapamycin, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase–interacting kinases, impact the translation of different subsets of mRNAs. We then place these mechanisms of translation regulation in the context of chronic pain states, evaluate currently available therapies, and examine the potential for developing novel drugs. Considering the large body of evidence now published in this area, we propose that pharmacologically manipulating specific aspects of the translational machinery may reverse key neuronal phenotypic changes causing different chronic pain conditions. Therapeutics targeting these pathways could eventually be first-line drugs used to treat chronic pain disorders. <h3>Significance Statement</h3> Translational mechanisms regulating protein synthesis underlie phenotypic changes in the sensory nervous system that drive chronic pain states. This review highlights regulatory mechanisms that control translation initiation and how to exploit them in treating persistent pain conditions. We explore the role of mammalian/mechanistic target of rapamycin and mitogen-activated protein kinase–interacting kinase inhibitors and AMPK activators in alleviating pain hypersensitivity. Modulation of eukaryotic initiation factor 2α phosphorylation is also discussed as a potential therapy. Targeting specific translation regulation mechanisms may reverse changes in neuronal hyperexcitability associated with painful conditions.
Abstract 14597: High Left Ventricular Ejection Fraction and All-cause Mortality in Women With Ischemia: Data From the WISE (Women's Ischemia Syndrome Evaluation)
Authors: Stephanie Wu, Marie Lauzon, Jenna Maughan, Leslee J Shaw, Sheryl F Kelsey, R David D Anderson, Carl Pepine, C Noel Bairey Merz
Journal: Circulation (2020)

Background: Relatively high left ventricular ejection fraction (EF) (&gt;65%) was recently associated with higher all-cause mortality in women but not men undergoing noninvasive coronary angiography in the CONFIRM study, although this did not remain significant following adjustment for risk variables and mortality was not adjudicated. We investigated high EF and adjudicated all-cause mortality in the Women’s Ischemia Syndrome Evaluation (WISE) study. Methods: The WISE original cohort (enrolled 1996-2000), is a multicenter prospective study of women with suspected ischemic heart disease undergoing clinically indicated coronary angiography. EF was calculated by invasive left ventriculography. We investigated the relationship among high (&gt;65%), normal (55-65%) and low (&lt;55%) EF and adjudicated all-cause mortality using Kaplan Meier and regression analyses. Results: Overall 734 women included 298 (41%) high, 355 (48%) normal, and 81 (11%) low EF. The mean age was 58±11 years and mean EF was 65±11% (43%, 63% and 75% in the low, normal and high groups respectively). Over 10 years of follow-up, all-cause mortality occurred in 18% of patients, ranging from 12% in the high EF group to 41% in the low EF group. EF was associated with mortality among groups ( Figure ). Low EF remained a significant predictor of mortality compared to high EF, but normal EF compared to high EF did not in a multivariable regression model. Compared to women in the CONFIRM study, our cohort had higher mean EF (65% v. 62%), higher rates of obstructive CAD and diabetes, and lower rates of hypertension and dyslipidemia. Conclusions: Higher EF was not associated with higher all-cause mortality adjudicated predominantly cardiovascular in women with evidence of ischemia. Potential explanations for the lack of concordance with the CONFIRM study may include lack of death adjudication, differences in comorbidities, or other unknown factors.
There’s No Harm in Talking: Re-Establishing the Relationship Between Theological and Secular Bioethics
Authors: Michael McCarthy, Mary Homan, Michael Rozier
Journal: The American Journal of Bioethics (2020)

Theological and secular voices in bioethics have drifted into separate silos. Such a separation results in part from (1) theologians focusing less on conveying ideas in ways that contribute to a pluralistic and public bioethical discourse and (2) the dwindling receptivity of religious arguments within secular bioethics. This essay works against these drifts by putting forward an argument that does not bounce around a religious echo-chamber, but instead demonstrates how insights of Christian anthropology can be meaningfully responsive to secular bioethics' rightful concerns with inequality and injustice. We offer core concepts from Christian bioethics that encourage dialogue with secular and theological bioethicists. The theologically-grounded concepts, human dignity, sin, and the common good, provide intellectual resources to address major areas of bioethical concern that remain unresolved.
骨髄由来CD11b + Jagged2 + 細胞は大腸癌における上皮間葉転換と転移性を促進する
Authors: Caiado Francisco, Carvalho Tania, Rosa Isadora, Remedio Leonor, Costa Ana, Matos Joao, Heissig Beate, Yagita Hideo, Hattori Koichi, DA Silva Joao Pereira, Fidalgo Paulo, Pereira Antonio Dias, Dias Sergio
Journal: Cancer Research (2013)
Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis
Authors: Tricia M. Peters, Michael V. Holmes, J. Brent Richards, Tom Palmer, Vincenzo Forgetta, Cecilia M. Lindgren, Folkert W. Asselbergs, Christopher P. Nelson, Nilesh J. Samani, Mark I. McCarthy, Anubha Mahajan, George Davey Smith, Mark Woodward, Linda M. O’Keeffe, Sanne A.E. Peters
Journal: Diabetes Care (2020)

Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding.
Abstract 13065: Blood Pressure Response to Treadmill Cardiopulmonary Exercise Testing in Children With Normal Hearts
Authors: Takeshi Sasaki, Yuki Kawasaki, Daiji Takajo, Robert D Ross, Daisuke Kobayashi
Journal: Circulation (2020)

Background: Blood pressure (BP) response to the treadmill cardiopulmonary exercise test (CPET) has yet been studied with no standard criteria for abnormal BP responses in children. Our hypothesis was that the reference values of BP responses to the treadmill CPET should be defined by gender and age in children. Objectives: The objective of our study was to describe the BP responses to the treadmill CPET and propose the criteria for abnormal BP responses in children. Methods: The treadmill CPET data were retrospectively analyzed to evaluate the BP responses to exercise during the period of 8 years (2011-2018). Children aged &lt;18 years with normal hearts were included for the analysis. Results: Our cohort consisted of 1,085 children (males 59%) aged 7-17 years. The analysis of variance for Systolic BP at peak exercise (peak SBP) and change (Δ) of SBP showed significant age and gender effects and age-gender interaction effect ( p &lt;0.01). In the multiple linear regression model ( p &lt;0.001), peak SBP (mmHg) was predicted as 100.39 + 4.68 x age (years) for males; 132.27 + 1.37 x age (years) for females. The following criteria for abnormal BP responses in children were proposed. Hypertensive BP response were defined by peak SBP &gt;90% confidence interval upper limit of reference values based on age and gender. Blunted BP response was defined by 1) ΔSBP &lt;10 mmHg for age 7-11 years and &lt;20 mmHg for age 12-17 years in males; and ΔSBP &lt;10 mmHg in females. Conclusion: Blood Pressure response to the treadmill CPET was dependent on age and gender in children with normal hearts. The proposed criteria for abnormal BP responses in children should prove useful in interpreting BP responses in children during the CPET.
Abstract 14416: Mechano-arrhythmogenicity is Enhanced in Late Repolarisation During Acute Ischemia by a Calcium- and TRPA1-dependent Mechanism
Authors: Breanne A Cameron, T Alexander Quinn
Journal: Circulation (2020)

Introduction: Altered tissue mechanics in acute regional ischemia contribute to arrhythmias by a mechano-sensitive, Ca 2+ -dependent mechanism. This is facilitated by uncoupling of voltage-Ca 2+ dynamics, creating a vulnerable period (VP) in late repolarisation for stretch-induced arrhythmias (‘mechano-arrhythmogenicity’). However, cellular mechanisms driving mechano-arrhythmogenicity in acute ischemia are unknown. Objective: Define cellular mechanisms of mechano-arrhythmogenicity in the VP during acute ischemia in rabbit ventricular myocytes. Methods: Rabbit (♀, NZW) LV myocytes were transiently stretched (8-16% change in sarcomere length, 100 ms) during diastole or the VP in normal Tyrode (NT) or simulated ischemia (SI) solution (hyperkalemia, acidosis, metabolic inhibition). Drugs were used to buffer Ca 2+ (BAPTA), stabilise RyR (dantrolene), block mechano-sensitive TRPA1 channels (HC-030031), or block (DPI) or increase (bi-product of di-4-ANBDQPQ excitation) ROS production. Voltage-Ca 2+ was simultaneously monitored with fluorescent dyes (di-4-ANBDQPQ, Fluo-5F) and a single camera-optical splitter system. Results: SI shortened AP duration (APD NT =384 vs APD SI =219ms; p &lt;0.0001) more than Ca 2+ transient duration (CaTD NT =424 vs CaTD SI =357 ms; p &lt;0.0001) and increased the length of the VP (=CaTD-APD; VP NT =54 vs VP SI =146ms; n =50 cells for N NT =6 and N SI =14 rabbits ; p &lt;0.0001). Mechano-arrhythmogenicity (single ectopy and complex sustained activity) was increased in SI compared to NT, but only for stretch in the VP (7 vs 1% of stretches; n =50, N =6 each ; p &lt;0.005), and arrhythmias in the VP were proportionally more complex than those that occurred with stretch in diastole (100 vs 69%; n =50, N =6; p &lt;0.05). Arrhythmia incidence in the VP during SI was reduced by BAPTA (2% of stretches; p &lt;0.05), HC-030031 (1%; p &lt;0.005), and DPI (2%; p &lt;0.05), while dantrolene had no effect ( n =50, N =6 each). Fluorescence imaging during SI further increased mechano-arrhythmogenicity in both the VP and diastole (29 and 14%; n =42, N =4; p &lt;0.05). Conclusions: Acute ischemia enhances cellular mechano-arrhythmogenicity specifically in the VP through a mechanism involving Ca 2+ , ROS, and TRPA1, suggesting potential targets for anti-arrhythmic therapy.
Abstract 17223: Firefighting as an Independent Risk Factor for Atrial Fibrillation
Authors: Catherine Vanchiere, Rithika Thirumal, Aditya D Hendrani, Parinita Dherange, Angela Bennett, NACHIKET MADHAV APTE, Runhua Shi, Denise L Smith, Paari Dominic
Journal: Circulation (2020)

Air pollution and particulate matter (PM) contribute to respiratory and cardiovascular disease over both chronic and acute exposure periods. Firefighters (FF) are a unique population which experiences these exposures, and likewise has a high risk of cardiovascular disease and death. The mechanisms by which air pollution and PM are proposed to cause disease are also known to contribute to development of arrhythmia, in particular atrial fibrillation (AF). The management of AF in FF is particularly challenging because the high likelihood of physical injury on the job makes anticoagulation more risky. In light of this unique challenge, we were interested in the risk of AF development in FF, and hypothesized that FF have an increased risk of AF. We distributed an electronic survey to FF via representative organizations to collect self-reported demographic, occupational, and clinical data. Multivariate logistic regression was used to assess the odds of having AF with participants stratified by the number of fires fought per year (≤ 10 vs ≥11). 11,965 firefighters completed the survey, of whom 93.53% were male and 96.31% were 65 years of age or younger. FF who fought ≥11 fires/year had a significantly higher lifetime prevalence of AF compared to FF who fought ≤10 fires/year (4.71% vs. 2.70%, p &lt;0.001), and this relationship was seen to be dose-dependent (Figure 1). Multivariate logistic regression showed that, in addition to traditional risk determinants of AF like age, male sex, and hypertension, a higher number of fires fought per year (≥11) was independently associated with an increased risk of AF (OR 1.32, 95% CI 1.07 - 1.62, p =0.010).FF are a unique population with increased prevalence of AF, possibly related to occupational exposures. With over 1.1 million firefighters in the United States, it is imperative to conduct further research into the mechanisms behind this relationship, and to consider firefighting as a risk factor worthy of earlier screening and intervention.
Abstract 15937: Gender Disparities in Presentation and Outcomes for Patients Undergoing Endovascular Lower Extremity Interventions for Peripheral Artery Disease
Authors: Elizabeth M Lancaster, Bian Wu, Joel Ramirez, James Iannuzzi, Michael S Conte, Jade Hiramoto
Journal: Circulation (2020)

Introduction: Although data suggests higher rates of functional decline and inferior outcomes in women compared to men after interventions for peripheral artery disease (PAD), women remain underrepresented in contemporary studies. We used a large national database to better understand gender-based differences in presentation and outcomes for patients undergoing endovascular treatment for PAD. Methods: Patients in the Vascular Quality Initiative (VQI) database that underwent lower extremity (LE) endovascular interventions for symptomatic PAD from 2010-2019 were included. Descriptive statistics and multivariable analysis were performed. Results: 128,688 patients (40% female) underwent endovascular LE interventions for symptomatic PAD. Women were more likely to have chronic limb threatening ischemia compared to men (54% vs 51%) and more likely to have a preoperative ABI &lt;0.4 (20% vs 14%). Compared to men, women were older (mean [SD]: 68 [11] vs 70 [12]), more likely to be Black (19% vs 14%), and less likely to be smokers (34% vs 36%), diabetic (50% vs 54%), have CAD (28% vs 35%), or be on dialysis (8% vs 9%) (Table 1). Women were less likely to have exclusively infrapopliteal interventions (8% vs 14%) compared to men (p&lt;0.001 for all). Despite shorter procedural times in women, female gender was an independent predictor of in hospital mortality (OR 1.25, 95% CI 1.09-1.44) in a hierarchical multivariable model adjusting for age, race, smoking, and comorbidities. Women were more likely to be discharged to a rehab or nursing home (11% vs 10%, p&lt; 0.001) and less likely to be taking a statin medication (73% vs 78%, p&lt;0.001). Conclusions: Compared to men, women undergoing endovascular LE interventions for PAD are older, present with more severe disease, and have higher adjusted rates of in hospital mortality. More aggressive screening and medical treatment for PAD in women is needed to address these gender-based differences in disease presentation and clinical outcomes.
Abstract 13835: Anti-inflammatory Effect of Rosuvastatin in Patients With HIV Infection: A Randomized Controlled FDG-PET Study
Authors: Kevin E Boczar, Elliott Faller, Jerry Wang, Wanzhen Zeng, Gary R Small, Vicente Corrales-Medina, Robert deKemp, Natalie Ward, Rob S Beanlands, Paul MacPherson, Girish Dwivedi
Journal: Circulation (2020)

Introduction: Cardiovascular disease (CVD) is a major source of morbidity and mortality in HIV+ patients, which is thought to be in part due to a state of persistent systemic inflammation that results in accelerated atherosclerosis. Hypothesis: We hypothesized that inflammation, as measured by 18F-fluorodeoxyglucose (18F-FDG) uptake measured by 18F-FDG positron emission tomography/computed tomography (18F-FDG-PET/CT) in the bone marrow, spleen and thoracic aorta would improve in HIV+ patients following therapy with rosuvastatin compared to HIV+ patients not receiving a statin. Methods: HIV+ patients with a moderate Framingham risk score were enrolled in the study and randomized to treatment with rosuvastatin or usual treatment for 6 months. Patients were matched for age, sex, smoking status, Framingham risk score, duration of anti-retroviral therapy (ART) and type of ART. Fasting blood was collected and 18F-FDG-PET/CT imaging of bone marrow, spleen, and thoracic aorta was performed at baseline and 6 months. Results: Thirty-five HIV+ patients were enrolled in the study; 17 were randomized to treatment with rosuvastatin and 18 were randomized to the control group. There was a significant drop in the 18F-FDG bone marrow, spleen and thoracic aortic uptake in the statin-treated group compared to the control group (bone marrow: -10.3±16.9% versus 5.0±18.9%, p=0.0262; spleen: -9.8±20.3% versus 11.3±28.8%, p=0.0497; thoracic aorta: -8.6±24.5% versus 12.6±29.5%, p=0.0343). 18F-FDG changes over the study period are shown in Figure 1. Conclusions: The present study observed a significant decrease in 18F-FDG-PET uptake in the bone marrow, spleen, and thoracic aorta following treatment with rosuvastatin for 6 months in HIV+ patients. These data suggest a wide-range anti-inflammatory effect of rosuvastatin in HIV+ individuals with well-controlled infection on ART, ultimately resulting in decreased inflammatory activity in the arterial walls of these patients.
To WE, or not to WE, that is the question
Authors: Felix W Leung, Joseph W Leung
Journal: Gut (2020)

We read with interest the work by Rutter et al 1 who reported that ‘in enema-prepared unsedated screening sigmoidoscopies performed by screening-accredited endoscopists, no difference in patient-reported pain was seen when using either a carbon dioxide (CO2) or water-assisted sigmoidoscopy (WAS) intubation technique’. An elegant advancement of the understanding of the limitations of water assistance, the results with the endoscopist-centred WAS technique support the recommendations of ‘no need for screening sigmoidoscopists to switch to a WAS technique, nor should national policy be amended. Caution should be given to monitoring adenoma detection rate (ADR) if WAS is used in enema-prepared sigmoidoscopies’.1 These recommendations, however, do not preclude other patient-centred water-aided technique(s) to be evaluated in further studies.

The distinction between endoscopist-centred water immersion and patient-centred water exchange was explained in a related editorial.2 WAS was akin to …
Abstract IA18: Genomic evolution of brain metastases: Implications for precision medicine
Authors: Priscilla K. Brastianos
Journal: Cancer Research (2020)

Abstract Brain metastases are clinically devastating. Up to 25% of cancer patients will develop brain metastases and prognosis in this patient population continues to be poor. The vast majority of clinical trials in the US exclude patients with active brain metastases. Our understanding of how intracranial metastases genetically evolve from primary tumors has historically been limited, which has hampered the development of clinical trials for this patient population. In this presentation, I will present our ongoing work on genomic characterization of central nervous system metastases with a comparison to primary tumors and extracranial sites. Intracranial metastases demonstrate branched evolution, whereby the brain metastases and primary tumors share a common genetic ancestor yet both the primary tumor and brain metastasis continue to evolve independently. We also show that comprehensive genomic characterization of brain metastases, coupled with functional validation in mouse models of metastasis, can lead to the discovery of putative drivers of progression and metastasis. Taken together, our data implies that precision medicine approaches based solely on genetic characterization of extracranial sites tumors may miss potential therapeutic targets from which patients with brain metastases might benefit. Importantly, despite genetic heterogeneity between the brain metastases and extracranial sites, there are common clinically actionable genetic alterations across brain metastases of different histologies. We have translated these findings to clinical trials, including an NCI-sponsored cooperative group genomically-guided clinical trial in patients with progressive brain metastases (Alliance A071701). Citation Format: Priscilla K. Brastianos. Genomic evolution of brain metastases: Implications for precision medicine [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA18.
Abstract 14319: Effect of Natural Vascular Scaffolding (NVS) Treatment on Human Popliteal Arteries in vitro
Authors: Ejaz Ansari, Blake Anderson, Katalin Kauser
Journal: Circulation (2019)

Percutaneous transluminal angioplasty and stent placement is routinely performed on patients with atherosclerotic and stenosed blood vessels. Stenting the femoropopliteal vascular region can be pro...
Abstract 16718: The Impact of Prior Revascularization in Acute Myocardial Infarction Patients With Cardiogenic Shock: Prior Bypass Surgery a Marker of Worse Outcome?
Authors: Luis Gruberg, Puneet Gandotra, Samy Selim, Azhar Supariwala, Lawrence Ong
Journal: Circulation (2020)

Background: Cardiogenic shock (CS) in patients with acute myocardial infarction (AMI) is a marker of worse prognosis with extremely high mortality rates. We assessed the impact of previous surgical revascularization by CABG or percutaneous coronary intervention (PCI) on in-hospital outcomes of AMI patients with CS undergoing primary PCI. Methods: Between 1/2010 and 5/2019, a total of 1,170 patients were diagnosed with AMI and CS, defined by New York State Percutaneous Coronary Interventions Reporting System (PCIRS) as acute and persistent systolic blood pressure &lt;80 mmHg on mechanical or pharmacological support. Baseline clinical, angiographic and procedural characteristics, as well as in-hospital outcomes were prospectively collected among all patients undergoing primary PCI as part of the New York State PCIRS data collection. Results: There were no significant baseline differences between the two groups. Patients with a prior CABG were older and had a history of congestive heart failure. All other risk factors were similar (Table). There was a trend towards higher mortality rates in post CABG patients but longer length of stay in post PCI patients. The combined endpoint of death, reinfarction, acute kidney failure requiring dialysis or stroke (MARCCE) was numerically higher in post CABG patients but did not reach statistical significance. Conclusions: The results of this study show that in patients with AMI and CS undergoing PCI: 1) Patients with a prior history of CABG are usually older at presentation and had a prior history of heart failure; 2) there was a trend to higher in-hospital mortality rates in post CABG patient but MARCCE rates were similar in both groups.