tbuckley/cabot-search huggingface dataset:
Association of Statin Exposure With Histologically Confirmed Idiopathic Inflammatory Myositis in an Australian Population
Authors: Gillian E. Caughey, Genevieve M. Gabb, Saffron Ronson, Michael Ward, Timothy Beukelman, Catherine L. Hill, Vidya Limaye
Journal: JAMA Internal Medicine (2018)

<h3>Importance</h3> Statin medications are widely prescribed for cardiovascular risk reduction. Myalgia and rhabdomyolysis are well-recognized adverse effects of statins, and they resolve with the cessation of statin therapy. Idiopathic inflammatory myositis (IIM) is a heterogeneous group of autoimmune myopathies that may also be associated with statin use. Recently, statin-associated autoimmune myopathy has been recognized as a distinct entity with the presence of specific autoantibodies against hydroxymethylglutaryl–coenzyme A reductase, which results in a necrotizing myositis that does not resolve with cessation of statin therapy and requires treatment with immunosuppressive agents. <h3>Objective</h3> To examine the association between histologically confirmed IIM and current exposure to statin medications. <h3>Design, Setting, and Participants</h3> Population-based case-control study using the South Australian Myositis Database of all histologically confirmed cases of IIM diagnosed between 1990 and 2014 in patients 40 years or older (n = 221) and population-based controls from the North West Adelaide Health Study (n = 662), matched by age and sex in a 3:1 ratio of controls to cases. Data analysis using conditional logistic regression was performed from June 1, 2016, to July 14, 2017. <h3>Exposures</h3> Current statin medication use. <h3>Main Outcomes and Measures</h3> Unadjusted and adjusted (for diabetes and cardiovascular disease) odds ratios and 95% CIs for likelihood of inflammatory myositis. <h3>Results</h3> A total of 221 IIM cases met the inclusion criteria with a mean (SD) age of 62.2 (10.8) years, and 132 (59.7%) were female. Statin exposure at the time of IIM diagnosis was 68 of 221 patients (30.8%) and 142 of 662 matched controls (21.5%) (<i>P</i> = .005). There was an almost 2-fold increased likelihood of statin exposure in patients with IIM compared with controls (adjusted odds ratio, 1.79; 95% CI, 1.23-2.60;<i>P</i> = .001). Similar results were observed when patients with necrotizing myositis were excluded from the analysis (adjusted odds ratio, 1.92; 95% CI, 1.29-2.86;<i>P</i> = .001). <h3>Conclusions and Relevance</h3> In this large population-based study, statin exposure was significantly associated with histologically confirmed IIM. Given the increased use of statins worldwide and the severity of IIM, increased awareness and recognition of this potentially rare adverse effect of statin exposure is needed.
Risk of Thromboembolic Events After Percutaneous Left Atrial Radiofrequency Ablation of Atrial Fibrillation
Authors: HakanOral, AmanChugh, MehmetÖzaydın, EricGood, JackieFortino, SundarSankaran, ScottReich, PetarIgic, DarrylElmouchi, DavidTschopp, AlanWimmer, SujoyaDey, ThomasCrawford, FrankPelosi, KritJongnarangsin, FrankBogun, FredMorady
Journal: Circulation (2006)

Background— In patients with atrial fibrillation (AF), the risk of thromboembolic events (TEs) is variable and is influenced by the presence and number of comorbid conditions. The effect of percutaneous left atrial radiofrequency ablation (LARFA) of AF on the risk of TEs is unclear. Methods and Results— LARFA was performed in 755 consecutive patients with paroxysmal (n=490) or chronic (n=265) AF. Four hundred eleven patients (56%) had ≥1 risk factor for stroke. All patients were anticoagulated with warfarin for ≥3 months after LARFA. A TE occurred in 7 patients (0.9%) within 2 weeks of LARFA. A late TE occurred 6 to 10 months after ablation in 2 patients (0.2%), 1 of whom still had AF, despite therapeutic anticoagulation in both. Among 522 patients who remained in sinus rhythm after LARFA, warfarin was discontinued in 79% of 256 patients without risk factors and in 68% of 266 patients with ≥1 risk factor. Patients older than 65 years or with a history of stroke were more likely to remain anticoagulated de...
Medial Regeneration Using a Biodegradable Felt as a Scaffold Preserves Integrity and Compliance of a Canine Dissected Aorta
Authors: MitsuruSato, ShunsukeKawamoto, MikaWatanabe, NaoyaSakamoto, MasaakiSato, YasuhikoTabata, YoshikatsuSaiki
Journal: Circulation (2012)

Background—Repair of a dissected aorta involves reattaching the media with synthetic glue and/or reinforcement with nonbiodegradable felt. Late complications specific to each aspect of this procedure have been reported. We attempted to regenerate the media by using biodegradable felt. Methods and Results—We created a canine model of descending thoracic aortic dissection and compared 4 modes of aortic repair: biodegradable polyglycolic acid (PGA) felt in the media; PGA with basic fibroblast growth factor (bFGF) in the media; PGA with bFGF in the media plus external reinforcement with expanded polytetrafluoroethylene; and primary suture closure of the dissected lumen (control). Repaired aortic stumps were quantitatively tested for suture pull-out strength. Failure force improved 4-fold in all 3 medial reinforcement groups compared with controls. Additionally, animals were kept alive for histological examination and compliance testing 6 months after repair. Compliance of the aortic wall at the anastomotic si...
Long-Term Survival and Hemodynamics After Endothelin-A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition in Rats With Chronic Heart Failure
Authors: PaulMulder, HoussaineBoujedaini, VincentRichard, Jean-PaulHenry, SylvanieRenet, KlausMünter, ChristianThuillez
Journal: Circulation (2002)

Background— In patients with congestive heart failure (CHF) receiving ACE inhibitors, acute administration of selective endothelin (ET) antagonists additionally improves systemic and cardiac hemodynamics. We investigated, in a rat model of CHF, whether such acute synergistic effects are sustained and accompanied, in the long term, by an additional limitation of left ventricular remodeling or an increase in survival. Methods and Results— Rats were subjected to coronary artery ligation and treated for 3 or 9 months with vehicle or with the ACE inhibitor trandolapril (Tr) (0.3 mg/kg−1 per day−1), the ETA antagonist LU 135252 (LU, 30 mg/kg−1 per day−1), or their combination starting 7 days after ligation. After 3 months, the combination decreased LV systolic- and end-diastolic pressures (−32% and −80%, respectively) more markedly than Tr (−21% and −61%, respectively) or LU alone (−14% and −48%, respectively). Echocardiographic studies revealed that all treatments limited LV dilatation and increased LV fractio...
New Technique for Determining Instantaneous Myocardial Force-Velocity Relations in the Intact Heart
Authors: Williamgrossman, Haroldbrooks, Stevenmeister, Herbertsherman, Lewisdexter
Journal: Circulation Research (1971)

A new technique is described for the instantaneous determination of myocardial force-velocity relationships. The method employs electronic differentiation of the logarithm of intraventricular pressure, which yields a continuous on-line record of (dP/dt)P-1 (the ratio of the rate of rise of ventricular pressure [dP/dt] to the simultaneous ventricular pressure [P]). A further technique is described for the automatic projection of force-velocity vector loops, displaying (dP/dt)P-1 on the ordinate against ventricular pressure on the abscissa in a beat-to-beat fashion. An excellent correlation (r=0.982) was demonstrated between (dP/dt)P-1 determined by conventional methods and that derived electronically by use of the logarithmic amplifier circuit. Experimental studies are described which document the responsiveness of (dP/dt)P-1 determined by the present method to interventions known to affect myocardial contractility. An increase in (dP/dt)P-1 was observed following infusions of CaCl2, norepinephrine, and gl...
Functional Implications of Interactions of Extracellular Ions with Ligands of the Cell Membrane
Authors: Aserrothstein
Journal: Circulation (1962)

Three examples are discussed in which interactions of chemical agents with ligands of the plasma membrane have been chemically characterized and in which the resulting disturbance in membrane function has been quantitatively measured. Uranyl ion reacts with phosphoryl groups and specifically blocks the transfer of glucose across the membrane. Cationic redox dyes and mercuric chloride react with sulfhydryl groups and destroy the structural integrity of the membrane. Arsenate competes with phosphate for a specific active-transport system and blocks the system by irreversibly combining with one of its components.
Abstract 5333: Methylation profiling identifies two subclasses of cutaneous squamous cell carcinoma related to distinct cell types of origin
Authors: Manuel Rodríguez Paredes, Felix Bormann, Günter Raddatz, Julian Gutekunst, Carlota Lucena-Porcel, Florian Köhler, Elisabeth Wurzer, Katrin Schmidt, Joachim Röwert-Huber, Evgeniya Denisova, Lars Feuerbach, Esther Herpel, Ingo Nindl, Thomas G. Hofmann, Marc Winnefeld, Frank Lyko
Journal: Cancer Research (2018)

Abstract Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer type and arises from keratinocytes. Most cSCC progress from a UV-induced precancerous lesion termed actinic keratosis (AK). Despite various efforts to characterize these lesions molecularly, the etiology of AK and its progression to cSCC remain only partially understood. Here we have used Infinium MethylationEPIC BeadChips to interrogate the DNA methylation status of about 850.000 CpGs in epidermis samples from healthy skin, AK and cSCC. Importantly, we found that the premalignant AK samples displayed classical features of cancer methylomes and were highly similar to cSCC methylomes. Further analysis identified typical features of stem cell methylomes, such as a reduced DNA methylation age, non-CpG methylation and stem cell-related keratin and enhancer methylation patterns. Interestingly, this signature was detected only in one half of the AK and cSCC samples, while the other half showed keratin and enhancer methylation patterns that were more closely related to the control epidermis. These findings suggest the existence of two distinct subclasses of AK and cSCC that originate from distinct keratinocyte differentiation stages. Citation Format: Manuel Rodríguez Paredes, Felix Bormann, Günter Raddatz, Julian Gutekunst, Carlota Lucena-Porcel, Florian Köhler, Elisabeth Wurzer, Katrin Schmidt, Joachim Röwert-Huber, Evgeniya Denisova, Lars Feuerbach, Esther Herpel, Ingo Nindl, Thomas G. Hofmann, Marc Winnefeld, Frank Lyko. Methylation profiling identifies two subclasses of cutaneous squamous cell carcinoma related to distinct cell types of origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5333.
Abstract 5375: Whole-genome sequencing reveals genomic signatures associated with the immunologic microenvironments in Chinese NSCLC patients
Authors: Cheng Wang, Juncheng Dai, Yayun Gu, Zhibin Hu, Hongbing Shen
Journal: Cancer Research (2018)

Abstract Over the past decades, next-generation sequencing has accelerated the systematic characterization of genomic events, including single base substitutions and small insertions/deletions (indels), and has yielded substantial insights into the unique and shared genomic features of the two NSCLC subtypes. Genomic studies of lung cancer have mainly been conducted in patients from Western countries; however, Chinese lung cancer patients have distinct epidemiologic and genomic features, highlighting the presence of specific etiologic mechanisms in addition to smoking. To reveal the underlying mechanisms, we presented a comprehensive genomic landscape of 149 Non-Small Cell Lung Cancer (NSCLC) cases. We identified 15 potential driver genes and three mutational signatures, two of which have been connected with APOBEC enzymes and smoking. In addition, we revealed that Chinese patients are specially characterized by not only highly clustered and functional EGFR mutations but also a mutational signature, that is associated with inflammatory tumor-infiltrating lymphocytes (P = 0.001). The EGFR mutation rate is significantly increased with the proportion of the MS3 signature (P&amp;lt;0.001). As a classic tumor-enabling hallmark, inflammatory infiltration may contribute to the accumulation of EGFR mutations, especially in never-smokers. Additionally, patients with a higher proportion of the MS3 signature carried a higher contribution of characterized chromosomal rearrangements (P&amp;lt;0.001). The results revealed specific genomic features in the inflammatory microenvironments in Chinese patients with potential implications for understanding the etiology, prevention and therapy of NSCLC. Citation Format: Cheng Wang, Juncheng Dai, Yayun Gu, Zhibin Hu, Hongbing Shen. Whole-genome sequencing reveals genomic signatures associated with the immunologic microenvironments in Chinese NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5375.
The IκB Kinase β/Nuclear Factor κB Signaling Pathway Protects the Heart From Hemodynamic Stress Mediated by the Regulation of Manganese Superoxide Dismutase Expression
Authors: ShungoHikoso, OsamuYamaguchi, YukoNakano, ToshihiroTakeda, ShigemikiOmiya, IsamuMizote, ManabuTaneike, TakafumiOka, TakahitoTamai, JotaOyabu, YoshihiroUno, YasushiMatsumura, KazuhikoNishida, KeiichiroSuzuki, MikihikoKogo, MasatsuguHori, KinyaOtsu
Journal: Circulation Research (2009)

Cardiomyocyte death plays an important role in the pathogenesis of heart failure. The nuclear factor (NF)-κB signaling pathway regulates cell death, however, the effect of NF-κB pathway on cell death can vary in different cells or stimuli. The purpose of the present study was to clarify the in vivo role of the NF-κB pathway in response to pressure overload. First, we subjected C57Bl6/J mice to pressure overload by means of transverse aortic constriction (TAC) and examined the activity of the NF-κB pathway in response to pressure overload. IκB kinase (IKK) and NF-κB were activated after TAC. Then, we investigated the role of the activation using cardiac-specific IKKβ-deficient mice (CKO). CKO displayed normal global cardiac structure and function compared with control littermates. We subjected CKO and control mice to pressure overload. One week after TAC, CKO showed cardiac dilation, dysfunction, and lung congestion, which are characteristics of heart failure. The number of apoptotic cells in the hearts of...
Abstract P104: Serum Homocysteine is Not Independently Associated with an Atherogenic Lipid Profile: The Very Large Database of Lipids (VLDL-21) Study
Authors: Joshua Lupton, Renato Quispe, Krishnaji Kulkarni, Seth S Martin, Steven R Jones
Journal: Circulation (2016)

Background: Hyperhomocysteinemia is an independent risk factor for cardiovascular disease, but the mechanism for this risk remains unclear. Complicating this association, reducing serum homocysteine (Hcy) has not been shown to decrease cardiovascular disease events in randomized controlled trials. This study aims to examine the relationship between Hcy and several lipid measures. Methods: Our analyses included a subset of 18,297 U.S. adults from the Very Large Database of Lipids, who had an extended lipid panel by density gradient ultracentrifugation, which included direct measurement of triglycerides (TG), and the cholesterol concentration of low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), non-HDL-C, very low-density lipoprotein (VLDL-C), and remnant-lipoprotein cholesterol (RLP-C: IDL-C + VLDL3-C). Additional measurements were levels of Hcy, hemoglobin A1c (HbA1c), insulin, creatinine, and blood urea nitrogen (BUN). Subjects were categorized into Hcy quartiles. Linear regression models were performed using lipid measures and Hcy as dependent and independent variables respectively, and further adjusted with potential confounders (age, sex, HbA1c, insulin, creatinine, and BUN levels) in multivariable regression. Results: In unadjusted analysis, levels of LDL-C (p&lt;0.001), non-HDL-C (p&lt;0.001) and HDL-C (p&lt;0.001) were 7-10% lower whereas levels of TG (p&lt;0.001), VLDL-C (p=0.016) and RLP-C (p&lt;0.001) were 2-6% higher in the highest Hcy quartile. These associations between Hcy levels and lipids were eliminated (p-value range: 0.101-0.750) when controlling for age, sex, HbA1c, insulin, creatinine, and BUN. Conclusions: Although high levels of Hcy were associated with 2-6% higher TG-rich lipoproteins in unadjusted analysis, after adjustment for confounders our findings do not support the hypothesis that hyperhomocysteinemia is associated with an atherogenic lipid profile.
Phospholipid Metabolite 1-Palmitoyl-Lysophosphatidylcholine Enhances Human Ether-a-Go-Go-Related Gene (HERG) K+ Channel Function
Authors: JingxiongWang, HuizhenWang, HongHan, YiqiangZhang, BaofengYang, StanleyNattel, ZhiguoWang
Journal: Circulation (2001)

Background Lysophosphatidylcholine (LPC), a naturally occurring phospholipid metabolite, accumulates in the ischemic heart and causes extracellular K+ accumulation and action potential shortening. LPC has been incriminated as a biochemical trigger of lethal cardiac arrhythmias, but the underlying mechanisms remain poorly understood. Methods and Results We studied the effect of 1-palmitoyl-LPC (Pal-LPC) on currents resulting from human ether-a-go-go-related gene (HERG) expression in human embryonic kidney (HEK) cells using whole-cell patch-clamp techniques. Bath application of Pal-LPC consistently and reversibly increased HERG current (IHERG). The effects of Pal-LPC were apparent as early as 3 minutes after application of the drug, reached maximum within 10 minutes, and were reversible on washout. Pal-LPC increased IHERG at voltages between −20 and +30 mV, with greater effects at stronger depolarization. However, Pal-LPC did not affect the voltage-dependence of IHERG activation. In contrast, Pal-LPC signif...
Topical Crisaborole—A Potential Treatment for Recalcitrant Palmoplantar Psoriasis
Authors: Allison B. Robbins, Ankit Gor, Melanie R. Bui
Journal: JAMA Dermatology (2018)

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Abstract 5072: Immunohistochemical expression of CC-chemokine receptor-like 2/CCRL2 in a prostate cancer tissue microarray
Authors: Niradiz Reyes, Ines Benedetti, Jan Geliebter
Journal: Cancer Research (2018)

Abstract Background: CCRL2 is a presumed member of the atypical chemokine receptor family, whose members are increasingly recognized as key components of the regulatory network of inflammation and immunity in cancer and may have a major effect on anti-inflammatory and immunotherapeutic strategies. Recent studies have reported the expression of CCRL2 in different human cancer cell lines and tissues. However, its function and expression in prostate cancer has not been previously addressed. The aim of this work was to determine the protein expression profile of the atypical chemokine receptor CCRL2 in human prostate cancer tissue using a tumor microarray approach. Methods: A tissue microarray was constructed using 231 cores of matched prostate cancer and benign prostatic tissue from 47 patients with a previous diagnosis of localized prostate cancer, which underwent surgical resection as their primary treatment. CCRL2 expression was evaluated by immunohistochemistry using a monoclonal, anti-human-CCRL2 antibody. An H score was calculated in each spot as the sum of expression intensity (0-3+) by extent (0%-100%). Differences in CCRL2 protein expression were assessed by comparing H-Scores between benign and cancerous tissues using Mann-Whitney test for non-Gaussian distribution. Results: Immunohistochemical evaluation of CCRL2 at the protein level in a prostate tissue microarray constructed with clinical specimens confirmed its overexpression in malignant prostatic tissue. CCRL2 staining was present predominantly in the cytoplasm of prostate cancer tumor cells. Compared to benign epithelial cells, CCRL2 expression was significantly higher in epithelial tumor cells in cores with prostate cancer compared to cores with benign tissue (p=0.0001). Conclusions: Immunohistochemistry of prostate cancer tissue specimens arrayed in a tissue microarray revealed that CCRL2 expression was significantly stronger in epithelial cells in cancerous acini compared to epithelial cells in matched adjacent benign acini from the same patient. To this point, the physiological effects of CCRL2 expression in epithelial cancer cells are unclear. Citation Format: Niradiz Reyes, Ines Benedetti, Jan Geliebter. Immunohistochemical expression of CC-chemokine receptor-like 2/CCRL2 in a prostate cancer tissue microarray [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5072.
Rethinking Gamma-secretase Inhibitors for Treatment of Non–small-Cell Lung Cancer: Is Notch the Target?
Authors: Sharon R. Pine
Journal: Clinical Cancer Research (2018)

Lung cancer is the leading cause of cancer-related deaths among men and women. γ-Secretase inhibitors, a class of small-molecule compounds that target the Notch pathway, have been tested to treat non-small-cell lung cancer (NSCLC) in preclinical and clinical trials. Although γ-secretase inhibitors elicit a response in some tumors as single agents and sensitize NSCLC to cytotoxic and targeted therapies, they have not yet been approved for NSCLC therapy. We discuss our recently published preclinical study using the γ-secretase inhibitor AL101, formerly BMS906024, on cell lines and PDX models of NSCLC, primarily lung adenocarcinoma. We propose that Notch pathway mutations may not be the most suitable biomarker for predicting NSCLC response to γ-secretase inhibitors. γ-Secretases have over 100 known γ-secretase cleavage substrates. Many of the γ-secretase substrates are directly involved in carcinogenesis or tumor progression, and are ideal candidates to be the "on-target" biomarkers for γ-secretase inhibitors. We propose the need to systematically test the γ-secretase and other targets as potential biomarkers for sensitivity before continuing clinical trials. Now that we have entered the postgenome/transcriptome era, this goal is easily attainable. Discovery of the biomarker(s) that predict sensitivity to γ-secretase inhibitors would guide selection of the responder population that is most likely to benefit and move the compounds closer to approval for therapeutic use in NSCLC.