tbuckley/cabot-search huggingface dataset:
Podocyte-Specific Induction of Krüppel-Like Factor 15 Restores Differentiation Markers and Attenuates Kidney Injury in Proteinuric Kidney Disease
Authors: Yiqing Guo, Jesse Pace, Zhengzhe Li, Avi Ma’ayan, Zichen Wang, Monica P. Revelo, Edward Chen, Xiangchen Gu, Ahmed Attalah, Yaqi Yang, Chelsea Estrada, Vincent W. Yang, John C. He, Sandeep K. Mallipattu
Journal: Journal of the American Society of Nephrology (2018)

Background Podocyte injury is the hallmark of proteinuric kidney diseases, such as FSGS and minimal change disease, and destabilization of the podocyte’s actin cytoskeleton contributes to podocyte dysfunction in many of these conditions. Although agents, such as glucocorticoids and cyclosporin, stabilize the actin cytoskeleton, systemic toxicity hinders chronic use. We previously showed that loss of the kidney-enriched zinc finger transcription factor Krüppel-like factor 15 (KLF15) increases susceptibility to proteinuric kidney disease and attenuates the salutary effects of retinoic acid and glucocorticoids in the podocyte. Methods We induced podocyte-specific KLF15 in two proteinuric murine models, HIV-1 transgenic ( Tg26 ) mice and adriamycin (ADR)-induced nephropathy, and used RNA sequencing of isolated glomeruli and subsequent enrichment analysis to investigate pathways mediated by podocyte-specific KLF15 in Tg26 mice. We also explored in cultured human podocytes the potential mediating role of Wilms Tumor 1 (WT1), a transcription factor critical for podocyte differentiation. Results In Tg26 mice, inducing podocyte-specific KLF15 attenuated podocyte injury, glomerulosclerosis, tubulointerstitial fibrosis, and inflammation, while improving renal function and overall survival; it also attenuated podocyte injury in ADR-treated mice. Enrichment analysis of RNA sequencing from the Tg26 mouse model shows that KLF15 induction activates pathways involved in stabilization of actin cytoskeleton, focal adhesion, and podocyte differentiation. Transcription factor enrichment analysis, with further experimental validation, suggests that KLF15 activity is in part mediated by WT1. Conclusions Inducing podocyte-specific KLF15 attenuates kidney injury by directly and indirectly upregulating genes critical for podocyte differentiation, suggesting that KLF15 induction might be a potential strategy for treating proteinuric kidney disease.
Abstract 18386: ROS-Induced Mitochondrial Translocation of Phosphatases Cancels Cell-Protective Signals Activated by Phosphorylation of Mitochondrial Protective Kinases
Authors: Wataru Ohwada, Masaya Tanno, Toshiyuki Yano, Atsushi Kuno, Takayuki Miki, Satoko Ishikawa, Yuki Tatekoshi, Koki Abe, Kouhei Ohno, Masashi Mizuno, Kei Nakata, Tetsuji Miura
Journal: Circulation (2016)

Background: Protein kinases localizing in mitochondria are thought to mediate pro-survival signaling. However, their regulatory mechanisms remain unclear. Here, we examined intra-mitochondrial localizations of pro-survival kinases and the role of reactive oxygen species (ROS) in their regulation. Methods and Results: Mitochondria were isolated from HEK293 cells and incubated in trypsin at 1-1,000 μg/ml for stepwise digestion; trypsin eliminated TOM20, an outer membrane (OM) protein, and cytochrome oxidase IV, an inner membrane (IM) protein, at 1 and 1,000 μg/ml, respectively. We estimated the amounts of proteins in the OM and IM by Western blot analyses. At baseline, 62% and 22% of mitochondrial GSK-3β were localized in the OM and IM, respectively, the remaining 16% presumably being in the matrix. Sub-mitochondrial localization of ERK was similar to that of GSK-3β (53% in the OM and 25% in the IM), whereas Akt was mainly localized in the IM (41%), with 31% residing in the OM. Treatment with IGF-1 (50 nmol...
Assessment of the Safety Risk of Dermatoscope Magnets in Patients With Cardiovascular Implanted Electronic Devices
Authors: Ayelet Rishpon, Ralph Braun, Martin A. Weinstock, Stephen Kulju, Andrea Grenga, Cristian Navarrete-Dechent, Nadeem G. Marghoob, Jan Steffel, Ashfaq A. Marghoob
Journal: JAMA Dermatology (2018)

Cardiovascular implanted electronic devices (CIEDs) are susceptible to electromagnetic interference. Dermatologists regularly use devices containing magnets, including dermatoscopes and their attachments, which could pose a hazard to patients with CIEDs. To investigate the safety risk of magnets in dermatoscopes to patients with CIEDs. This cross-sectional observational study was conducted between January 1, 2018, and March 31, 2018, in a controlled laboratory setting. Two experiments were performed. In the first experiment (performed in the Dermatology Service at Memorial Sloan Kettering Cancer Center, New York), dermatoscopes that contain magnets were obtained from 3 manufacturers. Using a magnometer, the magnetic field strength of the dermatoscopes was measured over the magnet; at the faceplate; and at a distance of 0.5 cm, 1 cm and 15 cm away from the faceplate. In the second experiment (performed in the University Heart Center Zurich, Zurich, Switzerland), ex vivo measurements were conducted to determine how the dermatoscopes affected old-generation and new generation CIEDs (pacemakers and implantable defibrillators). Magnetic field strength as measured directly over the dermatoscope magnet; at the faceplate; and at distances of 0.5 cm, 1 cm, and 15 cm from the faceplate. Pacemaker and defibrillator operation when exposed to dermatoscopes. After conducting 24 measurements, the magnetic field (measured in gauss [G]) strength varied between 24.26 G and 163.04 G over the dermatoscope magnet, between 2.22 G and 9.98 G at the dermatoscope faceplate, between 0.82 G and 2.4 G at a distance of 0.5 cm, and between 0.5 G and 1.04 G at a distance of 1 cm; it was 0 for all devices at a 15 cm distance. The field strength at the faceplate was found to be generally below the CIED industry standard safety threshold. None of the dermatoscopes in the ex vivo experiment exerted any demonstrable disruptions or changes to the CIEDs. In real life, dermatoscope magnets likely present no measurable safety risk to patients with CIEDs. Using the polarized noncontact mode permits dermoscopy to be performed at least 0.5 cm from the skin surface, where the magnetic field strength was well below the 5-G safety threshold.
Abstract P054: A Novel Index of Insulin Resistance and Segment-specific Pulse Wave Velocity: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Anna K Poon, Michelle L Meyer, Elizabeth Selvin, James S Pankow, David Couper, Joshua W Knowles, Laura Loehr, Gerardo Heiss, Hirofumi Tanaka
Journal: Circulation (2016)

Background: Carotid-femoral pulse wave velocity (cfPWV) is a reference measure of central (elastic) artery stiffness and a risk factor for cardiovascular disease. Femoral-ankle pulse wave velocity (faPWV) is a measure of peripheral (musculo-elastic) arterial stiffness. The ratio of fasting triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) is a novel and practical marker of insulin resistance (IR), a dysregulation that often precedes diabetes. While diabetes is a known risk factor for arterial stiffening, associations of IR with segment-specific measures of PWV, in those without diabetes, have not been well characterized. Objective: To characterize the cross-sectional association of IR, as indexed by TG/HDL-C, with central and peripheral arterial stiffness by race and gender in older adults without diagnosed diabetes. We hypothesized that TG/HDL-C is positively associated with cfPWV and inversely associated with faPWV. Methods: Our study population included 2477 white and 564 African American adults without diagnosed diabetes examined in 2011-2013 by the ARIC study. cfPWV (cm/s) and faPWV (cm/s) were measured using the Omron VP-1000 Plus system. TG (mg/dL)/HDL-C (mg/dL) was evaluated continuously and categorically. For TG/HDL-C categories, race and gender specific receiver operator characteristic curves were used to determine cut points corresponding to the 75th percentile of fasting insulin, optimized using the Youden index. Elevated TG/HDL-C was dichotomously defined by cut points. Multivariable linear regression was used to model associations, adjusted for age, heart rate, gender, current smoking, and race-center; analyses were stratified by race and gender. Results: The study population was 19% African American and 62% women; mean age was 75 years (SD: 5). TG/HDL-C was positively and monotonically associated with cfPWV, and inversely associated with faPWV. Overall, compared to those without elevated TG/HDL, those with elevated TG/HDL-C had higher cfPWV (β=56 cm/s, 95% CI 35, 78) and, although not significant, lower faPWV (β=-9 cm/s, 95% CI -22, 5). cfPWV was higher in those with elevated TG/HDL-C: 59 cm/s (95% CI 32, 87) in white women, 40 cm/s (95% CI 3, 78) in white men, 50 cm/s (95% CI -20, 120) in African American women, and 101 cm/s (95% CI -10, 212) in African American men. faPWV was lower in white women (β=-23 cm/s, 95% CI -42, -4), but not statistically different in other subgroups. The association of elevated TG/HDL-C with cfPWV and faPWV did not differ by race or gender (p-values &gt;0.1 for all tests for interaction). Conclusions: Higher levels of IR, as indexed by TG/HDL-C, were associated with higher central arterial stiffness and lower peripheral arterial stiffness. These results suggest a role of IR in arterial stiffening in older adults without diabetes.
Abstract 19958: Occult Left Atrial Dysfunction in Severe Pulmonary Arterial Hypertension: A Novel Application of Left Atrial Strain
Authors: Amita Singh, Kanako Kishiki, Victor Mor-Avi, Francesco Maffessanti, Mardi Gomberg-Maitland, Roberto M Lang, Karima Addetia
Journal: Circulation (2016)

Background: Evidence of left ventricular (LV) systolic dysfunction in severe pulmonary arterial hypertension (PAH) has been reported. We sought to determine the presence of left atrial (LA) dysfunc...
High-Sensitivity Cardiac Troponin I and Clinical Risk Scores in Patients With Suspected Acute Coronary Syndrome
Authors: Andrew R. Chapman, Kerrick Hesse, Jack Andrews, Kuan Ken Lee, Atul Anand, Anoop S. V. Shah, Dennis Sandeman, Amy V. Ferry, Jack Jameson, Simran Piya, Stacey Stewart, Lucy Marshall, Fiona E. Strachan, Alasdair Gray, David E. Newby, Nicholas L. Mills
Journal: Circulation (2018)

High-sensitivity cardiac troponin assays can help to identify patients who are at low risk of myocardial infarction in the emergency department. We aimed to determine whether the addition of clinical risk scores would improve the safety of early rule-out pathways for myocardial infarction.In 1935 patients with suspected acute coronary syndrome, we evaluated the safety and efficacy of 2 rule-out pathways alone or in conjunction with low-risk TIMI (Thrombolysis In Myocardial Infarction) (0 or 1), GRACE (Global Registry of Acute Coronary Events) (≤108), EDACS (Emergency Department Assessment of Chest Pain Score) (<16), or HEART (History, ECG, Age, Risk factors, Troponin) (≤3) scores. The European Society of Cardiology 3-hour pathway uses a single diagnostic threshold (99th percentile), whereas the High-STEACS (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome) pathway applies different thresholds to rule out (<5 ng/L) and rule in (>99th percentile) myocardial infarction.Myocardial infarction or cardiac death during the index presentation or at 30 days occurred in 14.3% of patients (276/1935). The European Society of Cardiology pathway ruled out 70%, with 27 missed events giving a negative predictive value of 97.9% (95% CI, 97.1-98.6). The addition of a HEART score ≤3 reduced the proportion ruled out by the European Society of Cardiology pathway to 25% but improved the negative predictive value to 99.7% (95% CI, 99.0-100; P<0.001). The High-STEACS pathway ruled out 65%, with 3 missed events for a negative predictive value of 99.7% (95% CI, 99.4-99.9). No risk score improved the negative predictive value of the High-STEACS pathways, but all reduced the proportion ruled out (24% to 47%; P<0.001 for all).Clinical risk scores significantly improved the safety of the European Society of Cardiology 3-hour pathway, which relies on a single cardiac troponin threshold at the 99th percentile to rule in and rule out myocardial infarction. Where lower thresholds are used to rule out myocardial infarction, as applied in the High-STEACS pathway, risk scores halve the proportion of patients ruled out without improving safety.URL: https://www.clinicaltrials.gov . Unique identifier: NCT01852123.
Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase
Authors: Roger W. Hunter, Curtis C. Hughey, Louise Lantier, Elias I. Sundelin, Mark Peggie, Elton Zeqiraj, Frank Sicheri, Niels Jessen, David H. Wasserman, Kei Sakamoto
Journal: Nature Medicine (2018)
Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells
Authors: Michal A. Stanczak, Shoib S. Siddiqui, Marcel P. Trefny, Daniela S. Thommen, Kayluz Frias Boligan, Stephan von Gunten, Alexandar Tzankov, Lothar Tietze, Didier Lardinois, Viola Heinzelmann-Schwarz, Michael von Bergwelt-Baildon, Wu Zhang, Heinz-Josef Lenz, Younghun Han, Christopher I. Amos, Mohammedyaseen Syedbasha, Adrian Egli, Frank Stenner, Daniel E. Speiser, Ajit Varki, Alfred Zippelius, Heinz Läubli
Journal: Journal of Clinical Investigation (2018)

First-generation immune checkpoint inhibitors, including anti-CTLA-4 and anti-programmed death 1 (anti-PD-1) antibodies, have led to major clinical progress, yet resistance frequently leads to treatment failure. Thus, new targets acting on T cells are needed. CD33-related sialic acid-binding immunoglobulin-like lectins (Siglecs) are pattern-recognition immune receptors binding to a range of sialoglycan ligands, which appear to function as self-associated molecular patterns (SAMPs) that suppress autoimmune responses. Siglecs are expressed at very low levels on normal T cells, and these receptors were not until recently considered as interesting targets on T cells for cancer immunotherapy. Here, we show an upregulation of Siglecs, including Siglec-9, on tumor-infiltrating T cells from non-small cell lung cancer (NSCLC), colorectal, and ovarian cancer patients. Siglec-9-expressing T cells coexpressed several inhibitory receptors, including PD-1. Targeting of the sialoglycan-SAMP/Siglec pathway in vitro and in vivo resulted in increased anticancer immunity. T cell expression of Siglec-9 in NSCLC patients correlated with reduced survival, and Siglec-9 polymorphisms showed association with the risk of developing lung and colorectal cancer. Our data identify the sialoglycan-SAMP/Siglec pathway as a potential target for improving T cell activation for immunotherapy.
Abstract P043: Association Between Maternal Smoking During Pregnancy and Childhood Blood Pressure and Lipids in Fifth Grade Children Born Full Term
Authors: Amna Umer, Candice Hamilton, Cris Britton, Lee Pyles, Collin John, William Neal, Christa Lilly
Journal: Circulation (2016)

Introduction: Maternal smoking during pregnancy is a well-established risk factor for childhood obesity. However, the relationship between maternal smoking and other childhood cardiovascular disease (CVD) risk factors is unclear. The objective of the study was to assess these associations in fifth grade children. Methods: The study used longitudinally linked data from three cross-sectional datasets (the WV Birth Score Project, the Birth certificate at birth, and the Coronary Artery Risk Detection in Appalachian Communities Project in fifth grade West Virginian children who were born full term (N=19,583). The main outcome variables included fifth-grade CVD risk factors (e.g., systolic blood pressure [SBP], diastolic blood pressure and lipid levels including total cholesterol, high-density lipoprotein cholesterol [HDL], low-density lipoprotein cholesterol, log transformed triglyceride [log-TG]), which were significantly correlated with maternal smoking during pregnancy at the bivariate level. Each significant dependent variable was regressed on the main exposure variable with additional covariates (child’s age, sex, race, maternal education at child’s birth, family history of CVD, and birth weight). Childhood body mass index (BMI) was added to the regression model to assess for its role as a potential mediator. Results: The significant CVD risk factors associated with maternal smoking during pregnancy included SBP: r=0.02, p= 0.002; HDL: r=-0.06 p&lt;0.0001, and TG: r=0.06, p&lt;0.0001. The results of multiple regression analysis showed significant association between maternal smoking during pregnancy and TG and HDL, which attenuated but remained statistically significant after assessing for BMI as a potential mediator. The association was not significant for SBP (Table 1). Conclusion: Our results showed that maternal smoking during pregnancy was an independent risk factor for higher TG and lower HDL after adjusting for covariates and the relationship is partially mediated by the childhood current BMI.
Abstract 14543: The Mitral Regurgitation Severity Index: Revisiting a Spectral Doppler based Echocardiographic Tool for the Assessment of Mitral Regurgitation Severity
Authors: Mohamed Shokr, Emmanuel Akintoye, Alexandros Briasoulis, Tesfaye Telila, Ashraf Mostafa, Ahmed Rashed, Luis Afonso
Journal: Circulation (2016)

Introduction: Accurate assessment of mitral regurgitation (MR) severity is vital in making decision about corrective surgery. However, existing metrics are limited in terms of high inter-observer v...
Abstract 10904: Undetectable Serum Cardiac Troponin I Does Not Preclude a Diagnosis of Giant Cell Myocarditis
Authors: Nisha A Gilotra, Nicole Minkove, Mosi K Bennett, Ryan J Tedford, Charles Steenbergen, Marc K Halushka, Daniel P Judge, Stuart D Russell
Journal: Circulation (2015)

Introduction: Giant cell myocarditis (GCM) is characterized by a fulminant and life-threatening course requiring prompt attention and advanced therapies. Suspicion for GCM is one of the only class I indications for performing an endomyocardial biopsy (EMB) for unexplained heart failure. GCM involves a polymorphous inflammatory cell infiltrate alongside myocyte damage, but may be missed due to the limitations of EMB. Elevated serum cardiac Troponin I (cTnI) is highly specific and sensitive for cardiac injury. Due to the destructive nature of GCM, cTnI would be expected to be elevated in this condition. Hypothesis: We hypothesized that cTnI level is not predictive of GCM on EMB. Methods: The Johns Hopkins Hospital EMB database was queried for acute myocarditis cases. Peak cTnI at time of presentation was obtained from the medical record. Results: Six patients with GCM were identified (Table 1). Peak cTnI values were: &lt;0.06, 0.09, 0.32, 1.8, 15.48 and 26.68 ng/mL. The patients with cTnI of &lt;0.06 and 0.09 ng/mL had evidence of extensive myocyte necrosis on biopsy. Five patients required mechanical circulatory support and/or orthotopic heart transplant, four of whom passed away during index hospitalization. Thirty-seven cases of non-giant cell myocarditis were identified (Table 2). cTnI ranged from undetectable to 192 ng/mL (median 0.47 ng/mL; interquartile range: 6.52 ng/mL). Conclusions: To our knowledge, no data exist on the role of cTnI in diagnosis and prognosis in GCM. Based on our experience, cTnI cannot be used as a screening tool or prognostic marker in GCM, nor should a negative or low-level troponin influence the decision to perform EMB.
Comparing Adjuvant vs Early-Salvage Radiotherapy After Radical Prostatectomy
Authors: Thenappan Chandrasekar, Steven A. Narod, Robert K. Nam
Journal: JAMA Oncology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Neutralizing Antibodies Inhibit Chikungunya Virus Budding at the Plasma Membrane
Authors: Jing Jin, Jesús G. Galaz-Montoya, Michael B. Sherman, Stella Y. Sun, Cynthia S. Goldsmith, Eileen T. O'Toole, Larry Ackerman, Lars-Anders Carlson, Scott C. Weaver, Wah Chiu, Graham Simmons
Journal: Cell Host & Microbe (2018)
Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial
Authors: M. Staehler, R.J. Motzer, D.J. George, H.S. Pandha, F. Donskov, B. Escudier, A.J. Pantuck, A. Patel, L. DeAnnuntis, H. Bhattacharyya, K. Ramaswamy, G. Zanotti, X. Lin, M. Lechuga, L. Serfass, J. Paty, A. Ravaud
Journal: Annals of Oncology (2018)

BackgroundAdjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59–0.98; two-sided P= 0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial.Patients and methodsPatients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1 : 1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients' health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).ResultsPatients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ∼1 month (median) after start of treatment and resolved within ∼3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases.ConclusionsIn S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects.Clinical trial registrationClinicalTrials.gov, NCT00375674.