tbuckley/cabot-search huggingface dataset:
Cell-based assays for dissecting the PI3K/AKT pathway
Authors: Coby Carlson, Michael Hancock, Kun Bi, Kurt Vogel
Journal: Cancer Research (2008)

3513  The PI3K/AKT signaling pathway is fundamental for many aspects of cell cycle, growth, death and survival. As such, it also plays a pivotal role in the genesis of numerous diseases, including cancer and diabetes. Indeed, compounds that target this network have proven efficacious, warranting further high-throughput drug discovery efforts in this area. The considerable degree of crosstalk and feedback regulation that exists within the pathway, however, underscores the complexity that comes along with investigating it. Therefore, cell-based methods are critical for proper interrogation of compounds that activate or inhibit the PI3K/AKT pathway, as these intricacies are lost when using purified components in a biochemical experiment. To this end, we have created a series of complementary assay technologies that enable detailed analysis at different points up-and-down the pathway. Here we focus on two cell-based assay formats: CellSensor® reporter assays for pathway readout and LanthaScreen™ GFP cellular assays for target-specific phosphorylation. The stable CellSensor® cell line features tetracycline-inducible FOXO3 expression and utilizes a FOXO3 response element upstream of a beta-lactamase reporter gene that can be detected using sensitive, quantitative FRET-based substrates that are amenable to high-throughput screening (HTS). This assay provides an effective end-point readout of PI3K/AKT/FOXO3 pathway alteration upon exposure to drug candidates or other stimuli. The cellular LanthaScreen™ platform utilizes a time-resolved FRET-based method to monitor the phosphorylation of a given kinase substrate in the pathway. By expressing the protein of interest inside the cell as a fusion with GFP (which serves as the acceptor), phosphospecific antibodies labeled with a FRET donor partner (e.g., terbium) can then be used to quantitatively detect this post-translational modification event following cell lysis. We report three different targets that can be used to dissect the regulation of the pathway, specifically as it applies to mTOR. These assays look at phosphorylation of 1) PRAS40 at Thr246 as a robust readout of Akt signaling; 2) PDCD4 at Ser457 as a rapamycin-sensitive substrate for p70 S6 kinase; and 3) Akt at Ser473, which is rapamycin insensitive and serves as an mTORC2-specific cellular assay. These homogenous (no-wash) LanthaScreen™ assays offer an attractive alternative to traditional methods (such as western blotting or ELISA) and are useful for HTS applications. Whether the pathway is activated or inhibited, each of our assays show correct EC50 or IC50 values and display excellent statistical data (Z’ factor). In addition, each assay is tested for performance under numerous conditions and validated with various agonists and inhibitors. Together, these systems constitute a portfolio of cell-based assays with the potential to facilitate identification of novel modulators of PI3K/AKT signaling.
TCT-320 Prophylactic Veno-Arterial–Extracorporeal Membrane Oxygenation in Patients Undergoing High-Risk Percutaneous Coronary Interventions
Authors: Floris van den Brink, Tom Meijers, Krischan Sjauw, Sjoerd H. Hofma, Alexander Nap, Peter Symersky, Ad Van Boven, Paul Knaapen
Journal: Journal of the American College of Cardiology (2019)
Could psoralen plus ultraviolet A1 (‘ <scp>PUVA</scp> 1’) work? Depth penetration achieved by phototherapy lamps
Authors: I.R.M. Barnard, E. Eadie, L. McMillan, H. Moseley, T. Brown, K. Wood, R. Dawe
Journal: British Journal of Dermatology (2019)

Psoralen and ultraviolet A (PUVA) is useful in treating various hand and foot skin
KLF15-Wnt–Dependent Cardiac Reprogramming Up-Regulates SHISA3 in the Mammalian Heart
Authors: Claudia Noack, Lavanya M. Iyer, Norman Y. Liaw, Eric Schoger, Sara Khadjeh, Eva Wagner, Monique Woelfer, Maria-Patapia Zafiriou, Hendrik Milting, Samuel Sossalla, Katrin Streckfuss-Boemeke, Gerd Hasenfuß, Wolfram-Hubertus Zimmermann, Laura C. Zelarayán
Journal: Journal of the American College of Cardiology (2019)

The combination of cardiomyocyte (CM) and vascular cell (VC) fetal reprogramming upon stress culminates in end-stage heart failure (HF) by mechanisms that are not fully understood. Previous studies suggest KLF15 as a key regulator of CM hypertrophy. This study aimed to characterize the impact of KLF15-dependent cardiac transcriptional networks leading to HF progression, amenable to therapeutic intervention in the adult heart. Transcriptomic bioinformatics, phenotyping of Klf15 knockout mice, Wnt-signaling-modulated hearts, and pressure overload and myocardial ischemia models were applied. Human KLF15 knockout embryonic stem cells and engineered human myocardium, and human samples were used to validate the relevance of the identified mechanisms. The authors identified a sequential, postnatal transcriptional repression mediated by KLF15 of pathways implicated in pathological tissue remodeling, including distinct Wnt-pathways that control CM fetal reprogramming and VC remodeling. The authors further uncovered a vascular program induced by a cellular crosstalk initiated by CM, characterized by a reduction of KLF15 and a concomitant activation of Wnt-dependent transcriptional signaling. Within this program, a so-far uncharacterized cardiac player, SHISA3, primarily expressed in VCs in fetal hearts and pathological remodeling was identified. Importantly, the KLF15 and Wnt codependent SHISA3 regulation was demonstrated to be conserved in mouse and human models. The authors unraveled a network interplay defined by KLF15–Wnt dynamics controlling CM and VC homeostasis in the postnatal heart and demonstrated its potential as a cardiac-specific therapeutic target in HF. Within this network, they identified SHISA3 as a novel, evolutionarily conserved VC marker involved in pathological remodeling in HF.
TCT-266 Long-Term Clinical Follow-Up of Small Coronary De Novo Lesions Treated With a Novel Second-Generation Paclitaxel-Coated Balloon Catheter
Authors: Javier Benezet, Barbara Serrano, Dolores Cañadas, Antonio Agarrado, Ana Del Rio, Manuel J. Oneto
Journal: Journal of the American College of Cardiology (2019)
Male sex and Breslow thickness are important risk factors for recurrence of localized melanoma in Korean populations
Authors: Yeongjoo Oh, Sooyie Choi, Mi Yeon Cho, Kyoung Ae Nam, Sang Joon Shin, Jee Suk Chang, Byung Ho Oh, Mi Ryung Roh, Kee Yang Chung
Journal: Journal of the American Academy of Dermatology (2019)
The Case for Mandating Buprenorphine Training for Pediatric Resident Physicians
Authors: Megana Dwarakanath
Journal: JAMA Pediatrics (2019)

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 Pediatrics 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 Pediatrics journal
Abstract 18004: Diagnosis of Obstructive Sleep Apnea in Patients With Congenital Long QT Syndrome
Authors: Abu Shamsuzzaman, Rhonda Szczesniak, Matthew Fenchel, Raouf Amin
Journal: Circulation (2013)

Introduction: Obstructive sleep apnea (OSA) is a common health problem which affects about a quarter of US adults. OSA is increasingly linked to cardiovascular diseases including hypertension, heart failure, myocardial infarction, cardiac arrhythmias and sudden cardiac death (SCD). Congenital long QT syndrome (LQTS) is a common cause of SCD in children and young adults during exercise and sleep. LQT3 (SCN5A) and LQT2 (HERG) genotypes are particularly at increased risk for SCD during sleep. We tested the hypothesis that increased numbers of patients with congenital LQTS have OSA compared to controls matched for age gender and BMI. Methods: A complete medical history and a standard 12-lead surface ECG were obtained in LQTS and controls. Polysomnography (PSG) was conducted in 32 LQTS patients (20 LQT1 and 12 LQT2) and 40 controls matched for age, gender and BMI. Blinded interpretation of the sleep studies were carried out by a single investigator board certified in Sleep Medicine. OSA was defined by the presence of AHI ≥5 events/hour for adults (≥18 years) and &gt;1 event/hour for children (&lt;18 years). Results: The PSG results show that 16 LQTS patients (50%) have clinically significant OSA compared to 6 controls (15%) in the controls. There are 7 LQTS patients who have history of early childhood adenotonsillectomy and only 2 of them have OSA on the PSG results. Considering very close relationship between adenotonsillar hypertrophy in children and OSA, these children might have OSA in early childhood. Therefore, total 21 LQTS patients (65%) have OSA on the PSG and/or adenotonsillectomy. Presence of OSA is equally distributed in LQT1 and LQT2 genotypes. Conclusion: OSA is more common in patients with congenital LQTS compared to healthy matched controls. Apneic events during sleep are associated with exaggerated sympathetic responses which might be potential mechanisms for triggering arrhythmias and thus increased risk of SCD during sleep.
TCT-469 Percutaneous Coronary Intervention Performance in Spontaneous Coronary Artery Dissection: Insight From an Italian Multicenter Registry
Authors: Enrico Cerrato, Giorgio Quadri, Chiara Cavallino, Italo Porto, Luca Bettari, Alfonso Franzè, Luca Lo Savio, Andrea Demarchi, Francesco Rametta, Umberto Barbero, Cristina Rolfo, Marco Pavani, Fabio Ferrari, Alessandra Truffa Giachet, Gianluca Campo, Elisabetta Bordoni, Angelo Di Leo, Federico Beqaraj, Giuseppe Pietro Greco Lucchina, Francesco Cassano, Francesco Tomassini, Ferdinando Varbella
Journal: Journal of the American College of Cardiology (2019)
TCT-36 Clinical Predictors of Hypo-Attenuated Leaflet Thickening Following Transcatheter Aortic Valve Replacement With 320-Multislice Scanner: A Single-Center Experience
Authors: Hashrul Rashid, Michael Michail, Abdul Rahman Ihdayhid, Sean Tan, Nancy Khav, James Cameron, Arthur Nasis, Robert Gooley
Journal: Journal of the American College of Cardiology (2019)
Prophylactic technique for preventing inward stent migration during placement of multiple plastic stents in a patient with surgically altered anatomy
Authors: Kenta Kachi, Yasuki Hori, Kazuki Hayashi, Itaru Naitoh, Michihiro Yoshida, Hiromi Kataoka
Journal: Endoscopy (2019)

Endoscopic biliary stenting is a widely accepted method to treat benign and malignant biliary strictures [1] [2]. Multiple plastic stents are recommended for treating benign biliary strictures [3] [4]. However, there is a risk of inward migration of a previously placed stent during insertion of the subsequent stent owing to interference of the stent in the biliary stricture. In the case of surgically altered anatomy in particular, few suitable devices are available to remove a migrated stent from an inward bile duct, and it is difficult to recover the situation [5]. Therefore, it is necessary to prevent inward stent migration when placing multiple stents. Here, we report a prophylactic technique to place multiple plastic stents safely and reliably in a patient with a surgically altered anatomy ([Fig. 1]).
David Oliver: Vocation takes doctors only so far
Authors: David Oliver
Journal: BMJ (2019)

The word “vocation” is often raised in letters or online comments responding to stories about doctors and our training, terms, and conditions. But is it a useful concept or a justification for treating us poorly?

Remarks such as “It’s supposed to be a vocation” are used to criticise doctors who want decent pay settlements, more flexible or family friendly hours, or reduced clinical sessions to avoid punitive pension liabilities. It’s never long before someone says, “But they took the Hippocratic oath!” This is no longer the norm in every medical school (despite the myth), although its principles are still relevant to the ethics of modern practice.1 The subtext is that selfless dedication to patients and our profession should …
Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma
Authors: Michael E. Wechsler, Stanley J. Szefler, Victor E. Ortega, Jacqueline A. Pongracic, Vernon Chinchilli, John J. Lima, Jerry A. Krishnan, Susan J. Kunselman, David Mauger, Eugene R. Bleecker, Leonard B. Bacharier, Avraham Beigelman, Mindy Benson, Kathryn V. Blake, Michael D. Cabana, Juan-Carlos Cardet, Mario Castro, James F. Chmiel, Ronina Covar, Loren Denlinger, Emily DiMango, Anne M. Fitzpatrick, Deborah Gentile, Nicole Grossman, Fernando Holguin, Daniel J. Jackson, Harsha Kumar, Monica Kraft, Craig F. LaForce, Jason Lang, Stephen C. Lazarus, Robert F. Lemanske, Dayna Long, Njira Lugogo, Fernando Martinez, Deborah A. Meyers, Wendy C. Moore, James Moy, Edward Naureckas, J. Tod Olin, Stephen P. Peters, Wanda Phipatanakul, Loretta Que, Hengameh Raissy, Rachel G. Robison, Kristie Ross, William Sheehan, Lewis J. Smith, Julian Solway, Christine A. Sorkness, Lisa Sullivan-Vedder, Sally Wenzel, Steven White, Elliot Israel
Journal: New England Journal of Medicine (2019)

Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients.
Randomized Phase II Trial and Tumor Mutational Spectrum Analysis from Cabozantinib versus Chemotherapy in Metastatic Uveal Melanoma (Alliance A091201)
Authors: Jason J. Luke, Daniel J. Olson, Jacob B. Allred, Carrie A. Strand, Riyue Bao, Yuanyuan Zha, Timothy Carll, Brian W. Labadie, Bruno R. Bastos, Marcus O. Butler, David Hogg, Pamela N. Munster, Gary K. Schwartz
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The surface receptor MET is highly expressed on primary uveal melanoma; MET inhibitors demonstrated early clinical signals of efficacy in slowing uveal melanoma growth. The primary objective of our study was to compare the progression-free survival rate at 4 months (PFS4) of patients with uveal melanoma treated with cabozantinib or chemotherapy. Patients and Methods: Patients with metastatic uveal melanoma and RECIST measurable disease were randomized 2:1 to receive either cabozantinib (arm 1) versus temozolomide or dacarbazine (arm 2) with restaging imaging every two cycles. Cross-over from arm 2 to cabozantinib after progression was allowed (arm 2X). Available tumor specimens were analyzed by whole-exome sequencing (WES) and results were correlated with outcome. Results: Forty-six eligible patients were accrued with 31, 15, and 9 in arms 1, 2, and 2X, respectively. Median lines of prior therapy, including hepatic embolization, were two. Rates of PFS4 in arm 1 and arm 2 were 32.3% and 26.7% (P = 0.35), respectively, with median PFS time of 60 and 59 days (P = 0.964; HR = 0.99). Median overall survival (OS) was 6.4 months and 7.3 months (P = 0.580; HR = 1.21), respectively. Grade 3–4 Common Terminology Criteria for Adverse Events were present in 61.3%, 46.7%, and 37.5% in arms 1, 2, and 2X, respectively. WES demonstrated a mean tumor mutational burden of 1.53 mutations/Mb and did not separate OS ≤ or &amp;gt;1 year (P = 0.14). Known mutations were identified by WES and novel mutations were nominated. Conclusions: MET/VEGFR blockade with cabozantinib demonstrated no improvement in PFS but an increase in toxicity relative to temozolomide/dacarbazine in metastatic uveal melanoma.
RNA-Binding Protein <i>ZFP36L1</i> Suppresses Hypoxia and Cell-Cycle Signaling
Authors: Xin-Yi Loh, Qiao-Yang Sun, Ling-Wen Ding, Anand Mayakonda, Nachiyappan Venkatachalam, Mei-Shi Yeo, Tiago C. Silva, Jin-Fen Xiao, Ngan B. Doan, Jonathan W. Said, Xue-Bin Ran, Si-Qin Zhou, Pushkar Dakle, Pavithra Shyamsunder, Angele Pei-Fern Koh, Ruby Yun-Ju Huang, Benjamin P. Berman, Soo-Yong Tan, Henry Yang, De-Chen Lin, H. Phillip Koeffler
Journal: Cancer Research (2019)

Abstract ZFP36L1 is a tandem zinc-finger RNA-binding protein that recognizes conserved adenylate-uridylate–rich elements (ARE) located in 3′untranslated regions (UTR) to mediate mRNA decay. We hypothesized that ZFP36L1 is a negative regulator of a posttranscriptional hub involved in mRNA half-life regulation of cancer-related transcripts. Analysis of in silico data revealed that ZFP36L1 was significantly mutated, epigenetically silenced, and downregulated in a variety of cancers. Forced expression of ZFP36L1 in cancer cells markedly reduced cell proliferation in vitro and in vivo, whereas silencing of ZFP36L1 enhanced tumor cell growth. To identify direct downstream targets of ZFP36L1, systematic screening using RNA pull-down of wild-type and mutant ZFP36L1 as well as whole transcriptome sequencing of bladder cancer cells {plus minus} tet-on ZFP36L1 was performed. A network of 1,410 genes was identified as potential direct targets of ZFP36L1. These targets included a number of key oncogenic transcripts such as HIF1A, CCND1, and E2F1. ZFP36L1 specifically bound to the 3′UTRs of these targets for mRNA degradation, thus suppressing their expression. Dual luciferase reporter assays and RNA electrophoretic mobility shift assays showed that wild-type, but not zinc-finger mutant ZFP36L1, bound to HIF1A 3′UTR and mediated HIF1A mRNA degradation, leading to reduced expression of HIF1A and its downstream targets. Collectively, our findings reveal an indispensable role of ZFP36L1 as a posttranscriptional safeguard against aberrant hypoxic signaling and abnormal cell-cycle progression. Significance: RNA-binding protein ZFP36L1 functions as a tumor suppressor by regulating the mRNA stability of a number of mRNAs involved in hypoxia and cell-cycle signaling.
A ceRNA Circuitry Involving the Long Noncoding RNA Klhl14-AS, Pax8, and Bcl2 Drives Thyroid Carcinogenesis
Authors: Sara C. Credendino, Maria L. Bellone, Nicole Lewin, Elena Amendola, Remo Sanges, Swaraj Basu, Romina Sepe, Myriam Decaussin-Petrucci, Nadia Tinto, Alfredo Fusco, Mario De Felice, Gabriella De Vita
Journal: Cancer Research (2019)

Klhl14-AS is a long noncoding RNA expressed since early specification of thyroid bud and is the most enriched gene in the mouse thyroid primordium at E10.5. Here, we studied its involvement in thyroid carcinogenesis by analyzing its expression in cancer tissues and different models of neoplastic transformation. Compared with normal thyroid tissue and cells, Klhl14-AS was significantly downregulated in human thyroid carcinoma tissue specimens, particularly the anaplastic histotype, thyroid cancer cell lines, and rodent models of thyroid cancer. Downregulating the expression of Klhl14-AS in normal thyroid cells decreased the expression of thyroid differentiation markers and cell death and increased cell viability. These effects were mediated by the binding of Klhl14-AS to two miRNAs, Mir182-5p and Mir20a-5p, which silenced Pax8 and Bcl2, both essential players of thyroid differentiation. MIR182-5p and MIR20a-5p were upregulated in human thyroid cancer and thyroid cancer experimental models and their effects on Pax8 and Bcl2 were rescued by Klhl14-AS overexpression, confirming Klhl14-AS as a ceRNA for both Pax8 and Bcl2. This work connects deregulation of differentiation with increased proliferation and survival in thyroid neoplastic cells and highlights a novel ceRNA circuitry involving key regulators of thyroid physiology.
The Risk and Cost of Limited Clinician and Patient Accountability in Health Care
Authors: S. Claiborne Johnston
Journal: JAMA (2019)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Pain severity and use of analgesic medication in adults with atopic dermatitis: a cross‐sectional study
Authors: J.P. Thyssen, A.‐S. Halling‐Sønderby, J.J. Wu, A. Egeberg
Journal: British Journal of Dermatology (2019)

Adult patients with atopic dermatitis (AD) report skin pain, but the relationship with disease severity, anatomical location and use of pain medication is unclear. To examine pain in adults with AD. We performed a cross‐sectional study of nationwide healthcare data and survey data from the Danish Skin Cohort. In total, 3208 randomly selected adults from the general population and 3834 adults with a dermatologist‐verified diagnosis of AD present in adulthood were included. Patient‐Oriented SCORing Atopic Dermatitis determined AD severity, and numerical rating scales estimated the severity of pruritus and skin pain. Complete information on the use of analgesic medication was obtained from the Danish nationwide prescription registry. Respectively, 6·8%, 55·5%, 34·0% and 3·7% of the AD cohort reported that they were asymptomatic, or had mild, moderate or severe disease at the time of assessment. Skin pain was positively associated with AD severity and itch. Higher skin pain scores were observed in plantar, chest and palmar areas. Use of pain medication was not increased in patients with AD. Patients with AD did not display increased use of pain medication, but few had severe disease. The close relationship observed between itch and pain highlights the potential benefits of established AD treatments to also reduce skin pain in AD. What's already known about this topic? There is increased awareness about skin pain being a significant burden of atopic dermatitis (AD). What does this study add? We found that skin pain is increased with AD severity and itch. The comparable use of pain medication in patients with AD and controls suggests that dermatological treatments reduce skin pain.
TCT-560 Impact of Infrapopliteal Run-Off on Clinical Outcomes Following Endovascular Intervention in Patients With Iliac and Superficial Femoral Arterial Disease
Authors: Woohyeun Kim, Seung-Woon Rha, Byoung Geol Choi, Se Yeon Choi, Jae Kyeong Byun, Won Young Jang, Yoonjee Park, Dong Oh Kang, Ja Yeon Choi, Jin Oh Na, Cheol Ung Choi, Chang Gyu Park, Hong Seog Seo
Journal: Journal of the American College of Cardiology (2019)