tbuckley/cabot-search huggingface dataset:
Abstract 2448: Chemotherapy drug-induced AXL activation and cell survival signaling via reactive oxygen species that can be inhibited to enhance drug efficacy in mesothelioma
Authors: Derek B. Oien, Tamás Garay, Sarah Eckstein, Jeremy Chien
Journal: Cancer Research (2018)

Abstract Cellular oxidative stress is characterized by elevated reactive oxygen species (ROS), and is a frequent phenotype of cancer cells. The consequences of ROS are complex, where ROS can promote or inhibit tumorigenesis. In mesothelioma, asbestos exposure to serous membranes induces ROS through iron content and chronic inflammation, and ROS promote cell survival signaling in mesothelioma. On the other hand, a current chemotherapy regime for mesothelioma consisting of a platinum and antifolate agent combination also induce ROS. Mesothelioma is notoriously chemotherapy-resistant, and we propose that ROS induced by cisplatin and pemetrexed may promote cell survival signaling pathways, which ultimately may contribute to chemotherapy resistance. In The Cancer Genome Atlas datasets, we found AXL kinase expression is relatively high in mesothelioma compared to other cancer samples. We showed that ROS induce the phosphorylation of AXL, which was blocked by the selective inhibitor BGB324 in VMC40 and P31 mesothelioma cells. We also showed that cisplatin and pemetrexed induce the phosphorylation of AXL and Akt, which was also blocked by BGB324 as well as by N-acetylcysteine antioxidant. AXL knockdown in these cells enhances sensitivity to cisplatin and pemetrexed. Similarly, AXL inhibitor BGB324 also enhances sensitivity to cisplatin and pemetrexed. Finally, higher synergy was observed when cells were pretreated with BGB324 before adding chemotherapy. These results demonstrate cisplatin and pemetrexed induce ROS that activate AXL, and blocking AXL activation enhances the efficacy of cisplatin and pemetrexed. These results suggest AXL inhibition may represent an effective strategy to enhance the efficacy of chemotherapy in mesothelioma. We further hypothesize AXL signaling may be part of an adaptive response to chemotherapeutic agents, providing transient resistance to cisplatin and pemetrexed that may ultimately contribute to acquired chemotherapy resistance. Citation Format: Derek B. Oien, Tamás Garay, Sarah Eckstein, Jeremy Chien. Chemotherapy drug-induced AXL activation and cell survival signaling via reactive oxygen species that can be inhibited to enhance drug efficacy in mesothelioma [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 2448.
Politics and Professionalism
Authors: William Berger
Journal: Annals of Internal Medicine (2018)

Letters7 August 2018Politics and ProfessionalismWilliam Berger, MDWilliam Berger, MDMedical College of Wisconsin, Milwaukee, Wisconsin (W.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L18-0240 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I appreciate Sexauer's insights (1) and wish to expand on 2 of his many valid points. Professionalism cannot be taught online. Vague lists of generally accepted virtuous actions are of little use in understanding the nature and purpose of professionalism or in reliably guiding behavior. Before the term “professional” was co-opted to describe playing golf for money, it meant publicly professing a commitment to one's vocation. This transformative oath explicitly changes one's very identity and defines a new, special relationship to those the vocation serves. It is the culmination of one's calling. By this oath, one submits ...Reference1. Sexauer WP. Politics and professionalism. Ann Intern Med. 2018;168:299-300. [PMID: 29459970]. doi:10.7326/M16-2926 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Medical College of Wisconsin, Milwaukee, Wisconsin (W.B.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L18-0240. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoPolitics and Professionalism William P. Sexauer Politics and Professionalism William P. Sexauer Metrics 7 August 2018Volume 169, Issue 3Page: 203-204KeywordsArmed forcesBehaviorConflicts of interestDisclosureSexual identity ePublished: 7 August 2018 Issue Published: 7 August 2018 PDF downloadLoading ...
Abstract 3879: Enhancement of tumor penetration by drug-loaded nanoparticles: An innovative targeted strategy for neuroblastoma
Authors: Mirco Ponzoni, Chiara Brignole, Laura Emionite, Silvia Bruno, Daniela Guarnieri, Leopoldo Sitia, Matteo Bauckneht, Ambra Buschiazzo, Andrea Rossi, Daniela Di Paolo, Patrizia Perri, Flavio Curnis, Alessandro Gori, Angela Rita Sementa, Michele Cilli, Pier Paolo Pompa, Gianmario Sambuceti, Angelo Corti, Fabio Pastorino
Journal: Cancer Research (2018)

Abstract Background: Anti-cancer drugs-loaded targeted nanocarriers can reduce side-effects and improve therapeutic efficacy in preclinical studies. However, poorly perfused and dysfunctional tumour vessels limit the transport of the payload into the parenchyma of solid tumours. The use of tumour-penetrating nanocarriers might enhance tumour penetration and anti-tumour effects. Methods: A consensus motif, mediator of tissue penetration (TP) was added to a previously characterized neuroblastoma (NB)-targeting peptide (pep). In vitro NB cell association and internalization of TP-pep, either free or coupled to Stealth Liposomes (SL), were tested by FACS and confocal microscopy. In vitro cytotoxic potential of a novel doxorubicin (DXR)-loaded liposomal (TP-pep-SL[DXR]) was evaluated by MTS assay. Three mouse xenograft models mimicking the growth and spread of NB in humans (injection routes: subcutaneous; adrenal gland; tail vein) were enrolled to examine in vivo penetration, vascular permeability, tumour glucose consumption and sensitivity in response to TP-pep-SL[DXR]. Results: Compared to pep, TP-pep increases its cellular association in vitro on cell lines and cells derived from NB patients. When coupled to SL, TP-pep enhances liposomes penetration and cytotoxic effects in vitro and increases binding and penetration in a mouse model of NB. Moreover, in vivo accumulation of Evans Blue dye within the tumour mass reveals that TP-pep-SL[DXR] increases the tumour vascular permeability into NB tumour mass, but not in non-tumour tissues. Compared to pep-targeted liposomes, TP-pep-SL[DXR] leads to an increased anti-NB effect towards all the animal models tested. Conclusion: Our findings demonstrate that the enhancement of tumour penetration by drug-loaded nanoparticles might represent an innovative targeted strategy for NB. Citation Format: Mirco Ponzoni, Chiara Brignole, Laura Emionite, Silvia Bruno, Daniela Guarnieri, Leopoldo Sitia, Matteo Bauckneht, Ambra Buschiazzo, Andrea Rossi, Daniela Di Paolo, Patrizia Perri, Flavio Curnis, Alessandro Gori, Angela Rita Sementa, Michele Cilli, Pier Paolo Pompa, Gianmario Sambuceti, Angelo Corti, Fabio Pastorino. Enhancement of tumor penetration by drug-loaded nanoparticles: An innovative targeted strategy for neuroblastoma [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 3879.
Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention
Authors: Dominick J. Angiolillo, Deepak L. Bhatt, Christopher P. Cannon, John W. Eikelboom, C. Michael Gibson, Shaun G. Goodman, Christopher B. Granger, David R. Holmes, Renato D. Lopes, Roxana Mehran, David J. Moliterno, Matthew J. Price, Jacqueline Saw, Jean-Francois Tanguay, David P. Faxon
Journal: Circulation (2021)

A growing number of patients undergoing percutaneous coronary intervention (PCI) with stent implantation also have atrial fibrillation. This poses challenges for their optimal antithrombotic management because patients with atrial fibrillation undergoing PCI require oral anticoagulation for the prevention of cardiac thromboembolism and dual antiplatelet therapy for the prevention of coronary thrombotic complications. The combination of oral anticoagulation and dual antiplatelet therapy substantially increases the risk of bleeding. Over the last decade, a series of North American Consensus Statements on the Management of Antithrombotic Therapy in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention have been reported. Since the last update in 2018, several pivotal clinical trials in the field have been published. This document provides a focused updated of the 2018 recommendations. The group recommends that in patients with atrial fibrillation undergoing PCI, a non–vitamin K antagonist oral anticoagulant is the oral anticoagulation of choice. Dual antiplatelet therapy with aspirin and a P2Y 12 inhibitor should be given to all patients during the peri-PCI period (during inpatient stay, until time of discharge, up to 1 week after PCI, at the discretion of the treating physician), after which the default strategy is to stop aspirin and continue treatment with a P2Y 12 inhibitor, preferably clopidogrel, in combination with a non–vitamin K antagonist oral anticoagulant (ie, double therapy). In patients at increased thrombotic risk who have an acceptable risk of bleeding, it is reasonable to continue aspirin (ie, triple therapy) for up to 1 month. Double therapy should be given for 6 to 12 months with the actual duration depending on the ischemic and bleeding risk profile of the patient, after which patients should discontinue antiplatelet therapy and receive oral anticoagulation alone.
Abstract 17137: Safety and Effectiveness of Dabigatran Relative to Warfarin in Routine Clinical Practice - New Interim Results of Long-term Study Program
Authors: John D Seeger, Dorothee B Bartels, Krista Huybrechts, Chandrasekar Gopalakrishnan, Katsiaryna Bykov, Kristina Zint, Sebastian Schneeweiss
Journal: Circulation (2015)

Background: Dabigatran etexilate is a newer oral anticoagulant developed as an alternative to warfarin for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Although the efficacy and safety of dabigatran were established in a randomized trial, evaluation of its effects in routine clinical practice is ongoing. Objectives: Quantification of the comparative safety and effectiveness of dabigatran in routine care within two large US commercial health insurance databases (Truven MarketScan and Optum Clinformatics) Methods: Cohort design with propensity score (PS) matching to compare new initiators of dabigatran with warfarin between October 2010 and June 2013. Primary outcomes were stroke and major bleeding. Proportional hazards regression of time to outcome was conducted separately within each data source and results were pooled. Results: There were 22,736 PS matched dabigatran and warfarin initiators with NVAF pooled across data sources (MarketScan 18,726; Optum 4,010). The matching resulted in well balanced cohorts with no individual characteristic (including stroke and bleeding risk factors) having a standardized difference of greater than 0.1. The average follow-up for the as-treated analyses was 5 months for dabigatran and 4 months for warfarin. There were 69 strokes amongst dabigatran initiators and 84 strokes amongst warfarin initiators for a pooled HR of 0.71 (95% CI 0.51 – 0.98) (MarketScan HR = 0.65, 95% CI=0.45-0.93, Clinformatics HR = 1.05, 95% CI = 0.50-2.19). For the outcome of major hemorrhage, there were 429 events amongst dabigatran initiators and 480 events amongst warfarin initiators for a pooled HR of 0.77, 95% CI = 0.68 – 0.88) (MarketScan HR = 0.80, 95% CI = 0.70 - 0.92, Clinformatics HR = 0.55, 95% CI = 0.37 - 0.82). Pooled results in the full cohort were fairly consistent across numerous subgroup and sensitivity analyses, however, comparative conclusions within some subgroups are limited by small numbers and limited follow-up time. Conclusions: Analyses from this ongoing sequential long-term study program suggest a reduced risk of both stroke and major hemorrhage for dabigatran relative to warfarin. Continued follow-up will increase the sample size, permitting greater precision in effect estimates.
Extensively drug-resistant tuberculosis in South Africa: genomic evidence supporting transmission in communities
Authors: Sara C. Auld, N. Sarita Shah, Barun Mathema, Tyler S. Brown, Nazir Ismail, Shaheed Vally Omar, James C.M. Brust, Kristin N. Nelson, Salim Allana, Angela Campbell, Koleka Mlisana, Pravi Moodley, Neel R. Gandhi
Journal: European Respiratory Journal (2018)

Despite evidence that transmission is driving an extensively drug-resistant TB (XDR-TB) epidemic, our understanding of where and between whom transmission occurs is limited. We sought to determine whether there was genomic evidence of transmission between individuals without an epidemiologic connection. We conducted a prospective study of XDR-TB patients in KwaZulu-Natal, South Africa, during the 2011–2014 period. We collected sociodemographic and clinical data, and identified epidemiologic links based on person-to-person or hospital-based connections. We performed whole-genome sequencing (WGS) on the Mycobacterium tuberculosis isolates and determined pairwise single nucleotide polymorphism (SNP) differences. Among 404 participants, 123 (30%) had person-to-person or hospital-based links, leaving 281 (70%) epidemiologically unlinked. The median SNP difference between participants with person-to-person and hospital-based links was 10 (interquartile range (IQR) 8–24) and 16 (IQR 10–23), respectively. The median SNP difference between unlinked participants and their closest genomic link was 5 (IQR 3–9) and half of unlinked participants were within 7 SNPs of at least five participants. The majority of epidemiologically-unlinked XDR-TB patients had low pairwise SNP differences with at least one other participant, consistent with transmission. These data suggest that much of transmission may result from casual contact in community settings between individuals not known to one another.
Abstract LB-380: TMB calling in absence of matched normal: Learning germline behavior
Authors: Yiqing Tian, Wendell Jones, Natalie Mola, Victor J. Weigman
Journal: Cancer Research (2018)

Abstract In most standard cases, mutational burden is derived from samples where mutational calling is performed in tumor and matched normal specimens. While this is ideal to get a true sense of tumor-derived mutations, it creates limitations due to cost of extra sequencing or in many trials, unavailable for genomic profiling. Without this normal material, there are increased difficulties of eliciting the accurate somatic mutation calls away from natural variation. This is even further complicated by the fact that different tumor types have different spectra of mutations so a method built on an individual indication have risks of overfitting. We present here the results of our investigations of machine learning to build reliable germline variant estimates appropriate for use in calculating burden. In this draft, we examine two tumor mutation classification methods based on our latest TMB tool: random forest and neural network across multiple indications in TCGA. We compare calls made by these methods against burden scores that we have generated from our own paired tumor/normal method (sister submission) to determine accuracy. Using sampled tumor results from each indication, different models were built across both random forest and neural networks, showing accuracy in some indications, up to 98%. Looking to work to create and indication-independent classifier, validation results show we can reach an average of 89% accuracy where training is built across all indications. In all cases, cross validation was performed to prove the consistency of the classification method and test the algorithm on our latest tumor only data set against what was generated from paired results. Citation Format: Yiqing Tian, Wendell Jones, Natalie Mola, Victor J. Weigman. TMB calling in absence of matched normal: Learning germline behavior [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 LB-380.
RBFOX2 and alternative splicing in B-cell lymphoma
Authors: Hilmar Quentmeier, Claudia Pommerenke, Stephan H. Bernhart, Wilhelm G. Dirks, Vivien Hauer, Steve Hoffmann, Stefan Nagel, Reiner Siebert, Cord C. Uphoff, Margarete Zaborski, Hans G. Drexler
Journal: Blood Cancer Journal (2018)

RBFOX2 is a master regulator of alternative splicing 1 .This RNA-binding protein (RBP) is expressed in the brain 2 , muscle 3 , and embryonic stem cells 4 .RBFOX2 is required not only for the proper splicing of target RNAs, but also for cerebellar development 2 , myogenesis 3 , and for survival of human embryonic stem cells 4 .Hitherto, not much is known about the expression and function of RBFOX2 in hematopoetic tissues.In an early report, RBFOX2 had been shown to be capable of promoting inclusion of exon16 in protein 4.1R 5 .This splicing event is important for erythropoiesis because it increases the affinity of 4.1R for target genes 5 .In a recent study, expression of RBFOX2 was detected in the human T-cell line JURKAT and a functional antagonism of the RBPs RBFOX2 and CELF2 was demonstrated 6 .We wanted to describe the expression patterns of RBFOX2 in hematopoetic malignancies, to discover target genes and to unravel the consequence of RBFOX2 repression for target gene splicing and isoform expression.Expression array and Western blot analysis showed that human B non-Hodgkin lymphoma (B-NHL) cell lines are RBFOX2 negative or positive (Supplement 1A).To find the potential targets of the splice factor RBFOX2, we compared the expression of individual exons in RBFOX2negative and RBFOX2-positive cell lines.This approach relied on the assumption that the differential expression of this RBP would provoke changes in the expression of individual exons and would thereby allow identification of target genes.Supplement 1B shortlists these genes
Sleep and Exertional Periodic Breathing in Chronic Heart Failure
Authors: UgoCorrà, MassimoPistono, AlessandroMezzani, AlbertoBraghiroli, AndreaGiordano, PaolaLanfranchi, EnzoBosimini, MarcoGnemmi, PantaleoGiannuzzi
Journal: Circulation (2006)

Background— Sleep and exertional periodic breathing are proverbial in chronic heart failure (CHF), and each alone indicates poor prognosis. Whether these conditions are associated and whether excess risk may be attributed to respiratory disorders in general, rather than specifically during sleep or exercise, is unknown. Methods and Results— We studied 133 CHF patients with left ventricular ejection fraction (LVEF) ≤40%. During 1170±631 days of follow-up, 31 patients (23%) died. Nonsurvivors had higher New York Heart Association class, ventilatory response (Ve/Vco2 slope), and apnea-hypopnea index (AHI) and lower peak Vo2 (all P<0.01); lower LVEF and prescription of β-blockers, and shorter transmitral deceleration time (all P<0.05). Exertional oscillatory ventilation (EOV), established by cyclic fluctuations in minute ventilation that persisted for ≥60% of exercise duration with an amplitude ≥15% of the average resting value, was significantly more frequent in nonsurvivors (42% versus 15%, P<0.01). Mult...
Elevated Blood Pressure in Pregnancy and Subsequent Chronic Disease Risk
Authors: TuijaMännistö, PaulineMendola, MarjaVääräsmäki, Marjo-RiittaJärvelin, Anna-LiisaHartikainen, AnneliPouta, EilaSuvanto
Journal: Circulation (2013)

Background—Preeclampsia, a new-onset hypertensive disorder of pregnancy, is associated with lifetime cardiovascular disease risk, but less is known about risk after other pregnancy-related hypertension. Methods and Results—The Northern Finland Birth Cohort 1966 included all expected births from 1 year (N=12 055 women). Blood pressure measurements and other prospective data were determined from prenatal care records and questionnaires for 10 314 women. Subsequent diagnoses were ascertained from Finnish registries (average follow-up, 39.4 years). Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) estimate risks in hypertensive women compared with normotensive women. Hypertension during pregnancy was associated with increased risk of subsequent cardiovascular disease and arterial hypertension. Women with chronic hypertension and superimposed preeclampsia/eclampsia had high risk for future diseases. Gestational hypertension was associated with increased risk of ischemic heart disease (HR, 1.44 [...
Mechanisms of Ischemic Preconditioning in Rat Hearts
Authors: KeliHu, StanleyNattel
Journal: Circulation (1995)

Background Ischemic preconditioning attenuates the effects of subsequent sustained ischemia by a mechanism involving adenosine and G proteins in several species. Adenosine is not involved in ischemic preconditioning of rat hearts, the mechanisms of which are poorly understood. Methods and Results Reduction of isometric tension development was used as an index of the effects of ischemia in isolated, Langendorff-perfused rat hearts. Two 5-minute periods of ischemia followed by 10 minutes of reperfusion attenuated the reduction of developed tension caused by 30 minutes of ischemia and 15 minutes of reperfusion. Pretreatment with pertussis toxin (PTX), depletion of norepinephrine stores with reserpine, or blockade of α1-adrenoceptors with prazosin prevented the effects of ischemic preconditioning. Whereas α1B-receptor blockade with chloroethylclonidine blocked ischemic preconditioning, α1A-receptor blockade with 5-methylurapadil had no effect. The α-adrenergic agonist phenylephrine mimicked the effects of isc...