tbuckley/cabot-search huggingface dataset:
Immuno-oncological Efficacy of RXDX-106, a Novel TAM (TYRO3, AXL, MER) Family Small-Molecule Kinase Inhibitor
Authors: Yumi Yokoyama, Erin D. Lew, Ruth Seelige, Elizabeth A. Tindall, Colin Walsh, Patrick C. Fagan, Jack Y. Lee, Robin Nevarez, Joanne Oh, Kathleen D. Tucker, Marissa Chen, Amy Diliberto, Heather Vaaler, Kristen M. Smith, Amanda Albert, Gary Li, Jack D. Bui
Journal: Cancer Research (2019)

Expression of the TAM (TYRO3, AXL, MER) family of receptor tyrosine kinases (RTK) has been associated with cancer progression, metastasis, and drug resistance. In immune cells, TAM RTKs can dampen inflammation in favor of homeostatic wound-healing responses, thus potentially contributing to the evasion of cancer cells from immune surveillance. Here we characterize the small-molecule RXDX-106 as a selective and potent pan-TAM RTK inhibitor with slow dissociation kinetics and significant antitumor activity in multiple syngeneic tumor models. Expression of AXL and MER on both immune and tumor cells increased during tumor progression. Tumor growth inhibition (TGI) following treatment with RXDX-106 was observed in wild-type mice and was abrogated in immunodeficient mice, suggesting that the antitumor activity of RXDX-106 is, in part, due to the presence of immune cells. RXDX-106-mediated TGI was associated with increased tumor-infiltrating leukocytes, M1-polarized intratumoral macrophages, and activation of natural killer cells. RXDX-106 proportionally increased intratumoral CD8+ T cells and T-cell function as indicated by both IFNγ production and LCK phosphorylation (pY393). RXDX-106 exhibited its effects via direct actions on TAM RTKs expressed on intratumoral macrophages and dendritic cells, leading to indirect activation of other immune cells in the tumor. RXDX-106 also potentiated the effects of an immune checkpoint inhibitor, α-PD-1 Ab, resulting in enhanced antitumor efficacy and survival. Collectively, these results demonstrate the capacity of RXDX-106 to inhibit tumor growth and progression and suggest it may serve as an effective therapy against multiple tumor types. SIGNIFICANCE: The pan-TAM small-molecule kinase inhibitor RXDX-106 activates both innate and adaptive immunity to inhibit tumor growth and progression, indicating its clinical potential to treat a wide variety of cancers.
Use of Extracorporeal Photopheresis (ECP) in the Treatment of Patients with Cutaneous T-Cell Lymphoma (CTCL), 2010-2015
Authors: You-Li Ling, Xingyue Huang, Ghaith Mitri, An Pham, Belinda Lovelace, Robert M. Knobler, Xin Gao
Journal: Blood (2017)
Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1–2 trial
Authors: Johann S de Bono, Nicole Concin, David S Hong, Fiona C Thistlethwaite, Jean-Pascal Machiels, Hendrik-Tobias Arkenau, Ruth Plummer, Robert Hugh Jones, Dorte Nielsen, Kristian Windfeld, Srinivas Ghatta, Brian M Slomovitz, James F Spicer, Jeffrey Yachnin, Joo Ern Ang, Paul Morten Mau-Sørensen, Martin David Forster, Dearbhaile Collins, Emma Dean, Reshma A Rangwala, Ulrik Lassen
Journal: The Lancet Oncology (2019)
bTMB-High Basket trial: A multicenter phase II trial of nivolumab monotherapy in patients with advanced gastrointestinal cancers with high blood tumor mutational burden (bTMB).
Authors: Yoshiaki Nakamura, Yoshito Komatsu, Ken Kato, Eiji Shinozaki, Hideaki Bando, Takeshi Kato, Tomohiro Nishina, Taito Esaki, Shogo Nomura, Gakuto Ogawa, Ayako Sugama, Miki Fukutani, Akihiro Sato, Justin Odegaard, Takeshi Kuwata, Kouji Matsushima, Tetsuya Nakatsura, Hiromichi Nakajima, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2019)

TPS179 Background: Tumor mutational burden (TMB) is an emerging biomarker for immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Analysis of circulating tumor DNA (ctDNA) has been reported to effectively identify patients likely to respond to ICIs by effectively and non-invasively evaluating the TMB in the tumor in NSCLC and gastric cancer. Methods: We are conducting an investigator-initiated multicenter phase II basket trial to investigate efficacy and safety of nivolumab monotherapy in patients with advanced gastrointestinal (GI) cancers with high bTMB identified by ctDNA analysis as part of the Nationwide Cancer Genome Screening Project (SCRUM-Japan GI-SCREEN). Eligibility criteria include histologically confirmed unresectable or recurrent GI malignancies; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and high bTMB identified by a 73-gene sequencing ctDNA panel (Guardant360) regardless of microsatellite instability status. Patients will be enrolled into one of four disease-specific cohorts (colorectal, gastric, esophageal, and other GI cancer cohort), and receive intravenous nivolumab monotherapy of 360 mg every 3 weeks. The bTMB score is calculated by adjustment of mutation count by tumor fraction, and tentative bTMB level cut-offs were determined according to objective response rate (ORR) reported for ICI treatment for each tumor subtype in previous trials. The trial will utilize a two-stage design with a Bayesian hierarchical model, and tentative bTMB level cut-off will be re-assessed in the first stage. Primary endpoint in each stage is the disease control rate at 6 week and the ORR assessed by investigators per RECIST v1.1, respectively. Target sample size is determined as 70 in total so that the statistical power in each disease-specific cohort calculated based on a Bayesian posterior distribution attains 70 to 80% with one-sided alpha level in each cohort of approximately 10%. For biomarker analysis, tumor tissue and ctDNA will be serially collected and analyzed by whole-exome, transcriptome, and T cell receptor sequencing. This trial was initiated since September 2018. Clinical trial information: UMIN000033182.
Abstract 17996: Is There Gender Differences in Effect of CYP2C19 Polymorphisms or Low-grade Inflammation on Coronary Microvascular Disorder (CMVD)?
Authors: tomonori akasaka, Seiji Hokimoto, Hisao Ogawa
Journal: Circulation (2015)

Background: Specific CYPs localized in vascular smooth muscle and endothelium contribute to the regulation of vascular tone and homeostasis. CYP2C19 poor metabolizer(PM) is reported to be an independent risk factor for coronary artery disease. And, CYP2C19 PM is correlated with an increase in the circulating levels of hs-CRP in female. However, it is unknown whether CYP2C19 genotype is associated with the coronary microvascular disorder (CMVD).So, we examined gender differences in effect of CYP2C19 genotype and low grade inflammation on CMVD. Methods: We examined CYP2C19 genotypes in patients with CMVD (n=54) diagnosed by an intracoronary acetylcholine infusion test, with healthy subjects (n=76) serving as the control. CMVD was defined as the presentation of no coronary artery stenosis in angiography, no epicardial spasms, inversion of lactic acid levels between intracoronary and coronary sinuses in the intracoronary acetylcholine-provocation test, and an adenosine triphosphate-induced CFR&lt;2.5. CYP2C19 genotypes were divided into 3 groups: (1) CYP2C19*1/*1 , extensive metabolizer (EM), (2) one loss-of-function allele (*1/*2, *1/*3; intermediate metabolizer [IM]), and (3) two loss-of-function alleles (*2/*2, *2/*3, *3/*3;[PM]). Results: The ratios of CYP2C19 genotype (EM,IM,and PM) were 31,39,and 30% in CMVD , and 32,49,and 19% in control. There is no significant difference in frequency of CYP2C19 genotype in overall (P=0.146). But, PM frequency was significantly higher in CMVD in only female (34% vs 16%, P=0.042). In level of hs-CRP, there is no significant difference between CMVD and control (0.111±0.080 vs 0.083±0.128,P=0.122), but significantly higher in CMVD in only female (0.112±0.106 vs 0.066±0.106,P=0.002). Moreover, in CMVD, mean of hs-CRP in CYP2C19 PM is significantly higher than that of EM in female (0.115±0.074 vs 0.046±0.039,P=0.034). Multivariate analysis for CMVD indicated that hypertension and chronic kidney disease are predictive factors among all subjects (OR 3.931,P=0.003, OR 3.146,P=0.026). High level of hs-CRP and CYP2C19 PM are predictive factors for CMVD in only female (OR3.864,P=0.047, OR6.079,P=0.042). Conclusion: CYP2C19 PM and low grade inflammation may be associated with CMVD, especially in female.
A CRISPR/Cas9 Based Kinome Screen Identifies Bruton Tyrosine Kinase (BTK) As an Important Determinant of Asparaginase Treatment Response in Acute Lymphoblastic Leukemia
Authors: Miriam Butler, Laurens Van Der Meer, Jiangyan Yu, Silvia Jenni, Maria Pamela Dobay, Peter Hoogerbrugge, Beat Bornhauser, Jean-Pierre Bourquin, Roland P. Kuiper, Frank van Leeuwen
Journal: Blood (2017)
Coarctation of the Aorta
Authors: Carl L. Backer, Kerry Paape, Vincent R. Zales, Thomas J. Weigel, Constantine Mavroudis
Journal: Circulation (1995)

Background The first successful surgical repair of coarctation of the aorta (CoAo) was performed in 1944, but during the years that followed a high incidence of recoarctation was seen, ranging from 20% to 86%. In response to that problem, the patch aortoplasty was introduced in 1957; however, true aneurysms were found in the aortic wall opposite the patch after Dacron patch aortoplasty, particularly when the coarctation ridge was excised. The purpose of our review was to evaluate the results of patch aortoplasty for CoAo using a relatively new material, polytetrafluoroethylene (PTFE), and an operative technique that does not involve resection of the coarctation ridge. Methods and Results Between 1979 and 1993, 125 infants and children underwent PTFE patch aortoplasty for CoAo; 111 of the procedures were primary repairs, and 14 were reoperations. Diagnoses were isolated CoAo (96 patients), CoAo and ventricular septal defect (15 patients), and CoAo with complex intracardiac anomaly (14 patients). Patient age at the time of repair ranged from 4 days to 17 years (mean age, 5.1±4.5 years). There were no instances of intraoperative mortality or paraplegia. There were 4 deaths from 10 to 40 days postoperatively, all in neonates (mean age, 33 days) who received additional intracardiac procedures for complex associated anomalies. Follow-up has ranged from 6 months to 12.5 years (mean, 4.5±3.2 years). All children had postoperative chest roentgenograms, 80 (66%) patients have had a postoperative echocardiogram and 16 (13%) a cardiac catheterization. One patient had successful repair of a false aneurysm 4 months postoperatively. No patient has developed a late true aneurysm. Of the patients &lt;1 month of age at the time of CoAo repair (12 patients), 6 patients had recurrent CoAo (gradient &gt;20 mm Hg) compared with only 4 recurrences in 97 patients &gt;1 month of age at the time of repair ( P &lt;.001). Conclusions For children &gt;1 year of age, PTFE patch aortoplasty remains our procedure of choice for CoAo repair because of the low mortality rate, low recoarctation rate, and absence of late true aneurysms. We have stopped using this technique for infants &lt;1 month of age because of the high recurrence rate.
Regarding a Letter to a Dying Friend
Authors: Lawrence J. Hergott
Journal: Annals of Internal Medicine (2019)

Ad Libitum19 February 2019Regarding a Letter to a Dying FriendLawrence J. Hergott, MDLawrence J. Hergott, MDCenter for Bioethics and Humanities, University of Colorado School of Medicine, Denver, Colorado (L.J.H.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M18-2537 Audio Reading - “Regarding a Letter to a Dying Friend” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Regarding a Letter to a Dying Friend," by L.J. Hergott. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Through long hours and too many deaths,this I have learned:every word counts now.Your friend spends his daysconsumed by the news.He needs you.Choose your words thoughtfully,and not about you.Write nothing that derailsor otherwise impairsthe one with little time left.Write something soon that kindlesyour bond.Thank him for enriching your life,and for his many affectionscompelling you to write to him.Tell him of your heavy sadnessto learn that the tumor had spread,that the agonizing treatments had failed.Manifest respect,and concern,never pity.Tell him how moved you areby his courage.Emphasize the obvious in him-no surprise-an unremitting sense ofstrength,and grace.... Author, Article, and Disclosure InformationAffiliations: Center for Bioethics and Humanities, University of Colorado School of Medicine, Denver, Colorado (L.J.H.)Current Author Address: Lawrence J. Hergott, MD; e-mail, [email protected]net. PreviousarticleNextarticle Advertisement Audio Reading - “Regarding a Letter to a Dying Friend” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Regarding a Letter to a Dying Friend," by L.J. Hergott. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 19 February 2019Volume 170, Issue 4Page: 274KeywordsMemory ePublished: 19 February 2019 Issue Published: 19 February 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract 15548: Temporal Effects of Targeted Release of Recombinant Tissue Inhibitor of Matrix Metalloproteinase Post Myocardial Infarction: Relation to Determinants of Remodeling
Authors: David C Lobb, Brendan P Purcell, Jeremy R McGarvey, Christina M Logdon, Heather Doviak, Jason O’Neill, James A Shuman, Randall L Echols, Craig P Novack, Kia N Zellars, Sara Pettaway, Joseph H Gorman, Robert C Gorman, Aarif Khakoo, TaeWeon Lee, Roy A Black, Jason A Burdick, Francis G Spinale
Journal: Circulation (2013)

Background: : Changes in LV matrix structure occur following a myocardial infarction (MI) and lead to progressive LV failure. This process is accompanied by an imbalance between matrix metalloproteinase (MMP) induction and tissue inhibitors of MMPs (TIMPs), as well as prolonged local inflammation, such as increased interleukins (ILs). This study tested the hypothesis that targeted TIMP augmentation through regional injection of a degradable hyaluronic acid (HA) based hydrogel containing recombinant TIMP-3 (HA/rTIMP-3) slowed the course of LV dysfunction and local MMP/IL levels. Methods/Results: MI was induced in adult pigs randomized to receive targeted rTIMP-3 (HA/rTIMP-3; n=8; 9-100uL injections, 20 ug rTIMP-3/injection), HA alone (n=9), or saline (MI only; n=8) and LV function (LV ejection fraction) serially measured for 14 days post-MI. Then MMP-9, a highly expressed MMP by inflammatory cells, as well as IL-8, a marker of inflammation, were assessed by rtPCR (Figure). As a function of Day 1 Post-MI, L...
Up to 250 cardiac deaths at leading London hospital are to be reviewed
Authors: Clare Dyer
Journal: BMJ (2019)

Heart surgery deaths at a leading London NHS trust, which had higher mortality rates than other cardiac centres over a four year period, are to be reviewed by an independent team of experts.

The review of deaths at St George’s University Hospitals NHS Foundation Trust follows an investigation last year by former NHS England deputy medical director Mike Bewick. Bewick’s investigation found a “persistent toxic atmosphere” with surgeons “working in camps.”

The latest review, commissioned by NHS Improvement, will be carried out by a …
Abstract 19096: Evaluating Hypertrophic Cardiomyopathy Disease-Gene Associations Using the Clinical Genome Resource (ClinGen) Gene Curation Framework
Authors: Jodie Ingles, Jennifer Goldstein, Colleen Caleshu, Edward Corty, Stephanie Crowley, Kristen Dougherty, Jennifer McGlaughon, Laura Milko, Ana Morales, Bryce Seifert, Christopher Semsarian, Natasha Strande, Courtney Thaxton, Kate Thomson, Peter van Tintelen, Kathleen Wallace, Roddy Walsh, James Ware, Quinn Wells, Nicola Whiffin, Leora Wikowski, Ray Hershberger, Birgit Funke
Journal: Circulation (2017)

Introduction: Hypertrophic cardiomyopathy (HCM), defined as unexplained left ventricular hypertrophy, is mainly caused by variants in genes encoding components of the cardiac sarcomere. Gene testing panels can include many genes with varying strength of evidence to support their association with HCM. Here we apply a systematic approach to assessing disease-gene associations. Methods: The ClinGen HCM Gene Curation group comprises >20 international experts and biocurators. Using the Clinical Genome Resource (ClinGen) gene-disease clinical validity framework, we will curate available data to classify the clinical validity of 55 genes for an HCM phenotype. The gene list was based on (1) Presence on >30% of HCM gene panels in the NCBI Genetic Testing Registry, (2) Inclusion in the Illumina TruSight HCM panel and (3) Expert opinion. Curations were performed by biocurators, overseen by a cardiac expert, and discussed on regular conference calls to reach a final consensus gene-disease validity classification. Whe...
Abstract 19400: Gender Differences in the Alpha-1 HDL Association With Diabetes Mellitus
Authors: John R Nelson, Michael R Mehan, Leigh E Alexander, Rosalynn D Gill
Journal: Circulation (2017)

Introduction: High density lipoprotein (HDL) exists as multiple subpopulations. HDL subpopulations were measured using the Boston Heart (BH) HDL Map. Low levels of large, α-1 HDL particles (α-1) are associated with adverse cardiovascular outcomes. Low HDL-C, high triglycerides (Tg), high Tg/HDL-c ratio and low large HDL particles measured by other methodologies are associated with Diabetes Mellitus (DM). It is unknown if the prevalence of DM in men and women in a large cohort is related to α-1 levels measured by this methodology and whether this association differs by gender as demonstrated in the Tg/HDL-C ratio. Methods: A retrospective cohort of 55,765 samples (ages 18 - 80) was developed from patients who received testing at BH. Test results were stratified by gender and split into quartiles. Odds ratios were calculated between each quartile and the first quartile. Area under the curve (AUC) were calculated from age-controlled logistic regression models. Results: DM prevalence decreased between Q1 (27....
Venoarterial ECMO for Adults
Authors: Maya Guglin, Mark J. Zucker, Vanessa M. Bazan, Biykem Bozkurt, Aly El Banayosy, Jerry D. Estep, John Gurley, Karl Nelson, Rajasekhar Malyala, Gurusher S. Panjrath, Joseph B. Zwischenberger, Sean P. Pinney
Journal: Journal of the American College of Cardiology (2019)
Trends in radiation dose and technique for anal canal squamous cell carcinoma.
Authors: Stephen Abel, Richard White, Shaakir Hasan, Gene Grant Finley, Dulabh K. Monga, Moses S. Raj, Alexander V. Kirichenko, James McCormick, Rodney E Wegner
Journal: Journal of Clinical Oncology (2019)

621 Background: Anal canal squamous cell carcinoma (SCC) is managed definitively with chemo and XRT, reserving surgery for salvage. Many different radiation dose schemes have been used, varying from 30 Gy to doses exceeding 60 Gy. RTOG 0529 established IMRT as a standard of care for anal canal SCC, using doses of 50.4-54 Gy. We used the National Cancer Database(NCDB) to examine trends in dose selection and radiation technique over time, as well as any potential effect on outcome. Methods: We queried the NCDB from 2004-2015 for cases of anal canal SCC stage 1-3, treated with definitive doses of XRT to the pelvis with chemo. Dose escalation was defined as &gt; 54 Gy. Univariable and multivariable analyses were performed to identify factors predictive of increased dose and overall survival (OS). Propensity-adjusted Cox proportional hazard ratios for survival were used to account for indication bias. Results: We identified 7,792 patients meeting the eligibility criteria, with 4,269 treated to conventional doses and 3,163 treated to &gt; 54 Gy. Patients that were older, had government or private insurance, were treated with IMRT, or at an academic center in a more recent year were less likely to get dose escalation. Increasing T and N stage were predictive of escalated dose. The use of dose escalation decreased over time, from 50% in 2005 to 30% in 2015. In contrast, IMRT use increased over that time from 2% to 63%. On multivariable analysis increasing age, higher comorbidity score, treatment at an academic center, and increasing stage corresponded to worse OS. Increased income, private insurance, IMRT use, increased distance to facility, and female gender all predicted improved OS. Multivariable analysis with propensity score included confirmed increased age, higher comorbidity score, income, distance, and gender as predictive of OS. In addition, escalated dose was found to have inferior outcome (OR: 1.10 95%CI: 1.01-1.20, p = 0.03). Conclusions: The results of this NCDB analysis show a steady increase in the use of IMRT over time, with a corresponding decrease in dose escalation. In this study, dose escalation was shown to have inferior outcomes, although that result is likely influenced by the increasing age, stage, and comorbidity scores in that group of patients.
Home Oxygen Therapy for Children. An Official American Thoracic Society Clinical Practice Guideline
Authors: Don Hayes, Kevin C. Wilson, Katelyn Krivchenia, Stephen M. M. Hawkins, Ian M. Balfour-Lynn, David Gozal, Howard B. Panitch, Mark L. Splaingard, Lawrence M. Rhein, Geoffrey Kurland, Steven H. Abman, Timothy M. Hoffman, Christopher L. Carroll, Mary E. Cataletto, Dmitry Tumin, Eyal Oren, Richard J. Martin, Joyce Baker, Gregory R. Porta, Deborah Kaley, Ann Gettys, Robin R. Deterding
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Section:ChooseTop of pageAbstract <<ContentsSummary of Recommendation...IntroductionMethodsDefinition of HypoxemiaConsequences of Untreated...Indications for HOTProviding HOTDiscontinuation of HOTConclusionsReferencesCITING ARTICLES