tbuckley/cabot-search huggingface dataset:
Abstract 271: Role of Arterial AT1 Receptor on the Regulation of GRK4 in Hypertension
Authors: Ken Chen, Li Liu, Caiyu Chen, Pedro A Jose, Chunyu Zeng
Journal: Circulation Research (2014)

G protein-coupled receptor kinase 4 (GRK4) gene variants or increased GRK4 expression, via impairment of renal dopamine receptor and enhancement of renin angiotensin system function, impairs renal sodium excretion, resulting in sodium retention and an increase in blood pressure. Increased aortic stiffness, a risk factor in cardiovascular disease, may be related to increased activity of the renin-angiotensin system Whether or not GRK4 and the angiotensin type 1 receptor (AT1R) interact in the aorta is not known. We now report that GRK4 is expressed in vascular smooth muscle cells (VSMCs) of the aorta. Exogenous expression of the GRK4 variant 142V in aortic A10 cells increased AT1R protein expression and AT1R-mediated increase in intracellular calcium concentration. The increased AT1R expression was caused by an increase in AT1R mRNA expression via NF-kappa B, because blockade of NF-kappa B abolished those effects of GRK4 A142V. As compared with control (vector-transfected) cells, cells expressing 142V had higher NF-kappa B activity and more NF-kappa B bound to AT1R promoter. The increased AT1R expression in cells expressing GRK4 142V was associated with decreased AT1R degradation, which was ascribed to the lower AT1R phosphorylation. There was direct interaction between GRK4 and AT1R in A10 cells which was decreased by GRK4 that could have caused the lower AT1R phosphorylation and degradation. The regulation of GRK4 of AT1R expression was confirmed in GRK4142V transgenic mice, the AT1R expression was higher, while AT1R phosphorylation was lower in aorta in GRK4 142V than control mice. Angiotensin II-mediated vasoconstriction was higher in A142V mice. This study provides a mechanism that GRK4, via regulation of arterial AT1R expression and function, engaged into the pathogenesis of hypertension.
Preseason performance on cervical, vestibular and divided attention measures in youth ice hockey players
Authors: Kathryn J Schneider, Luz Palacios-Derflingher, Chevonne Codd, Qian Shi, Willem H Meeuwisse, Carolyn A Emery
Journal: British Journal of Sports Medicine (2017)

Objective To determine preseason values on cervical, vestibular and divided attention measures in youth ice hockey players aged 10-14 years Design Cross-Sectional study Setting Sport Injury Prevention Research Centre, Alberta, Canada Participants Youth Ice Hockey players (n=934, age 10-14 years). Outcome measures Numeric pain rating scores for neck pain, headache, dizziness; Cervical flexor endurance test (CFE), cervical flexion rotation test (CFRT), cervical spine strength, head perturbation test, functional gait assessment (FGA), walking while talking test (WWTT), head thrust test and dynamic visual acuity (DVA). Main results Symptoms of neck pain, headaches and dizziness were reported by 17%, 18% and 10% of participants respectively. The median time of CFE was 27.0 seconds (IQR: 19.9, 40.7). CFRT was positive in 52 (6.2%) participants. Median anterolateral cervical spine strength was 8.0 lbs (IQR: 6.1, 10.3) right and 7.8 lbs (IQR: 6.0, 10.1) left. 13% of participants were unable to maintain a stationary head position when an external force was applied. 48% of participants performed less than perfect on the FGA. Time to complete a complex task while walking increased 40 foot walking time by a median of 6.4 seconds (IQR: 4.0, 10.3). Head thrust test was positive in 33 (3.7%) participants. Clinical DVA score was a median of 0.2 logMar (IQR: 0.1, 0.3). Conclusions Symptoms are common at baseline and outcomes on many commonly used clinical tests may be different for healthy 10-14 year olds compared to the adult literature. These findings form an important reference point for the interpretation of post-injury testing. Competing interests None.
Fulvestrant response prediction from transcriptome data obtained from primary breast cancer biopsies.
Authors: Troels Dreier Christensen, Anna Sofie Kappel Buhl, Ib Jarle Christensen, Knud Mejer Nelausen, Eva Balslev, Ann S. Knoop, Eva Brix, Peter Michael Vestlev, Niels Henrik Hollander, Bent Ejlertsen, Annie Rasmussen, Ulla Hald Buhl, Anker Hansen, Nils Brunner, Peter Buhl Jensen, Steen Knudsen, Dorte Nielsen
Journal: Journal of Clinical Oncology (2016)

e12056 Background: Fulvestrant is a highly selective estrogen receptor (ER) antagonist used in the treatment of postmenopausal patients with ER-positive advanced breast cancer. To identify patients who are sensitive to fulvestrant we applied a multigene mRNA-based Drug Response Predictor (DRP) broadly validated by Wang et al1 and for fulvestrant by Knudsen et al2. The DRP is based on measuring the full transcriptome in cell lines sensitive and cell lines resistant to a drug compared with expression patterns in tumors. Methods: To evaluate patients’ transcriptomes from primary biopsies and response to therapy at relapse, a total of 545 consecutive patients with advanced disease were included from five participating hospitals. After patient informed consent mRNA was extracted and assayed on Affymetrix Gene Chip U133p2 arrays from formalin fixed paraffin embedded diagnostic biopsies. Of these 545 patients, 112 patients with ER-positive breast cancer received fulvestrant in one of the first three lines of treatment for advanced disease between November 2008 and November 2015 Patients were during treatment evaluated every 3 to 4 months using CT scans and clinical examination. The primary analysis was a Cox regression model of the prediction scores stratified by treatment line and time to disease progression calculated from the start of treatment and until the start of a new treatment. Results: Of 112 patients treated with fulvestrant 75 progressed within 6.4 months median (1.0-38.9 months). Of the 112 patients 81 had received prior adjuvant antihormone therapy and 30 had not. One patient was without accessible data about prior adjuvant antihormone therapy. Conclusions: In a real world setting mRNA from the original diagnostic biopsy can be used to predict a later fulvestrant response only if the patients are unexposed to previous adjuvant endocrine therapy. Such transcriptome data supports the hypothesis that development of clinical resistance pathways can be detected and followed. Hazard ratio 95% confidence limits P-value No prior adjuvant antihormone therapy 0.31 0.10-0.97 0.044 Prior adjuvant antihormone therapy 0.88 0.38-2.04 0.76 1Wang et al JNCI (2013) 105 (17): 1284-1291. 2Knudsen et al PLoS ONE 9(2): e87415.
Hybrid capture-based next-generation sequencing (HC NGS) in melanoma to identify markers of response to anti-PD-1/PD-L1.
Authors: Douglas Buckner Johnson, Garrett Michael Frampton, Matthew J. Rioth, Erik Yusko, Riley Ennis, David Fabrizio, Joel R. Greenbowe, Siraj Mahamed Ali, Dennie T Frederick, Igor Puzanov, Justin M. Balko, Justin Cates, Jeffrey S. Ross, Harlan Robins, Vincent A. Miller, Phil Stephens, Ryan J. Sullivan, Jeffrey Alan Sosman, Christine Marie Lovly
Journal: Journal of Clinical Oncology (2016)

105 Background: Agents blocking programmed death-1/ligand (aPD1) induce durable responses in many melanoma patients (pts). Greater numbers of somatic mutations have been linked to high aPD1 response rates (RR) in other cancers. We assessed whether number and/or type of mutations (mut) using HC NGS correlated with outcomes to aPD1 in melanoma. Methods: HC NGS on 236-315 genes was performed on archival samples from pts who received aPD1 (comprising ~1.25 megabases [MB]). A novel algorithm extrapolated genomic mutational load (ML) from this panel. Intratumoral T cell clonal expansion was determined by T cell receptor (TCR) sequencing. ML and TCR clonality were correlated with with aPD1 outcomes. Results: Responders to aPD1 had higher ML compared to non-responders in discovery (median 45.6 vs. 3.9 mut/MB; p=0.003, n=32), and validation cohorts (37.1 vs. 12.8 mut/MB; p=0.002, n=33). RR was superior in high ML pts compared to intermediate/low (Table) as was progression-free survival (PFS) (median not reached [MNR] vs. 89 days vs. 86 days, p<0.001) and overall survival (OS) (MNR vs. 300 days vs. 375 days, p<0.001). Responders had more C>T transitions than non-responders (median 33.5 vs. 3.0, p<0.001). Melanomas with NF1 mutations had high ML (median 62.7 mut/MB) and high RR (74%); whereas BRAF mutant (12.0 mut/MB), NRAS mutant (17.6 mut/MB), and BRAF/NRAS/NF1wild-type (2.2 mut/MB) melanomas had lower median ML. TCR clonality did not correlate with response in these archival samples, nor did PD-L1 gene amplification (<1% incidence). Conclusions: ML as determined by HC NGS effectively stratified patients by likelihood of response. This approach may provide a widely available, clinically feasible predictor of response to aPD1. Cohort Mutational load group Response No Response P value Discovery High (n=11) 9 (82%) 2 (18%) 0.003 Intermediate (n=11) 4 (36%) 7 (64%) Low (n=10) 1 (10%) 9 (90%) Validation High (n=16) 14 (88%) 2 (12%) 0.001 Intermediate (n=13) 3 (23%) 10 (77%) Low (n=4) 1 (25%) 3 (75%) Combined High (n=27) 23 (85%) 4 (15%) <0.001 Intermediate (n=24) 7 (29%) 17 (71%) Low (n=14) 2 (14%) 12 (86%) High ML: >23.1 mut/MB; Intermediate: 3.2 – 23.1 mut/MB; Low: <3.2 mut/MB
Ultrasound-guided mammotome for diagnosis and minimally invasive excision of mammary clustered calcifications.
Authors: Wei Hu
Journal: Journal of Clinical Oncology (2017)

e13034 Background: To validate the ultrasound-guided vacuum-assisted breast biopsy system (Mammotome) for diagnosis and minimally invasive excision of calcification in breast. Methods: In 20 patients, breast calcification lesions diagnosed by mammography were excised by ultrasound-guided Mammotome system with 8-gauge probe. The samples were taken mammography and followed by pathological examination. Results: All lesions were removed accurately and thoroughly with satisfactory cosmetic outcomes. No clinically significant hematoma developed. Each mass was resected through 9.15±2.70 cores on average over a mean of 11.65±3.88 minutes. Two cases of them were histologically diagnosed as ductal carcinoma in situ and 8 cases were fibroadenoma and 10 cases were adenosis. Conclusions: Ultrasound-guided Mammotome system can profit to diagnose and treat breast calcification lesions which is ultrasound positive. Ultrasound detection rate of microcalcifications is up to the instrument resolution and the operator's experience and patience.
Résultats préliminaires du coloscanner (coloscopie virtuelle) dans la détection des polypes colorectaux comparé à la coloscopie
Authors: ME Cadi, R Chollet, T Mansourbach, O Lucidarme, T Poynard, P Grenier
Journal: Endoscopy (2005)

Déterminer la sensibilité et le temps d'analyse du coloscanner dans la détection des polypes coliques.
Diagnosis and risk stratification of Barrett’s dysplasia by flow cytometric DNA analysis of paraffin-embedded tissue
Authors: Won-Tak Choi, Jia-Huei Tsai, Peter S Rabinovitch, Thomas Small, Danning Huang, Aras N Mattis, Sanjay Kakar
Journal: Gut (2017)

Objective The diagnosis of dysplasia in Barrett’s oesophagus (BO) can be challenging, and reliable ancillary techniques are not available. This study examines if DNA content abnormality detected by flow cytometry can serve as a diagnostic marker of dysplasia and facilitate risk stratification of low-grade dysplasia (LGD) and indefinite for dysplasia (IND) patients using formalin-fixed paraffin-embedded (FFPE) BO samples with varying degrees of dysplasia. Design DNA flow cytometry was performed on 80 FFPE BO samples with high-grade dysplasia (HGD), 38 LGD, 21 IND and 14 negative for dysplasia (ND). Three to four 60-micron thick sections were cut from each tissue block, and the area of interest was manually dissected. Results DNA content abnormality was identified in 76 HGD (95%), 8 LGD (21.1%), 2 IND (9.5%) and 0 ND samples. As a diagnostic marker of HGD, the estimated sensitivity and specificity of DNA content abnormality were 95% and 85%, respectively. For patients with DNA content abnormality detected at baseline LGD or IND, the univariate HRs for subsequent detection of HGD or oesophageal adenocarcinoma (OAC) were 7.0 and 20.0, respectively (p =&lt;0.001). Conclusions This study demonstrates the promise of DNA flow cytometry using FFPE tissue in the diagnosis and risk stratification of dysplasia in BO. The presence of DNA content abnormality correlates with increasing levels of dysplasia, as 95% of HGD samples showed DNA content abnormality. DNA flow cytometry also identifies a subset of patients with LGD and IND who are at higher risk for subsequent detection of HGD or OAC.
Development and validation of a residual risk score to predict breast cancer risk in unaffected women negative for mutations on a multi-gene hereditary cancer panel.
Authors: Elisha Hughes, Thaddeus Judkins, Susanne Wagner, Richard J. Wenstrup, Jerry S. Lanchbury, Alexander Gutin
Journal: Journal of Clinical Oncology (2017)

1579 Background: Women who are unaffected with cancer but have a significant family history of breast cancer (BC) are frequently referred for hereditary cancer testing with multi-gene panels; however, &lt; 10% test positive for clinically actionable mutations. Large-scale genotyping studies have identified common variants (primarily single-nucleotide polymorphisms) that individually confer modest BC risk, but together may explain the genetic susceptibility for BC in many women without monogenic mutations. Here, we describe the development and validation of a polygenic residual risk score in a large, consecutive cohort of women who tested negative for mutations in known BC susceptibility genes. Methods: This IRB-approved study includes women of European ancestry tested with a multi-gene hereditary cancer panel who were negative for mutations in 11 genes associated with BC ( BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1). Clinical information was collected from provider-completed test request forms. The dataset was divided into a training (July – November 2016) and validation cohort (November 2016 – April 2017). Multivariable logistic regression models were used to evaluate 94 common variants and develop candidate residual risk scores as predictors of personal BC history (invasive ductal carcinoma, IDC) in the training cohort. Independent variables included age, personal/family cancer history, and ancestry. An optimal subset of the 94 common variants and a residual risk score will be selected through cross-validation followed by independent validation. Results: The training cohort includes 11,838 women (median age 47 years), 18% of whom reported a personal history of IDC and 36% of whom reported BC in a first-degree relative. Results from validation of the residual risk score in an independent cohort of approximately 12,000 women will be completed at the time of presentation. Conclusions: The validation and clinical implementation of a residual risk score for women at risk for hereditary BC may offer significant potential for the management of high-risk, unaffected women who test negative for monogenic BC mutations.
Hepatolymphomania
Authors: Marlys Hearst Witte
Journal: Hepatology (2004)

An avid fan of Landmarks in Hepatology and an earlier contributor to Hal Conn's Hepatology Elsewhere, I read with nostalgia Adrian Reuben's gentle reflections on the long-standing overflow versus underfill controversy in the genesis of "cirrhotic ascites" at the moment of hepatology great Telfer B. Reynolds's passing.1 Then I noticed the phrase "and a little lymphatic insufficiency" with reference 2 to our 1980 Gastroenterology paper expounding the "lymph imbalance theory." At that moment, the generally good-natured "cup runneth over" controversy was reawakened in me. If he were here, my late (March 7, 2003) husband,3 surgeon Charles Witte (also a Hepatology Elsewhere-ologist), would have drafted with me a rapid-fire letter to the editor: All edema, as Ernest Starling pointed out, represents an imbalance between lymph (e.g., hepatosplanchnic lymph/ascites) formation and lymph absorption; strikingly elevated thoracic duct lymph formation (8-10 times normal; i.e., 13-15 or more liters per day, hardly a "little" bit of lymph) is a hallmark of cirrhosis (whether or not ascites is present) and results largely from uncontrolled portal hypertension; successful treatments of cirrhotic ascites work by either reducing the elevated lymph formation or enhancing still further lymph absorption, or both; and sodium retention can't produce ascites alone without, by definition, a concomitant or preceding lymph imbalance, and so on.4 And the controversy, likely with T.B. Reynolds weighing in, would be reignited! The "lymphomania" in me aroused, I next spied another "lymph note" in the breezy "Legend of the Lardaceous Liver" Landmark that just appeared.5 Reference is made to the Dane Thomas Bartholin, who first described the thoracic duct in 1654. But he is not as stated also the "discoverer of the lymphatic system." In 1627, Gaspar Asellius of Padua cried out, "Eureka," when he first glimpsed the glistening chyliferous vessels of the postprandial dog, coincidentally the same time that William Harvey described the to-be-more-touted blood circulation. So, thanks to HEPATOLOGY, hepatolymphologists worldwide (those elite members of both the American Association for the Study of Liver Diseases and the International Society of Lymphology) can still have something to say about the nexus between the liver/portal bed and the lymphatic system! Marlys Hearst Witte M.D.*, * Tucson, AZ.
Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors
Authors: Charles L. Dulberger, Curtis P. McMurtrey, Angelique Hölzemer, Karlynn E. Neu, Victor Liu, Adriana M. Steinbach, Wilfredo F. Garcia-Beltran, Michael Sulak, Bana Jabri, Vincent J. Lynch, Marcus Altfeld, William H. Hildebrand, Erin J. Adams
Journal: Immunity (2017)
T-cell Receptors for Clinical Therapy: <i>In Vitro</i> Assessment of Toxicity Risk
Authors: Andre Kunert, Matthias Obenaus, Cor H.J. Lamers, Thomas Blankenstein, Reno Debets
Journal: Clinical Cancer Research (2017)

Abstract Adoptive therapy with T-cell receptor (TCR)–engineered T cells has shown promising results in the treatment of patients with tumors, and the number of TCRs amenable for clinical testing is expanding rapidly. Notably, adoptive therapy with T cells is challenged by treatment-related side effects, which calls for cautious selection of target antigens and TCRs that goes beyond their mere ability to induce high T-cell reactivity. Here, we propose a sequence of in vitro assays to improve selection of TCRs and exemplify risk assessments of on-target as well as off-target toxicities using TCRs directed against cancer germline antigens. The proposed panel of assays covers parameters considered key to safety, such as expression of target antigen in healthy tissues, determination of a TCR's recognition motif toward its cognate peptide, and a TCR's cross-reactivity toward noncognate peptides. Clin Cancer Res; 23(20); 6012–20. ©2017 AACR.
Abstract 95: Increased Circulating Endothelial Microparticles In The Acute Phase Of Kawasaki Disease
Authors: Hideyuki Nakaoka
Journal: Circulation (2015)

Backgroud: Kawasaki disease (KD) is a typically acute inflammatory syndrome that takes the form of systemic vasculitis. The acute inflammation and subsequent reparative process may lead to lasting changes in arterial structure even in the convalescence of KD including increased endothelial dysfunction. Endothelial microparticles (EMPs) are vesicles formed by the cell membrane after endothelial activation, and their composition can be used to characterize the status of the parent endothelial cell. EMPs were reported in cardiovascular diseases with endothelial dysfunction, such as acute coronary syndrome, pulmonary hypertension, diabetes, and vasculitis. Our aim of this study is to elucidate whether EMPs are involved in vasculitis during acute stage of Kawasaki disease. Method: We enrolled 9 patients (aged 3 months to 14 years, 6 male, 3 female), 7 common febrile children and 5 healthy children. KD patients in the convalescent phase were divided into two subgroups; coronary artery lesion (CAL, n=2) and no coronary lesion (NCAL, n=7). Blood samples were collected at the time of diagnosis before the initiation of IVIG treatment, then immediately after the first IVIG infusion and at 2-4 weeks after disease onset. Samples were measured using flow cytometry. Result: The percentage counts of EMPs were 2.90±1.26% in KD children before initial treatment, which were significantly higher (P&lt;0.005) than those of disease controls (0.12±0.13%) and healthy controls (0.09±0.08%) before initial treatment, and reached normal levels within 4 weeks (0.05±0.05%). The highest percentage count of EMPs (5.47%) was observed in the patient with CAL before initial treatment. Further, prolonged high percentage count of EMPs (3.34%) was recognized in the patient with multiple gaint aneurysms at 2 weeks after onset. Conclusion: The relation between the increased levels of EMPs and the involvement of CAL may suggest that EMPs could serve as a sensitive marker of the severity of endothelial dysfunction and vasculitis in patients with KD. Although the function of EMPs has not been fully elucidated, there is evidence that it plays an important role for distinct inflammatory reactions in endothelium.
Fermeture endoscopique de perforations colorectales apres resection muqueuse ou dissection sous-muqueuse endoscopiques par clips
Authors: D Coumaros, N Tsesmeli, D Tzilves, J Marescaux
Journal: Endoscopy (2009)

Introduction: Bien que le risque de perforation par endoscopie soit faible, le développement croissant des techniques de résection muqueuse endoscopique (EMR) et de dissection sous-muqueuse endoscopique (ESD) pourrait se traduire par une augmentation importante du nombre de complications. Le but de ce travail est de démontrer que les perforations colorectales après EMR ou ESD peuvent être traitées de manière non invasive par l'utilisation de clips.
Abstract 5891: Incidence and Prognostic impact of Spontaneous Conversion to Sinus Rhythm in Patients with Permanent Atrial Fibrillation treated with Cardiac Resynchronization Devices
Authors: Maurizio Gasparini, Christophe Leclercq, Aysha Arshad, François Regoli, Arnaud Rosier, Paola Galimberti, Ganesh Kamath, Claude Daubert, Catherine Klersy, Policlinico S. Matteo, Jonathan S Steinberg
Journal: Circulation (2008)

INTRODUCTION : Anecdotal reports of spontaneous resumption to stable sinus rhythm (SR) of heart failure (HF) patients with permanent atrial fibrillation (PeAF) after cardiac resynchronization therapy (CRT) have been reported. If this incidence is appreciable, additional interventions may be indicated including placement of an atrial lead. METHODS: We retrospectively reviewed patients with PeAF who received CRT devices; standard CRT indications were applied. PeAF was defined as AF present for more than 1 year refractory to any rhythm control efforts. Rhythm was sampled at each follow-up visit, generally every 6 months. RESULTS: In total, 345 patients with PeAF were implanted with CRT devices (CRT-D 48%); mean age was 70±9 yrs and mostly male gender (83%). Ischemic HF was present in 154 patients (45%). Mean NYHA class was 3,1±0,5, 6MWT distance 308±113 meters, QRS 156±39 ms, LVEF 28±7%, and LVEDD 65±9 mm. PeAF had been present for 2,1 ± 1.6 years. Over a follow-up of 29 ± 24 months, 34 (9,9%) patients spontaneously reverted to stable (&gt; 3 months) SR. Most SR resumptions occurred within the 1 st year after CRT (28/34, 82%), but also occured even after 5 years (2/34). Mortality rate was 20,4 for PeAF compared to 2,5 per 100 patients-year for SR resumption (Log Rank p=0.004, see figure ) (HR= 0.13, 95% CI 0.031–0.512, p&lt; 0.0001). CONCLUSION : Spontaneous resumption to SR in HF patients with PeAF treated with CRT was observed in roughly 10% of cases, generally within 1 year from implant. SR resumption was associated with a significant 87% reduction of total mortality. Identification of predictors for return of SR may be useful to guide routine atrial lead placement in some patients.