tbuckley/cabot-search huggingface dataset:
Is abdominal hypopressive technique effective in the prevention and treatment of pelvic floor dysfunction? Marketing or evidence from high-quality clinical trials?
Authors: Saúl Martín-Rodríguez, Kari Bø
Journal: British Journal of Sports Medicine (2017)

In the late 1940s, Arnold Kegel first described pelvic floor muscle training (PFMT) to prevent and treat pelvic floor dysfunctions such as urinary incontinence (UI) and pelvic organ prolapse (POP). Several systematic reviews and Cochrane reviews conclude that there is level 1A evidence for prevention and treatment of PFMT for UI1 and POP.2 Despite the strong evidence for PFMT for these conditions, several other exercise regimens have been proposed and advocated to manage UI and POP. Specifically for stress UI, Pilates and Paula methods, Tai Chi and other methods based on breathing exercises and correction of body posture have very limited or questionable effects based on randomised controlled trials (RCTs).3 

The abdominal hypopressive technique (AHT) may be classified as a breathing exercise. It was developed in the 1980s by a physical therapist named Dr Marcel Caufriez, and is widely known and used in countries including France, Italy, Spain, Canada and countries of South America. Those in charge of …
Tumor Microvessel Density as a Prognostic Marker in High-Risk Renal Cell Carcinoma Patients Treated on ECOG-ACRIN E2805
Authors: Lucia B. Jilaveanu, Maneka Puligandla, Sarah A. Weiss, Xin Victoria Wang, Christopher Zito, Keith T. Flaherty, Marta Boeke, Veronique Neumeister, Robert L. Camp, Adebowale Adeniran, Michael Pins, Judith Manola, Robert S. DiPaola, Naomi B. Haas, Harriet M. Kluger
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Increased vascularity is a hallmark of renal cell carcinoma (RCC). Microvessel density (MVD) is one measurement of tumor angiogenesis; however, its utility as a biomarker of outcome is unknown. ECOG-ACRIN 2805 (E2805) enrolled 1,943 resected high-risk RCC patients randomized to adjuvant sunitinib, sorafenib, or placebo. We aimed to determine the prognostic and predictive role of MVD in RCC. Experimental Design: We obtained pretreatment primary RCC nephrectomy tissues from 822 patients on E2805 and constructed tissue microarrays. Using quantitative immunofluorescence, we measured tumor MVD as the area of CD34-expressing cells. We determined the association with disease-free survival (DFS), overall survival (OS), treatment arm, and clinicopathologic variables. Results: High MVD (above the median) was associated with prolonged OS for the entire cohort (P = 0.021) and for patients treated with placebo (P = 0.028). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib (P = 0.060). MVD was not associated with DFS (P = 1.00). On multivariable analysis, MVD remained independently associated with improved OS (P = 0.013). High MVD correlated with Fuhrman grade 1–2 (P &amp;lt; 0.001), clear cell histology (P &amp;lt; 0.001), and absence of necrosis (P &amp;lt; 0.001) but not with gender, age, sarcomatoid features, lymphovascular invasion, or tumor size. Conclusions: High MVD in resected high-risk RCC patients is an independent prognostic, rather than predictive, biomarker of improved OS. Further studies should assess whether incorporating MVD into clinical models will enhance our ability to predict outcome and if low MVD can be used for selection of high-risk patients for adjuvant therapy trials. Clin Cancer Res; 24(1); 217–23. ©2017 AACR.
Rational designing of an antidote nanoparticle decorated with abiotic polymer ligands for capturing and neutralizing target toxins
Authors: Hiroyuki Koide, Hiroki Tsuchida, Masahiko Nakamoto, Anna Okishima, Saki Ariizumi, Chiaki Kiyokawa, Tomohiro Asai, Yu Hoshino, Naoto Oku
Journal: Journal of Controlled Release (2017)
TCT-810 Geographical Variation in Anatomical and Procedural Characteristics for Left Main Coronary Artery Revascularization and Their Impact on Clinical Outcomes: Analysis From the EXCEL Trial
Authors: Aung Myat, David Hildick-Smith, Adam De Belder, Uday Trivedi, Marie-Claude Morice, David Kandzari, Nicholas Lembo, William Brown, Patrick Serruys, A. Pieter Kappetein, Joseph Sabik, Gregg Stone
Journal: Journal of the American College of Cardiology (2017)
A convenient and sensitive mTOR activity assay with native and recombinant mTOR
Authors: April Livengood, Peter Leland, Jue Wang, Kevin Harvey, Mo Saedi
Journal: Cancer Research (2008)

3560  Mammalian target of rapamycin (mTOR) is a member of the phosphoinositide-3-kinase (PI-3K) related kinase family and has roles in cell growth regulation and human tumorigenesis. mTOR regulates cell growth by controlling mRNA translation, ribosome biogenesis, metabolism, and autophagy. mTOR exists in two distinct multiprotein complexes: a nutrient-sensitive, rapamycin-sensitive complex (TORC1) that phosphorylates S6 kinase 1 (S6K1) and initiation factor 4E binding proteins and a growth factor-sensitive, rapamycin-insensitive complex (TORC2) that phosphorylates AKT.  We have developed a sensitive, non-radioactive, ELISA-based assay for mTOR kinase activity. This assay can be used for screening inhibitors of mTOR, and for the analysis of the activity of mTOR complexes isolated from cell lysates and other biological samples. Activity of mTOR is measured by the phosphorylation of the substrate p70S6K at Thr 389 using a phospho-specific antibody. The assay includes an active, truncated recombinant mTOR that contains the FAT, FRB (FKBP12-rapamycin binding), and C-terminal kinase domains that can be used as a target for inhibitors or as a standard for comparison with immunoprecipitated mTOR complexes from cell lysates. The activity of the recombinant mTOR isinhibited by the general PI-3K inhibitor wortmannin (low micromolar IC50) as well as by the rapamycin-FKBP12 complex (low nanomolar IC50). Enriched rat brain fractions or cell lysates are used as the source for native mTOR complexes. Antibodies specific for mTOR, the TORC1 protein raptor, or the TORC2 protein rictor can be used for the immunoprecipitation of mTOR complexes. The kinase activity of these complexes can be measured in the assay, facilitating the analysis of cellular regulation of mTOR function. The mTOR activity assay has also been miniaturized to a 384-well format for higher throughput analysis and reduced sample volumes. In summary, we have developed convenient tools for the measurement of the activity of both recombinant and native mTOR. These tools enable the screening of rapamycin analogues and other classes of mTOR inhibitors and the isolation and characterization of native mTOR complexes.
De-adoption and exnovation in the use of carotid revascularization: retrospective cohort study
Authors: Kimon Bekelis, Jonathan Skinner, Daniel Gottlieb, Philip Goodney
Journal: BMJ (2017)

Objective To determine physician characteristics associated with exnovation (scaling back on use) and de-adoption (abandoning use) of carotid revascularization.Design Retrospective longitudinal cohort study.Setting Medicare claims linked to the Doximity database provider registry, 2006-13.Participants 9158 physicians who performed carotid revascularization on Medicare patients between 2006 and 2013.Main outcome measures The primary outcomes were the number of carotid revascularization procedures for each physician per year at the end of the sample period, and the percentage change in the volume of carotid revascularization procedures.Results At baseline (2006-07), 9158 physicians performed carotid revascularization. By 2012-13 the use of revascularization in this cohort had declined by 37.7%, with two thirds attributable to scaling back (exnovation) rather than dropping the procedure entirely (de-adoption). Compared with physicians with fewer than 12 years of experience, those with more than 25 years of experience decreased use by an additional 23.0% (95% confidence interval -36.7% to -9.2%). The lowest rates of decline occurred in physicians specializing in vascular or thoracic surgery, for whom the procedures accounted for a large share of revenue. Physicians with high proportions of patients aged more than 80 years or with asymptomatic carotid stenosis were less likely to reduce their use of carotid revascularization.Conclusion Surgeons with more experience and the lowest share in carotid revascularization practice reduced their use of the procedure the most. These practice factors should be considered in quality improvement efforts when the evidence base evolves away from a specific treatment.
Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma
Authors: Elizabeth A. Reap, Carter M. Suryadevara, Kristen A. Batich, Luis Sanchez-Perez, Gary E. Archer, Robert J. Schmittling, Pamela K. Norberg, James E. Herndon, Patrick Healy, Kendra L. Congdon, Patrick C. Gedeon, Olivia C. Campbell, Adam M. Swartz, Katherine A. Riccione, John S. Yi, Mohammed K. Hossain-Ibrahim, Anirudh Saraswathula, Smita K. Nair, Anastasie M. Dunn-Pirio, Taylor M. Broome, Kent J. Weinhold, Annick Desjardins, Gordana Vlahovic, Roger E. McLendon, Allan H. Friedman, Henry S. Friedman, Darell D. Bigner, Peter E. Fecci, Duane A. Mitchell, John H. Sampson
Journal: Cancer Research (2017)

Median survival for glioblastoma (GBM) remains <15 months. Human cytomegalovirus (CMV) antigens have been identified in GBM but not normal brain, providing an unparalleled opportunity to subvert CMV antigens as tumor-specific immunotherapy targets. A recent trial in recurrent GBM patients demonstrated the potential clinical benefit of adoptive T-cell therapy (ATCT) of CMV phosphoprotein 65 (pp65)-specific T cells. However, ex vivo analyses from this study found no change in the capacity of CMV pp65-specific T cells to gain multiple effector functions or polyfunctionality, which has been associated with superior antitumor efficacy. Previous studies have shown that dendritic cells (DC) could further enhance tumor-specific CD8+ T-cell polyfunctionality in vivo when administered as a vaccine. Therefore, we hypothesized that vaccination with CMV pp65 RNA-loaded DCs would enhance the frequency of polyfunctional CMV pp65-specific CD8+ T cells after ATCT. Here, we report prospective results of a pilot trial in which 22 patients with newly diagnosed GBM were initially enrolled, of which 17 patients were randomized to receive CMV pp65-specific T cells with CMV-DC vaccination (CMV-ATCT-DC) or saline (CMV-ATCT-saline). Patients who received CMV-ATCT-DC vaccination experienced a significant increase in the overall frequencies of IFNγ+, TNFα+, and CCL3+ polyfunctional, CMV-specific CD8+ T cells. These increases in polyfunctional CMV-specific CD8+ T cells correlated (R = 0.7371, P = 0.0369) with overall survival, although we cannot conclude this was causally related. Our data implicate polyfunctional T-cell responses as a potential biomarker for effective antitumor immunotherapy and support a formal assessment of this combination approach in a larger randomized study.Significance: A randomized pilot trial in patients with GBM implicates polyfunctional T-cell responses as a biomarker for effective antitumor immunotherapy. Cancer Res; 78(1); 256-64. ©2017 AACR.
Abstract 14350: Hemoptysis as a Side Effect of Cryoballoon Pulmonary Vein Isolation in Atrial Fibrillation - A Retrospective Case-control Study
Authors: Kevin Bullert, Klaus-Jürgen Gutleben, Dieter Horstkotte, Stephan Molatta, Britta Körber, Georg Noelker
Journal: Circulation (2016)

Introduction:  Hemoptysis and pulmonary hemorrhage are rarely described as complications of cryoballoon ablation for pulmonary vein isolation (CB PVI). We aimed to evaluate a large single center cohort regarding frequency and possible risk factors for manifestation of these complications.   Hypothesis:  Hemoptysis and pulmonary tissue injury are rare complications of cryoballoon pulmonary vein isolation.   Methods:  Among 715 consecutive patients evaluated from a single center data base 4.3% (31 pts, 29 male, mean age 60.5 ± 11.5 years) were identified to have experienced hemoptysis following CB PVI.   Results:  Comparison to 31 matched controls from the same cohort revealed significantly lower ablation temperatures in the case group for the right inferior pulmonary vein (PV) (case group: -56.2 ± 26.6 °C; control group: 49.1 ± 13.2 °C; p = 0.004) and left inferior PV(case group -56.4 ± 11.9 °C; control group 47.2 ± 7.6 °C; p = 0.001) in a univariate analysis. All other procedural parameters were found to be not significantly different between the groups. Although pre-procedural levels of hemoglobin were comparable, post-procedural hemoglobin was also lower in the case-group (case-group: 12.9 ± 1.6 g/dl; control-group: 13.7 ± 1.5 g/dl; p    Conclusions:  Post-procedural hemoptysis after CB PVI seems to be a relatively frequent finding associated with low freezing temperatures and pulmonary tissue infiltration predominantly located at the right inferior PV.
The Cancer Genomics Cloud: Collaborative, Reproducible, and Democratized—A New Paradigm in Large-Scale Computational Research
Authors: Jessica W. Lau, Erik Lehnert, Anurag Sethi, Raunaq Malhotra, Gaurav Kaushik, Zeynep Onder, Nick Groves-Kirkby, Aleksandar Mihajlovic, Jack DiGiovanna, Mladen Srdic, Dragan Bajcic, Jelena Radenkovic, Vladimir Mladenovic, Damir Krstanovic, Vladan Arsenijevic, Djordje Klisic, Milan Mitrovic, Igor Bogicevic, Deniz Kural, Brandi Davis-Dusenbery
Journal: Cancer Research (2017)

The Seven Bridges Cancer Genomics Cloud (CGC; www.cancergenomicscloud.org) enables researchers to rapidly access and collaborate on massive public cancer genomic datasets, including The Cancer Genome Atlas. It provides secure on-demand access to data, analysis tools, and computing resources. Researchers from diverse backgrounds can easily visualize, query, and explore cancer genomic datasets visually or programmatically. Data of interest can be immediately analyzed in the cloud using more than 200 preinstalled, curated bioinformatics tools and workflows. Researchers can also extend the functionality of the platform by adding their own data and tools via an intuitive software development kit. By colocalizing these resources in the cloud, the CGC enables scalable, reproducible analyses. Researchers worldwide can use the CGC to investigate key questions in cancer genomics. Cancer Res; 77(21); e3-6. ©2017 AACR.
Inhibition of cMet activation by a one-armed antibody
Authors: Ralph H. Schwall, Camelia W. Adams, Zhong Zheng, Molly Romero, Elaine Mai, Barbara Moffat, Dorothea Reilly, Amy Lim, Eileen Duenas, Kelly Dodge, Laura Simmons, Arthur Huang, Daniel G. Yansura
Journal: Cancer Research (2004)

1424  The proto-oncogene cMet is a receptor tyrosine kinase that is expressed in many epithelial cancers. On binding by its ligand, HGF, cMet activates cellular pathways that promote proliferation and invasive growth, characteristics of aggressive tumor behavior. We have produced a panel of monoclonal antibodies to the extracellular domain of cMet, one of which, 5D5, inhibits binding by HGF. As a normal, bivalent antibody, 5D5 is a potent cMet activator, but the monovalent Fab is a potent HGF antagonist that inhibits HGF-induced proliferation and migration. However, the Fab has a very short half-life in vivo, which limits its utility in animal models. To address that issue, we have produced a one-armed version of 5D5 by co-expressing 3 polypeptides in E coli. The first is a chimeric light chain consisting of the VL domain from the 5D5 murine hybridoma fused to human kappa constant domain. The second is a chimeric heavy chain consisting of the VH domain from the 5D5 murine hybridoma fused to the constant domains of human IgG1. And the third is an Fc domain, beginning at the hinge and ending with the normal carboxy terminus. The heavy chain covalently associates with both the light chain, through the normal heavy-light disulfide bond, and the truncated Fc, through the normal heavy-heavy disulfide bonds at the hinge. The result is a dimeric Fc from which emanates a single antigen-binding arm. Also produced are smaller amounts of bivalent antibody and dimers of truncated Fc. To further promote formation of the desired product, a “knob” (T366W) was introduced into the truncated Fc construct and a corresponding “hole” (T366S, L368A, Y407V) into the heavy chain. With this modification, >95% of the protein produced is the one-armed antibody. The one-armed version of 5D5 binds cMet with a Kd ∼4 nM and retains the ability to displace HGF binding (IC50 ∼ 5 nM). Like the Fab, it inhibits HGF-stimulated tyrosine phosphorylation of cMet, and inhibits HGF-induced proliferation and migration. Unlike the Fab, which has a half-life in mice of ∼15 minutes, the one-armed 5D5 has a half-life of 4.3 days, approaching that for a normal human IgG1 (∼7 days). As judged by SDS PAGE, the one-armed 5D5 remained intact in circulation for the entire 14 days of the PK experiment. Treatment of nude mice with the one-armed 5D5 (10 mg/kg weekly x 4) at the same time that the mice were inoculated with U87 glioma cells, which express cMet and produce HGF in an autocrine manner, completely prevented tumor development. Moreover, the one-armed 5D5 caused complete, dose-dependent regression of U87 glioma tumors when treatment was delayed until tumors were established. These results suggest that the one-armed 5D5 could have therapeutic utility in HGF-dependent neoplasias.
The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study
Authors: Peter Kiessling, Rocio Lledo-Garcia, Shikiko Watanabe, Grant Langdon, Diep Tran, Muhammad Bari, Louis Christodoulou, Emma Jones, Graham Price, Bryan Smith, Frank Brennan, Ian White, Stephen Jolles
Journal: Science Translational Medicine (2017)

Pathogenic immunoglobulin G (IgG) autoantibodies characterize some human autoimmune diseases; their high concentration and long half-life are dependent on recycling by the neonatal Fc receptor (FcRn). Inhibition of FcRn is an attractive new treatment concept for IgG-mediated autoimmune diseases. Rozanolixizumab (UCB7665; CA170_01519.g57 IgG4P) is an anti-human FcRn monoclonal antibody. In cynomolgus monkeys, rozanolixizumab reduced IgG (maximum 75 to 90% by about day 10), was well tolerated, and did not increase risk of infection. We also report a first-in-human, randomized, double-blind, placebo-controlled, dose-escalating study of intravenous (IV) or subcutaneous (SC) rozanolixizumab in healthy subjects (NCT02220153). The primary objective was to evaluate safety and tolerability. Secondary objectives were assessment of rozanolixizumab pharmacokinetics and pharmacodynamics, including effects on circulating IgG concentrations. Forty-nine subjects were randomized to receive rozanolixizumab (n = 36) or placebo (n = 13) across six cohorts. The first three cohorts received IV doses, and the subsequent three cohorts received SC doses, of rozanolixizumab 1, 4, or 7 mg/kg (n = 6 for each cohort; plus n = 7 or 6 for placebo, respectively). The most frequent treatment-emergent adverse event [TEAE; headache, 14 of 36 (38.9%) subjects] was dose-dependent and more prominent after IV administration. Severe TEAEs occurred in four subjects, all in the highest-dose IV group [headache (n = 3) and back pain (n = 1)]. Rozanolixizumab pharmacokinetics demonstrated nonlinear increases with dose. There were sustained dose-dependent reductions in serum IgG concentrations (IV and SC rozanolixizumab). These data provide clinical evidence for the therapeutic potential of rozanolixizumab.
FRI0070 Safety and tolerability of a rapid infusion of remicade (infliximab) in the treatment of rheumatoid arthritis
Authors: RA Isern, C Sanders, G Hughes, S Toder, G Keenan
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The safety of infliximab has been established in both open-label and randomised controlled clinical trials in which patients received infliximab over 2 hrs. In clinical trials, no difference was observed in the incidence of infusion reactions at any infliximab dose between 3 and 10 mg/kg given over 2 h. This clinical experience supported the safety of administering infliximab 3 mg/kg over 1 hr (Maini, 1999). Current guidelines advise infusing infliximab over at least 2 h. <h3>Objectives</h3> To determine if infliximab given at 3 mg/kg over 1 hr is safe and well tolerated in the clinic setting. <h3>Methods</h3> Patients with active RA enrolled at selected sites in an ongoing open-label clinical trial of infliximab were eligible to receive two open-label 1-hr infusions of infliximab 3 mg/kg if they had previously tolerated four 2-hr infusions (at Weeks 0, 2, 6, and 14) without any moderate to severe infusion related reactions or hypersensitivity reactions and had no significant history of cardiac or renal impairment. Safety evaluations included measurements of vital signs during and immediately after the infusions of infliximab and assessment for adverse events. <h3>Results</h3> One hundred ninety patients (76% women and 24% men) received infliximab 3 mg/kg given over 1 hr. Patients ranged in age from 26 to 82 yrs (mean of 59.4 yrs). Twelve (6%) patients reported adverse events associated with the first or second 1-hr infusion of infliximab. Headache, hypersensitivity, and hypertension were each reported by two (1%) patients. The following adverse reactions were reported by one (0.5%) patient each: anaphylactic reaction, blood pressure decreased, chest tightness, dizziness, itching, maculopapular rash, and somnolence. Only 3 patients discontinued infliximab therapy as a result of an infusion-related reaction (1 with anaphylactic reaction and 2 with allergic reaction). All reactions, which were generally mild or moderate in nature, resolved within 1 day of onset. <h3>Conclusion</h3> Infliximab 3 mg/kg administered over 1 hr was well tolerated by these patients with active RA. <h3>Reference</h3> Maini RN, St. Clair EW, Maini RN, <i>et al</i>. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999;354:1032–1939
Partial splenic artery embolization for severe hepatic myelopathy in cirrhosis
Authors: Cyriac Abby Philips, Lijesh Kumar, Philip Augustine
Journal: Hepatology (2017)

Hepatic myelopathy (HM) is a devastating but rare complication of cirrhosis and portal hypertension that profoundly affects quality of life and improves only with liver transplantation. We present a case where progressive severe spastic paraparesis due to HM was substantially reversed with partial splenic artery emobilization (PSAE). (H epatology 2018;67:1169–1171)