tbuckley/cabot-search huggingface dataset:
OSU03012, a novel PDK1 inhibitor, decreases thyroid cancer proliferation and migration via multiple downstream pathways.
Authors: Leonardo M. Porchia, Marcy Guerra, Allan V. Espinosa, Motoyasu Saji, Samuel K. Kulp, Matthew D. Ringel, Ching-Shih Chen
Journal: Cancer Research (2006)

5138   Patients with progressive or poorly differentiated thyroid cancer frequently lose responsiveness to standard therapies and have a poor prognosis, creating a critical need to develop targets for therapies for progressive thyroid cancer. We have previously reported that invasive thyroid cancers are associated with overactivation of Akt and display Akt 1-dependent cell migration; and that Akt activation is essential for thyroid cancer cell proliferation and the action of a number of thyroid cancer oncogenes. More recently, we have demonstrated that aggressive thyroid cancers are associated with overexpression of EMT-related proteins, including vimentin and osteopontin, and by activation of p21-activated kinase (PAK), a central regulator of cytoskeletal changes involved in EMT that enhances vimentin expression and function. In addition, we have previously shown that vimentin expression is both necessary and sufficient for thyroid cancer cell invasion in vitro. OSU03012 (OSU) is a PDK1 inhibitor that is progressing to clinical trials through the NCI-RAID program. Because PDK-1 is upstream of both Akt and PAK, we hypothesized that OSU would inhibit proliferation and invasion, in association with reduced Akt and PAK activation. OSU treatment (2.5-10 μM) decreased cell proliferation of NPA (papillary), WRO (follicular), and ARO (anaplastic) thyroid cancer cells with IC50 values of 3.3, 6.7, and 6.1 μM respectively, at 24hr. In addition, a dose-dependent increase in apoptosis was observed over a concentration range of 2.5 - 10 μM in all cell lines, measured by DNA fragmentation and increased cleaved PARP. OSU treatment decreased phospho-Akt and phospho-PAK in parallel to these observations. For migration studies, NPA cells were used as they migrate most efficiently in vitro. OSU blocked NPA migration at doses lower than required to reduce cellular proliferation or Akt activity; however decreased levels of phospho-PAK at thr423 were detected at these concentrations. Transient overexpression of a PDK-1 independent constitutively active PAK abrogated the ability of OSU to block NPA cell migration. Vimentin phosphorylation at a PAK-specific site was also decreased in parallel to the reduction in PAK phosphorylation in NPA cells. Taken together, these data demonstrate that OSU, a novel PDK1 inhibitor, blocks thyroid cancer cell proliferation and migration through inhibition of both Akt and PAK. The effect on migration appears to be mediated mainly by inhibition of PAK activity, perhaps through altered intermediate filament organization by blocking vimentin phosphorylation. Thus, OSU-03012, a novel PDK1 inhibitor, inhibits thyroid cancer cell proliferation and migration through multiple pathways that are involved in thyroid cancer progression in patients.
HVEM: A novel cosignaling molecule of major interest in melanoma.
Authors: Nausicaa Malissen, Nicolas Macagno, Samuel Granjeaud, Clemence Granier, Vincent Moutardier, Caroline Gaudy Marqueste, Nadia Habel, Marion Mandavit, Bernard Guillot, Christine Pasero, Eric Tartour, Robert Ballotti, Jean Jacques Grob, Daniel Olive
Journal: Journal of Clinical Oncology (2017)

e14591 Background: Herpes Virus Entry Mediator (HVEM) is a member of the TNF superfamily, its ligation of the immunoglobulin family member B-lymphocyte and T-lymphocyte attenuator (BTLA) activates inhibitory signaling in T-cells and could play a role in evading host anti-tumor immunity. Ectopic overexpression of HVEM is associated with poor survival in some solid tumors. Our objectives were: -to evaluate HVEM expression in melanoma (MM) -to explore potential link of its overexpression with clinical outcomes -to understand the mechanisms by which HVEM was ectopically expressed in MM, and how HVEM-BTLA may play a role in MM. Methods: HVEM expression was analyzed by IHC in formalin-fixed samples of mm metastases and was correlated with OS in 130 patients. To better understand how HVEM could interfere with prognosis, relation of HVEM with its ligand BTLA was studied in the tumor and tumor microenvironment on 15 fresh metastases by flow cytometry after tumor dissociation. Bioinformatic studies based on TCGA and CCLE data combined to targeting of candidate genes by siRNA were used to investigate HVEM regulation on MM. Results: Patients with high HVEM expression on mm cells in their metastases have a significantly (p = 0.0142) poorer overall survival than those with a low expression. TCGA transcriptomic data support these results. From the mechanistic point of view, we could show that 1-HVEM expressed at the tumor cell surface interacts with BTLA expressed by tumor-infiltrated lymphocytes. 2-HVEM expression is neither linked to the mm mutational status nor inducible by IFN 3-Genes co-regulated with HVEM are associated with an aggressive gene signature 4- HVEM strongly correlate with MITF expression, MITF binds HVEM promoter, and its downregulation by siRNA results in a decrease in HVEM expression. Conclusions: A high expression of HVEM by mm metastases seems to be a pejorative prognostic marker. HVEM-BTLA interaction is a co-signaling system similar to the PD1-PDL1 one, but seem to be constitutive rather than inducible. HVEM and its co-regulated genes may constitute a signature of aggressiveness associated to MITF. High HVEM expression on mm cells may dampen anti-tumor immune responses, making HVEM and BTLA potential new targets for “checkpoint blockade” therapy.
Evaluation of a recombinant HER2 vaccine: Induction of specific antibodies, T-cells and preliminary activity in metastatic breast cancer patients
Authors: S. A. Limentani, M. Campone, T. Dorval, E. Tan-Chiu, G. Curigliano, R. De Boer, J. Canon, T. Bachelot, J. Louahed, V. G. Brichard
Journal: Journal of Clinical Oncology (2006)

631 Background: We designed a vaccine to induce T cells able to recognize epitopes from HER2 and to engender a polyclonal antibody reponse. Methods: The vaccine is a recombinant HER2 protein, including its extra and part of its intra-cellular domains (ECD/ICD), combined with a potent immunologic adjuvant. Cohorts of patients with Stage II/III breast cancer (BC) received 20, 100 or 500 μg in the adjuvant setting. Treatment comprised of six vaccinations over 14 weeks, for the 500-μg dose, recall injections were given on weeks 34 and 38. The trial was extended to include an alternative vaccination schedule: 500 μg on days 0, 28 and 98. In an on-going trial, patients with metastatic BC treated in the first line setting are receiving the 500-μg treatment and being assessed for clinical response. Results: The vaccine was well tolerated, with no symptomatic cardiotoxicity. Antibody (Ab) response against ECD was dose-dependent, with 2/12, 9/14 and 14/15 immune responders in the respective cohorts after four vaccinations. Response was dose-related. Ab isotypes were analyzed in the 500 μg cohort: in 50% of patients, high levels of IgM (30–60%) against ECD were found after four vaccinations. The switch towards IgG was complete in all patients after six vaccinations. The efficacy of booster vaccinations was observed mainly in patients with low IgM after eight weeks. After two vaccinations, Ab titers on the alternative 500 μg vaccination schedule were as high as after four vaccinations utilizing the initial schedule. The anti-ECD antibodies in 11/15 patients (500 μg level) bound HER2-overexpressing breast-cancer cell lines. In sera from 2 patients tested thus far, the gene-expression resembled that of trastuzumab. Assays show that specific T cells were obtained; detailed analysis is continuing. Among metastatic patients, two showed evidence of tumor regression after vaccination. Conclusions: The HER2 vaccine was well tolerated and induced (dose-dependently) anti-ECD Ab that bound the HER2 receptor. Data suggest that the vaccine also induced specific T-cell immunity. The alternative vaccination schedule may increase the Ab titers. This data justifies further evaluation of this vaccine in the phase II/III setting. [Table: see text]
α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming
Authors: Pu-Ste Liu, Haiping Wang, Xiaoyun Li, Tung Chao, Tony Teav, Stefan Christen, Giusy Di Conza, Wan-Chen Cheng, Chih-Hung Chou, Magdalena Vavakova, Charlotte Muret, Koen Debackere, Massimiliano Mazzone, Hsien-Da Huang, Sarah-Maria Fendt, Julijana Ivanisevic, Ping-Chih Ho
Journal: Nature Immunology (2017)
Abstract 179: Mechanical Assessment of the Drosophila Heart Reveals Conservation of Human Heart Failure Mechanisms
Authors: Gaurav Kaushik, Mayuko Nishimura, Rolf Bodmer, Anthony Cammarato, Adam J Engler
Journal: Circulation Research (2012)

Rationale: Current models for investigating the mechanisms of heart failure are limited by low throughput or genetic intractability. Therefore, we have developed a nanoindentation method to measure the intrinsic stiffness of the intact, living Drosophila heart tube to assess mechanical function in this rapidly aging, genetically malleable system which has been shown to experience age-related decline in cardiac function. Objective: Fruit fly strains universally experience decline in fractional shortening with age due to decreased diastolic diameter, though severity varies between strains. We compared a strain with significant decline in diameter with age and one without to examine the hypothesis that diastolic decline is the consequence of increase passive tension due to myocardial stiffening with age. Quantitative PCR was employed targeted towards mechanosensitive molecules known to be overexpressed in failing human hearts. Methods and Results: Female yw flies experience ∼18% reduction in diastolic diameter with age (59.3 at 1 week to 48.4 µm at 5 weeks of age, p &lt; 10-3) as calculated from m-mode kymographs of beating heart tube. Nanoindentation reveals 111% increase in stiffness (1.82 to 3.85 kPa, p &lt; 10-10) proximal to the cardiac cell-cell junctions. In contrast, w1118 flies experience ∼6% decline in diastolic diameter (74.1 to 69.5 µm, p = 0.049) and do not stiffen with age (p = 0.1923). qPCR reveals increased expression of cell-cell adhesion molecules in yw, such as vinculin and cadherin. Expression levels remain steady or decline in w1118. Further analysis reveals that w1118 experiences separation between juxtaposed muscle layers (410 nm at 1wk, 448 nm at 5wks) indicating matrix adhesion defects not observed in yw (0 nm, p &lt; 10-7 compared to 1wk w1118; 0 nm, p &lt; 10-8 compared to 5wk w1118). Conclusion: These data indicate structural changes in the fly are a consequence of adherens-junction-mediated mechanical remodeling similar to that which is observed in the failing human heart. Matrix defects and the lack of remodeling in w1118 suggest a link between costamere and adherens signaling during aging. Cardiac matrix content and adhesion signatures likely direct cardiac remodeling and function.
Temporal analysis of EGFR signaling in HeLa cells using a peptide-based multiplex immunoassay for site-specific tyrosine phosphorylation
Authors: Amy Hall, James Graham, Cheryl Murphy, Timothy Nadler, Neal Gordon, Kellie Watson, Jeffrey Radding
Journal: Cancer Research (2008)

3508  Tyrosine phosphorylation, a critical regulator of cellular signaling cascades, is dysregulated in various diseases, including cancer. Phosphorylation pathways overlap, intersect and feedback, creating complex signaling networks that requires a broad systems-level analysis to determine relevant phosphorylation patterns or “signatures” for defining disease models. An antibody array platform, with a peptide-based immunoassay design, was developed to detect 45 tyrosine phosphorylation sites on 34 different proteins simultaneously, in a single sample (Ti-Tyr™ Chip, Epitome Biosystems, Inc). As aberrant EGFR signaling has been implicated in various types of human cancers, we used this antibody array to identify and quantify time-dependent changes in phosphorylation downstream of the EGF receptor in HeLa cells, stimulated with EGF. Changes in site-specific phosphorylation of downstream targets were quantified for important regulators of migration (PLC gamma, FAK), cell proliferation (Her2, Shc, Crk, Erk) and receptor endocytosis /degradation (Cbl, Ack). Temporal and quantitative analysis demonstrated differences in EGF-induced p38 and Erk phosphorylation profiles. In addition, the cell surface receptor tyrosine kinases, EGFR and Her2, showed different temporal activation profiles suggestive of EGFR transactivation of Her2. Peptide-based immunoassays for tyrosine phosphorylation can be used for temporal and quantitative analysis of phosphorylation for profiling receptor tyrosine kinase signaling, at a site-specific level. Changes in tyrosine phosphorylation “signatures” can be used to monitor responses to pathway stimulation and therapeutic interventions.
Synovial tissue research: a state-of-the-art review
Authors: Carl Orr, Elsa Vieira-Sousa, David L. Boyle, Maya H. Buch, Christopher D. Buckley, Juan D. Cañete, Anca I. Catrina, Ernest H. S. Choy, Paul Emery, Ursula Fearon, Andrew Filer, Danielle Gerlag, Frances Humby, John D. Isaacs, Søren A. Just, Bernard R. Lauwerys, Benoit Le Goff, Antonio Manzo, Trudy McGarry, Iain B. McInnes, Aurélie Najm, Constantino Pitzalis, Arthur Pratt, Malcolm Smith, Paul P. Tak, Sander W. Tas, Rogier Thurlings, João E. Fonseca, Douglas J. Veale
Journal: Nature Reviews Rheumatology (2017)
Clinical academic workforce continues to shrink
Authors: Abi Rimmer
Journal: BMJ (2017)

The UK Medical Schools Council recently published the findings of its survey of clinical academic staffing.1 The council gathered data from all 33 publicly funded UK medical schools on 31 July 2016. The survey did not include the newly established private medical schools.

The survey found that UK medical schools employed 3041 full time equivalent clinical academic staff …
Multicentre, randomised clinical trial of paediatric concussion assessment of rest and exertion (PedCARE): a study to determine when to resume physical activities following concussion in children
Authors: Andrée-Anne Ledoux, Nicholas J Barrowman, Kathy Boutis, Adrienne Davis, Sarah Reid, Gurinder Sangha, Ken J Farion, Kevin Belanger, Mark S Tremblay, Keith Owen Yeates, Carol DeMatteo, Nick Reed, Roger Zemek
Journal: British Journal of Sports Medicine (2017)

Introduction Rest until symptom-free, followed by a progressive stepwise return to activities, is often prescribed in the management of paediatric concussions. Recent evidence suggests prolonged rest may hinder recovery, and early resumption of physical activity may be associated with more rapid recovery postconcussion. The primary objective is to determine whether the early reintroduction of non-contact physical activity beginning 72 hours postinjury reduces postconcussive symptoms at 2 weeks in children following an acute concussion as compared with a rest until asymptomatic protocol. Methods and analysis This study is a randomised clinical trial across three Canadian academic paediatric emergency departments. A total of 350 participants, aged 10–17.99 years, who present within 48 hours of an acute concussion, will be recruited and randomly assigned to either the study intervention protocol (resumption of physical activity 72 hours postconcussion even if experiencing symptoms) or physical rest until fully asymptomatic. Participants will document their daily physical and cognitive activities. Follow-up questionnaires will be completed at 1, 2 and 4 weeks postinjury. Compliance with the intervention will be measured using an accelerometer (24 hours/day for 14 days). Symptoms will be measured using the validated Health and Behaviour Inventory. A linear multivariable model, adjusting for site and prognostically important covariates, will be tested to determine differences between groups. The proposed protocol adheres to the RCT-CONSORT guidelines. Discussion This trial will determine if early resumption of non-contact physical activity following concussion reduces the burden of concussion and will provide healthcare professionals with the evidence by which to recommend the best timing of reintroducing physical activities. Trial registration number Trial identifier (Clinicaltrials.gov) NCT02893969 .
NEOD001 Demonstrates Organ Biomarker Responses in Patients with Light Chain Amyloidosis and Persistent Organ Dysfunction: Results from the Expansion Cohort of a Phase 1/2 Study
Authors: Morie A. Gertz, Raymond L. Comenzo, Heather Landau, Vaishali Sanchorawala, Brendan M. Weiss, Jeffrey A. Zonder, Jackie Walling, Gene G. Kinney, Martin Koller, Dale B. Schenk, Spencer D. Guthrie, Enchi Liu, Michaela Liedtke
Journal: Blood (2016)
AN INCREASING INCIDENCE OF INJURIES DURING THE SUPER RUGBY TOURNAMENT: A PROSPECTIVE STUDY OVER 4 YEARS INVOLVING 69 194 PLAYER-HOURS
Authors: Martin Schwellnus, Dina Christina Janse van Rensburg, Charl Janse van Rensburg, Esme Jordaan, Audrey Jansen van Rensburg, Wayne Derman, Clint Readhead
Journal: British Journal of Sports Medicine (2017)

Background Rugby Union has one of the highest reported incidences of match injuries among all professional sports. The Super Rugby tournament is played annually between professional rugby union teams from three rugby-playing nations in the Southern hemisphere. Objective To determine if the incidence of injuries in the Super Rugby tournament decreased over a 4-year period. Design Prospective cohort study. Setting Super Rugby tournament. Patients (or Participants) 774 male players from 5 South African teams. Assessment of Risk Factors) Medical staff of South African teams participating in the 2012, 2013, 2014 and 2015 tournaments recorded all time loss injuries (all injuries and match injuries) and exposure hours (69 194 total playing hours; 6 132 match hours). Main Outcome Measurements Incidence of all injuries and match injuries (per 1000 hours play). Results The incidence of all injuries (per 1000 player hours; 95% CI) for each year was as follows: 2012 (9.2; 7.9–10.8); 2013 (11.6; 10.1–13.3); 2014 (11.4; 9.8–13.2), and 2015 (12.4; 10.9–14.1). The incidence of all injuries in 2015 was significantly higher compared to 2012. The overall incidence of match injuries (per 1000 player hours; 95% CI) for each year was as follows: 2012 (83.3; 69.4–99.2); 2013 (120.4; 103.6–139.2); 2014 (98.6; 83.3–116.0), and 2015(119.1; 102.9–137.2). The incidence of match injuries in 2013 and 2015 was significantly higher compared to 2012 and 2014. Conclusions There is an increased incidence of all injuries and match injuries in the Super Rugby tournaments between 2012–2015. After 2012, the incidence of match injuries is consistently higher than previously reported for senior male rugby players at elite/professional level (89–96 per 1000 hrs). There is an urgent need to introduce targeted injury prevention strategies in the Super Rugby tournament to reduce the risk of injuries.
The relationship between operator volume and outcomes after percutaneous coronary interventions in high volume hospitals in 1994–1996
Authors: David J Malenka, Paul D McGrath, David E Wennberg, Thomas J Ryan, Mirle A Kellett, Samuel J Shubrooks, William A Bradley, Bruce D Hettlemen, John F Robb, Michael J Hearne, Theodore M Silver, Matthew W Watkins, John R O’Meara, Peter N VerLee, Daniel J O’Rourke
Journal: Journal of the American College of Cardiology (1999)

The purpose of this study was to examine the relationship between annual operator volume and outcomes of percutaneous coronary interventions (PCIs) using contemporaneous data.The 1997 American College of Cardiology (ACC)/American Heart Association task force based their recommendation that interventionists perform > or = 75 procedures per year to maintain competency in PCI on data collected largely in the early 1990s. The practice of interventional cardiology has since changed with the availability of new devices and drugs.Data were collected from 1994 through 1996 on 15,080 PCIs performed during 14,498 hospitalizations by 47 interventional cardiologists practicing at the five high volume (>600 procedures per hospital per year) hospitals in northern New England and one Massachusetts-based institution that support these procedures. Operators were categorized into terciles based on their annualized volume of procedures. Multivariate regression analysis was used to control for case-mix. In-hospital outcomes included death, emergency coronary artery bypass graft surgery (eCABG), non-emergency CABG (non-eCABG), myocardial infarction (MI), death and clinical success (> or = 1 attempted lesion dilated to < 50% residual stenosis and no death, CABG or MI).Average annual procedure rates varied across terciles from low = 68, middle = 115 and high = 209. After adjusting for case-mix, clinical success rates were comparable across terciles (low, middle and high terciles: 90.9%, 88.8% and 90.7%, Ptrend = 0.237), as were all the adverse outcomes including death (low-risk patients = 0.45%, 0.41%, 0.71%, Ptrend = 0.086; high-risk patients = 5.68%, 5.99%, 7.23%, Ptrend = 0.324), eCABG (1.74%, 2.05%, 1.75%, Ptrend = 0.733) and MI (2.57%, 1.90%, 1.86%, Ptrend = 0.065).Using current data, there is no significant relationship between operator volumes averaging > or = 68 per year and outcomes at high volume hospitals. Future efforts should be directed at determining the generalizability of these results.
Efficacy and safety of new direct antiviral agents in hepatitis C virus–infected patients with diffuse large B‐cell non‐Hodgkin's lymphoma
Authors: Marcello Persico, Andrea Aglitti, Rosa Caruso, Amalia De Renzo, Carmine Selleri, Catello Califano, Ludovico Abenavoli, Alessandro Federico, Mario Masarone
Journal: Hepatology (2017)

The association of hepatitis C virus (HCV) with non-Hodgkin's lymphoma (NHL) has been demonstrated throughout the world. The new interferon-free direct antiviral agents (DAAs) showed high efficacy and safety, and preliminary data seem to confirm their activity on low-grade NHL. The question arises as whether or not-and how-to treat the HCV-positive patients suffering from diffuse large B-cell lymphomas (DLBCLs). The aim of this observational study was to evaluate whether DAA antiviral treatment of DLBCL/HCV-infected patients in concomitance with chemotherapy is a safe and effective option. Twenty (13 males and 7 females) HCV genotype 1b-positive subjects, undergoing chemotherapy for DLBCL, were enrolled between June 2015 and December 2015. After informed consent, all patients underwent antiviral therapy (AVT) with sofosbuvir/ledipasvir and chemotherapy (14 rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and 6 cyclophosphamide, doxorubicin, vincristine, and prednisone) for DLBCL. Complete hematological (Revised European-American Lymphoma classification, Ann Arbor, and International Prognostic Index [IPI] scores) and hepatological (viral markers, liver stiffness, and biochemical parameters) evaluations were made. A historical retrospective cohort of 101 DLBCL/HCV-positive patients not undergoing AVT was enrolled for comparison. DAA-treated and untreated patients were similar for sex distribution, IPI score, and NHL stage, and differed for age (older in treated), chemotherapy and use of AVT. Overall survival (OS) and disease-free survival (DFS) were evaluated among a 52-week of follow-up. No statistical difference was found in OS after 52 weeks (P = 0.122), whereas a statistically significant higher DFS was achieved in treated patients (P = 0.036). At the multivariate analysis, only IPI score and AVT were independently correlated with a better DFS. No differences in adverse events were reported.DAA treatment in concomitance with chemotherapy was shown to be safe and effective in influencing remission of aggressive lymphomas in HCV patients. (Hepatology 2018;67:48-55).