tbuckley/cabot-search huggingface dataset:
Effect of cancer vaccine formulation on synergy with anti-CTLA-4 and anti-PD-L1 checkpoint blockade therapy of cancer.
Authors: Yared Hailemichael, Tihui Fu, Amber Woods, Kimberly Schluns, Victor H Engelhard, Padmanee Sharma, Willem W Overwijk
Journal: Journal of Clinical Oncology (2016)

3094 Background: A promising avenue to increase the efficacy of anti-CTLA-4 and anti-PD-(L)1 checkpoint blockade therapies is to enhance T cell induction through vaccination. Surprisingly, concurrent gp100 peptide vaccination decreased clinical efficacy of anti-CTLA-4 in patients with melanoma. As a result, it is currently unclear how to effectively combine checkpoint blockade therapy with vaccination. We used an animal model of gp100 peptide vaccination and CTLA-4/PD-L1 checkpoint blockade to understand this phenomenon and define parameters for successful combination of checkpoint blockade and vaccination. Methods: We treated established B16 melanoma tumors with anti-CTLA-4 therapy and concurrent vaccination with gp100/IFA and studied T cell expansion, trafficking and therapeutic effector function. Results: Anti-CTLA-4 monotherapy significantly increased intratumoral levels of TRP-2 melanoma antigen-specific Teffs, as well as total CD44hiCD11ahiCD8lo Teffs at the tumor site. Conversely, gp100/IFA vaccination-induced, gp100-specific CD8+ T cells accumulated at the inflamed vaccination site. Surprisingly, combination of gp100/IFA vaccination and anti-CTLA-4 therapy caused non-gp100-specific Teff, induced by anti-CTLA-4 therapy, to also accumulate at the vaccination site and not at the tumor site. This Teff sequestration at the vaccination site was dependent on IFN-g, CXCR3 and ICAM-1. Replacing the gp100/IFA formulation with a gp100-encoding viral vector or a non-persistent, water-based formulation potently synergized with anti-CTLA-4 or anti-PD-L1 resulting in a high proportion of complete cure. Conclusions: Persistent vaccine formulations can fail to synergize, or even diminish the efficacy of, CTLA-4/PD-(L)1 checkpoint–based cancer immune therapy through the induction of aberrant T cell trafficking to the vaccination site. A non-persistent vaccine formulation can reverse these undesirable effects and potently synergize with anti-CTLA-4 and/or anti-PD-(L)1 checkpoint blockade, resulting in significantly improved anti-tumor activity.
LDL/HDL Ratio Predicts the Rate of Uncovered Stent Strut Evaluated by Optical Coherence Tomography
Authors: Anjo Naofumi, Taguchi Isao, Komatsu Takaaki, Nakagawa Ayako, Nishiyama Naoki, Yamada Kota, Higashi Akihiro, Toratani Mizuho, Nakamura Hidehiko, Hori Yuichi, Komatsu Sachiko, Fujikake Akinori, Hayashi Akiko, Kuroyanagi Takanori, Nakahara Shiro, Chida Ryuji, Hisauchi Itaru, Sakai Yoshihiko
Journal: Circulation (2016)
Abstract 250: Adult Cardiac Stem Cells regulation by microRNAs
Authors: Alex J Matsuda, Ana I Pinheiro, Andreia Amaral, Margarida Gama-Carvalho, Luís Rosário, Jan Kajstura, Piero Anversa
Journal: Circulation Research (2013)

In recent years stem and progenitor cells have been identified in the heart, changing our understanding and therapeutic approach of heart disease. These cells can proliferate and differentiate in vitro into beating cardiomyocytes, endothelial and vascular smooth muscle cells, providing the potential for tissue regeneration and repair. microRNAs (miRs) have been identified as master switches controlling proliferation and differentiation, and in particular as key regulators of stem cells and cardiac development and function. Modulation of miR-regulated gene expression networks holds the potential to control cell fate and proliferation, with predictable biotechnological and therapeutic applications. We have characterized the expression profile of a subset of 100 miRs with reported functions in stem cell and tissue differentiation in mouse Sca1+ cardiac progenitor cells (CPCs). CPC miR expression profiles were compared with bone marrow mesenchymal stem cells (MSCs) and mouse embryonic heart (E=9) to obtain insights into the origins and function of this rare cell population. Within the miR panel that was studied, a subset with relative high expression levels in CPCs was identified, which may act as negative regulators of differentiation and proliferation. Although the overall expression profile of Sca1+ CPCs is closer to BM-MSCs, the most highly expressed miRs in CPCs are distinctive and predicted to target key genes involved in the control of cell proliferation and adhesion, vascular function and cardiomyocyte differentiation. Our results provide novel insights into the gene expression networks active in CPCs, which will now be explored in functional studies to identify key regulators of proliferation and differentiation.
Moderate dietary sodium restriction in outpatients with cirrhosis and ascites iIn the real life: adherence and more
Authors: Filippo Morando, Silvia Rosi, Silvano Fasolato, Salvatore Silvio Piano, Mariateresa Nardi, Marta Cavallin, Francesca Campagna, Sara Montagnese, Marialuisa Stanco, Lorenza Caregaro Negrin, Angelo Gatta, Paolo Angeli
Journal: Hepatology (2013)
08.50 Anti-destructive effect of rituximab and b-cell count in rheumatoid arthritis patients
Authors: Anastasia V Pivanova, Galina V Lukina, Yakov A Sigidin, Aleksandr V Smirnov, Kristina Kh Kuzikyants, Anna Yu Kuznetsova, Evgeni L Nasonov
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objective</h3> To study the impact of B-cells depleting therapy (RTM) on joint destruction in correlation with B-cells counts. <h3>Materials and methods</h3> The study included 61 RA pts (average disease duration 10,1±7,7 y., mean DAS28 6,3±0,94, RF-positive - 87%, ACCP–positive 93%) undergoing RTM therapy. Clinical effect was scored by EULAR criteria, radiographic progression was assessed using Sharp/van der Heijde (SvH) modified scoring method. B-cell level was measured with flow cytometry. <h3>Results</h3> By Week 48 after 2 RTM course good response was documented in 29,7% pts, good and satisfactory - in 85,3%; remission was achieved in 14,6% pts. There was no radiographic progression in remission pts., in 83% of pts with low disease activity and in 33% - with moderate disease activity. Of note, further progression in joint space narrowing was more pronounced than bony tissue destruction - in 32% and 25%m respectively. Clinical and anti-destructive effects were often dis-matching: bone destruction was abrogated without any clinical improvement in 54% of pts. There was no significant difference in clinical effects of RTM dosing regimens (1000 mg x2 or 500 mg x2). More potent anti-destructive effect was documented in pts getting higher RTM dose values. No significant influence of B-cells depletion on radiographic progression of the disease was noticed. Although, in RA pts achieving remission B-cell depletion was more notable as compared to pts with active disease. <h3>Conclusion</h3> Therapeutic effect of two dosing regimens was similar, but the protective effect against bone destruction was more pronounced with higher RTM doses. Radiographic progression did not show any correlation with the degree of B-cells depletion. Most pronounced B-cells depletion was documented in pts achieving remission.
Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer
Authors: Svasti Haricharan, Nindo Punturi, Purba Singh, Kimberly R. Holloway, Meenakshi Anurag, Jacob Schmelz, Cheryl Schmidt, Jonathan T. Lei, Vera Suman, Kelly Hunt, John A. Olson, Jeremy Hoog, Shunqiang Li, Shixia Huang, Dean P. Edwards, Shyam M. Kavuri, Matthew N. Bainbridge, Cynthia X. Ma, Matthew J. Ellis
Journal: Cancer Discovery (2017)

Abstract Significant endocrine therapy–resistant tumor proliferation is present in ≥20% of estrogen receptor–positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor–resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care. Significance: MutL deficiency in a subset of ER+ primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy–resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168–83. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1047
De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017
Authors: G Curigliano, H.J. Burstein, E.P. Winer, M. Gnant, P. Dubsky, S. Loibl, M. Colleoni, M.M. Regan, M. Piccart-Gebhart, H.-J. Senn, B. Thürlimann, F. André, J. Baselga, J. Bergh, H. Bonnefoi, S.Y. Brucker, F. Cardoso, L. Carey, E. Ciruelos, J. Cuzick, C. Denkert, A. Di Leo, B. Ejlertsen, P. Francis, V. Galimberti, J. Garber, B. Gulluoglu, P. Goodwin, N. Harbeck, D.F. Hayes, C.-S. Huang, J. Huober, H. Khaled, J. Jassem, Z. Jiang, P. Karlsson, M. Morrow, R. Orecchia, K.C. Osborne, O. Pagani, A.H. Partridge, K. Pritchard, J. Ro, E.J.T. Rutgers, F. Sedlmayer, V. Semiglazov, Z. Shao, I. Smith, M. Toi, A. Tutt, G. Viale, T. Watanabe, T.J. Whelan, B. Xu
Journal: Annals of Oncology (2017)
LEFT VENTRICULAR REMODELING IN YOUNG BLACK ATHLETES
Authors: Giorgio Galanti, Loira Toncelli, Niccolò Gori, Valentina Di Tante, Gabriele Mascherini, Benedetta Tosi
Journal: British Journal of Sports Medicine (2017)

Background EKG analysis investigating the impact of the ethnicity on cardiac adaptation to exercise has shown a higher presence of abnormalities, including marked repolarization changes, and signs of left ventricular (LV) hypertrophy in black compared to white athletes. Despite the wide availability of EKG analysis, echocardiographic studies on young black and white athletes is lacking in literature. Objective Assess the effect in the secondary LV remodelling to load training in young black players compared to matched white players. Design 4 years longitudinal study. Setting Sport Medicine outpatients clinic. Patients 49 young black soccer players (BP) and 50 white matched soccer players (WP) at the first evaluation: BP=13.3±0.58 and WP=13.9±0.50 years. Interventions Echocardiography and EKG. Main Outcome Measurements Interventricular septum (IVS) and posterior wall (PW) thickness. Results No differences in weight, height, blood pressure in maximal ergometry test. Electrocardiographic repolarization changes were significantly more frequent in BP compared to WP (55% in BP vs 7% of WP). In BP we observed higher level of LV remodelling, consisted in higher LV wall thickness, i.e. higher interventricular septum (IVS) and posterior wall (PW) thickness (IVS: BP=9.99±0.17, WP=9.07±0.14, p&lt;0.001. PW: BP=9.61±0.25, WP=8.85±0.3 mm, p&lt;0.001). At the beginning, BP showed a significantly higher left ventricular remodelling (IVS: BP=9.14±0.6, WP=8.54±0.21 mm, p&lt;0.001. PW: BP=8.98±0.6, WP=8.4±0.26, p&lt;0.001). Afterwards we observed an increase in LV wall thickness and chambers diameters proportionally with the increase in body-size and LV mass. (IVS: BP=10.87±0.23, WP=9.09±0.28 mm, p&lt;0.001. PW: BP=11.69±1.32, WP=9.02±0.24 mm, p&lt;0.001). Conclusions Also in young blacks athletes we can find an higher cardiac wall thickness compared to their Caucasian peers. This differences remained after 5 years giving probably reason of the fact that those remodelling events happened in the first years of life by genetic factors.
Abstract 18259: A Novel Approach to Address Door-to-ECG Time for Walk-In Patients by Training Non-Medical Staff to Recognize Symptoms of Possible Acute Coronary Syndrome
Authors: Joshua A Stanton, John A Spitzer, Lea A Becker, Barbara Craighead, David Burt, Tyler Johnson
Journal: Circulation (2013)

Problem: The ACTION Registry®--GWTG™ Dashboard revealed in previous studies that triage personnel are having difficulty identifying when to perform an appropriate ECG in the recommended 10 minute time frame. Those studies showed that 80% of the missed ECG’s were walk-in patients whose first point-of-contact was registration or security. We have since used this information to implement a novel approach to decrease the time between presentation and 1 st ECG completion for patients with ACS symptoms. Methods: A pilot training program was developed and aimed at registration and security staff. Six, 1 hour classes trained all 84 Emergency Department (ED) auxiliary staff to focus on risk factors and clinical symptoms of ACS using specific case studies. A five question post-test was given to gauge understanding and retention. Class participants also completed a survey highlighting what they learned, enjoyed, and how to improve the course. Results: All of the participants passed the 5 question post-test focusing on ACS recognition and appropriate action. Eighty-five percent reported that they now feel comfortable in identifying MI symptoms. Fifteen percent of the course participants reported feeling gratification at being a member of the healthcare team with an increased sense of empowerment. All participants were offered an additional web-based training regarding STEMI’s and 10% have volunteered to observe a cardiac catheterization in their free time. The triage personnel course participants have overwhelmingly requested more sessions or yearly classes as the course’s only improvement. Conclusions: This program demonstrates that non-medical staff can be trained to quickly recognize symptoms concerning for ACS which can expedite evaluation and treatment. This program has the potential to improve door-to-ECG times and in addition increases morale. Anecdotally, a registration staff member has already identified a patient and facilitated an ECG within 7 minutes who was quickly identified to be having a STEMI. This program could be a model for other departments across the country to successfully improve patient care with the additional benefit of increasing departmental morale.
ヒドロゲルマトリックスを介して造血幹細胞とニッチ細胞間の動的シグナル伝達を調節する【Powered by NICT】
Authors: P Mahadik Bhushan, A K Bharadwaj Narayanan, H Ewoldt Randy, A C Harley Brendan
Journal: Biomaterials (2017)
Nodal stage migration and prognosis in anal cancer: a systematic review, meta-regression, and simulation study
Authors: Hema Sekhar, Marcel Zwahlen, Sven Trelle, Lee Malcomson, Rohit Kochhar, Mark P Saunders, Matthew Sperrin, Marcel van Herk, David Sebag-Montefiore, Matthias Egger, Andrew G Renehan
Journal: The Lancet Oncology (2017)
Comprehensive next generation sequencing assay and bioinformatic pipeline for identifying pathogenic variants associated with hereditary cancers.
Authors: Oscar Puig, Eugene Joseph, Malgorzata Jaremko, Gregory Kellogg, Robert Wisotzkey, Roman Shraga, Bonny Patel, Andrew Pollock, Rebecca Fox, Mohammad Niknazar, Sasha Parets, Georges Duverger, Chihyu Chang, Alexander Bisignano
Journal: Journal of Clinical Oncology (2017)

e13105 Background: Diagnosis of hereditary cancer syndromes involves time-consuming comprehensive clinical and laboratory work-up, however, timely and accurate diagnosis is pivotal to the clinical management of cancer patients. Germline genetic testing has shown to facilitate the diagnostic process, allowing for identification and management of individuals at risk for inherited cancers. However, the laboratory diagnostics process requires not only development and validation of comprehensive gene panels to improve diagnostic yields, but a quality driven workflow including an end-to-end bioinformatics pipeline, and a robust process for variant classification. We will present a gene panel for the evaluation of hereditary cancer syndromes, conducted utilizing our novel end-to-end workflow, and validated in the CLIA-approved environment. Methods: A targeted Next-Generation Sequencing (NGS) panel consisting of 130 genes, including exons, promoters, 5’-UTRs, 3’-UTRs and selected introns, was designed to include genes associated with hereditary cancers. The assay was validated using samples from the 1000 genomes project and samples with known pathogenic variants. Elements software was utilized for end-to-end bioinformatic process ensuring adherence with the CLIA quality standards, and supporting manual curation of sequence variants. Results: Preliminary data from our current panel of genes associated with hereditary cancer syndromes revealed high sensitivity, specificity, and positive predictive value. Accuracy was confirmed by analysis of known SNVs, indels, and CNVs using 1000 Genomes and samples carrying pathogenic variants. The bioinformatics software allowed for an end-to-end quality controlled process of handling and analyzing of the NGS data, showing applicability for a clinical laboratory workflow. Conclusions: We have developed a comprehensive and accurate genetic testing process based on an automated and quality driven bioinformatics workflow that can be used to identify clinically important variants in genes associated with hereditary cancers. It's performance allows for implementation in the clinical laboratory setting.
Novel plasmid-mediated colistin resistance mcr-4 gene in Salmonella and Escherichia coli, Italy 2013, Spain and Belgium, 2015 to 2016
Authors: Alessandra Carattoli, Laura Villa, Claudia Feudi, Ludovica Curcio, Serenella Orsini, Andrea Luppi, Giovanni Pezzotti, Chiara Francesca Magistrali
Journal: Eurosurveillance (2017)

A novel mcr colistin resistance gene was identified in a strain of Salmonella enterica, monophasic variant of serovar Typhimurium (4,5,12:i:- ), isolated from a pig at slaughter in Italy in 2013, and in Escherichia coli strains collected during routine diagnostic of post-weaning diarrhoea in pigs from Spain and Belgium in 2015 and 2016. Immediate implementation of mcr-screening including this novel gene variant is required for Salmonella and E. coli from humans and food-producing animals in Europe.
2015/16 seasonal vaccine effectiveness against hospitalisation with influenza A(H1N1)pdm09 and B among elderly people in Europe: results from the I-MOVE+ project
Authors: Marc Rondy, Amparo Larrauri, Itziar Casado, Valeria Alfonsi, Daniela Pitigoi, Odile Launay, Ritva K Syrjänen, Giedre Gefenaite, Ausenda Machado, Vesna Višekruna Vučina, Judith Krisztina Horváth, Iwona Paradowska-Stankiewicz, Sierk D Marbus, Alin Gherasim, Jorge Alberto Díaz-González, Caterina Rizzo, Alina E Ivanciuc, Florence Galtier, Niina Ikonen, Aukse Mickiene, Veronica Gomez, Sanja Kurečić Filipović, Annamária Ferenczi, Monika R Korcinska, Rianne van Gageldonk-Lafeber, Marta Valenciano
Journal: Eurosurveillance (2017)

We conducted a multicentre test-negative case-control study in 27 hospitals of 11 European countries to measure 2015/16 influenza vaccine effectiveness (IVE) against hospitalised influenza A(H1N1)pdm09 and B among people aged ≥ 65 years. Patients swabbed within 7 days after onset of symptoms compatible with severe acute respiratory infection were included. Information on demographics, vaccination and underlying conditions was collected. Using logistic regression, we measured IVE adjusted for potential confounders. We included 355 influenza A(H1N1)pdm09 cases, 110 influenza B cases, and 1,274 controls. Adjusted IVE against influenza A(H1N1)pdm09 was 42% (95% confidence interval (CI): 22 to 57). It was 59% (95% CI: 23 to 78), 48% (95% CI: 5 to 71), 43% (95% CI: 8 to 65) and 39% (95% CI: 7 to 60) in patients with diabetes mellitus, cancer, lung and heart disease, respectively. Adjusted IVE against influenza B was 52% (95% CI: 24 to 70). It was 62% (95% CI: 5 to 85), 60% (95% CI: 18 to 80) and 36% (95% CI: -23 to 67) in patients with diabetes mellitus, lung and heart disease, respectively. 2015/16 IVE estimates against hospitalised influenza in elderly people was moderate against influenza A(H1N1)pdm09 and B, including among those with diabetes mellitus, cancer, lung or heart diseases.
FRI0433 High prevalence of hidradenitis suppurativa in patients with axial spondyloarthritis
Authors: S Arends, A Rondags, F Wink, B Horváth, A Spoorenberg
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Axial spondyloarthritis (SpA) is associated with several extra-articular manifestations such as the skin disease psoriasis. On the other hand, SpA was found to be more prevalent (3–4%) in patients with another skin disease: hidradenitis suppurativa (HS).<sup>1</sup> HS is a chronic, recurrent, debilitating inflammatory skin disease that involves deep-seated painful nodules in the inverse body regions, with an average prevalence of 1% in the European population and a female predominance (ratio 3:1).<sup>2</sup> Thus far, the prevalence of HS in axial SpA is not exactly known. <h3>Objectives</h3> To investigate the prevalence of HS in patients with axial SpA. <h3>Methods</h3> A self-screening questionnaire with validated questions concerning HS signs and symptoms including prototypical pictures was send to all participating patients from the Groningen Leeuwarden axial SpA (GLAS) cohort in 2016. All patients fulfilled the ASAS axial SpA criteria. Self-reported HS symptoms were verified by checking medical records and/or verification by phone, defined as diagnosis of HS by a dermatologist. <h3>Results</h3> In total, 588 questionnaires were send to the GLAS patients, of which 459 were returned and could be included in the final analysis (response rate 78%). Of the included patients, mean age was 50±13 years, 63% were male, mean symptom duration was 23±13 years, and 78% were HLA-B27 positive. The questionnaire data showed a high self-reported HS prevalence of 11%. HS symptoms were confirmed by doctor9s diagnosis in the large majority of these patients (41/50; 82%), resulting in an estimated HS prevalence of 9%. The next step will be the comparison of patient characteristics and clinical assessments between axial SpA patients with and without HS. <h3>Conclusions</h3> The present observational cohort study shows that HS is a common skin disease in patients with axial SpA. <h3>References</h3> Richette et al. J Rheumatol 2014;41(3):490–4. Zouboulis et al. J Eur Acad Dermatol Venereol 2015;29(4):619–44. <h3>Disclosure of Interest</h3> None declared