tbuckley/cabot-search huggingface dataset:
Abstract 347: The Success of Humanizing Miniature Hearts is the Right Cannulation
Authors: Duong T Nguyen, Matthew O’Hara, Cecilia Graneli, Bo Peng, Navina Gunther, David Hammer, Li-Ming Gan, Magnus Althage, Sepideh Hagvall
Journal: Circulation Research (2017)

The development of humanized miniature organs through decellularization of rodent organs and recellularization with human cells will provide higher quality translational evidence for in vitro models from animal to human within basic research and pharmacological applications. Here, we have focused on the preservation of the circulation network within rat hearts by cannulating the superior vena cava (SVC), ascending aorta (A), pulmonary vein (PV), and pulmonary artery (PA) (deemed 4-Flow). Compared to the conventional Langendorff, the 4-Flow cannulation is superior by allowing control of both atria and ventricles for non-invasive mechanical stimulation and most advantageous is access to both the coronary arteries and cardiac veins. Hence, the objectives are to thoroughly recellularize the heart and to conduct ventricular mechanical stimulation. Controlled perfusion was conducted with inflow via the SVC and A, and outflow via PV and PA. The resin cast of a decellularized heart in Figure 1A demonstrates that the retrograde flow in addition to antegrade flow through both coronary vascular networks permit efficient whole heart perfusion of solutions, cells, and factors. Multiphoton microscopy (1B) reveals that cells are perfused to capillaries and tissues but more so with enzymatic treatment (1C-D). All of the valves’ functionality are maintained, hence, mechanical stimulation of the left ventricle is possible via perfusion through the PV to expand the left chamber until the aortic valve opens to relieve the pressure (1E-F). Consequently, a 4-Flow humanized miniature heart is the complex in vitro model that will revolutionize the translation into patient studies.
Assessment of heterogeneity of PD-L1 expression in NSCLC, HNSCC, and UC with Ventana SP263 assay.
Authors: Marietta L. Scott, Paul Scorer, Nicola Lawson, Marianne J Ratcliffe, Craig Barker, Marlon Rebelatto, Jill Walker
Journal: Journal of Clinical Oncology (2017)

e14502 Background: Clinical assessment of PD-L1 status relies on the result of testing 1 FFPE section per patient (pt). Heterogeneity of PD-L1 expression within a single tissue block and between paired blocks from the same pt could impact pt classification. This study characterizes the intra-block and intra-case heterogeneity using the VENTANA PD-L1 (SP263) Assay in non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) and urothelial carcinoma (UC) for tumor cell (TC) and immune cell (IC) staining. Methods: Two blocks from the same tumor for 5 cases of each of 3 indications (30 unique blocks) representing a range of PD-L1 staining were commercially acquired and sectioned serially at 4 μm. Tumor continuity throughout the blocks was confirmed by staining sections 1 and 51 with H&amp;E. Sections 2, 25 and 50 were stained with VENTANA SP263 and scored by a single trained pathologist, using the SP263 scoring algorithm and interpretation guide. Total percentages of PD-L1+ TCs and ICs were determined. Multiple diagnostic cutoffs were applied to TC and IC scores from multiple sections within each block and pair of blocks to establish overall percentage agreement (OPA) within and between blocks at each cutoff. Additional data were available in NSCLC for 200 cases with repeat SP263 staining (minimum separation 70 μm). Results: TC PD-L1 status at all cutoffs showed no intra-block (sections ~100 μm apart) or intra-case heterogeneity (Table). IC PD-L1 status showed limited intra-block and intra-case heterogeneity, with IC % staining in discordant sections varying by no more than 5%. Results are supported by the 200 NSCLC cases, with a minimum TC OPA across cutoffs of 91% (78.5% for ICs). Conclusions: Intra-block and intra-case concordance of TC PD-L1 status is high, and IC PD-L1 agreement is good across cutoffs. This supports the reproducibility of pt PD-L1 status in NSCLC, HNSCC and UC, within and between blocks. [Table: see text]
SAT0118 Association of renin-angiotensin system imbalance with subclinical atherosclerosis and disease activity in rheumatoid arthritis
Authors: N. F. T. Braz, M. R. C. Pinto, É. L. M. Vieira, A. L. Teixeira, A. C. S. Silva, A. M. Kakehasi
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Rheumatoid arthritis (RA) is an independent risk factor for cardiovascular disease (CVD). The renin-angiotensin system (RAS) is a hormonal cascade with important role in hydroelectrolytic homeostasis, blood pressure and regulation of cardiovascular remodeling. Angiotensin II (Ang II) acts as a proinflammatory mediator (1). <h3>Objectives</h3> To investigate the association of serum levels of RAS components with the presence of subclinical atherosclerosis using carotid ultrasonography in women with RA. <h3>Methods</h3> Women with RA according to ACR/EULAR 2010 or ACR 1987 criteria and without clinical ischemic CVD were included. Disease activity was assessed using the DAS28. The presence of atherosclerotic plaques and the thickness of the medium-intimal complex (EMI) of the arterial wall in the common carotid artery were evaluated by ultrasonography, Serum levels of angiotensin (Ang) II, Ang-(1-7), angiotensin converting enzyme (ECA) and ECA II were determined by enzyme immunoassay. <h3>Results</h3> 50 women with RA, mean age 48.2 years (±7.32), mean duration of disease of 15.35 years (±8.56), DAS28 of 4.02 (±1.41) and CDAI of 14.23 (±11.53) were included. Seven patients presented altered EMI, eight had atherosclerotic plaque. The prevalence of risk factors for CVD was: 12% of smoking, 12% of family history of premature CVD, 46% of arterial hypertension, 10% of diabetes, 62% of dyslipidemia, 94% of abdominal obesity and 46% of metabolic syndrome. The control group consisted of 30 healthy women, mean age of 46.3 years (±7.72). RA patients had a higher serum concentration of Ang II (p&lt;0.01), Ang-(1-7) (p&lt;0.01), and ACE (p&lt;0.01) than the control group (table 1). There was a negative correlation between ECA II and EMI (p=0.041, rho -0.290). EMI correlated positively with age (p=0.022, rho 0.324), disease duration (p=0.012, rho 0.315) and overall Framingham risk (p=0.008, rho 0.368) and Ang II correlated positively with DAS28 (p=0.034, rho 0.301) and CDAI (p=0.040, rho 0.291). <h3>Conclusions</h3> Imbalance of RAS components, especially Ang II and ECA II, may be associated to CVD in RA patients. Ultrasonography of the carotid arteries can identify patients that could benefit from ECA blockade. <h3>Reference:</h3> [1] Chang Y, Wei W. Angiotensin II in inflammation, immunity and rheumatoid arthritis. Clin Exp Immunol 2015;179:137-145. doi: 10.1111/cei.12467 <h3>Acknowledgements:</h3> National Council for Scientific and Technological Development (CNPq), Foundation for Research Support of Minas Gerais (FAPEMIG) <h3>Disclosure of Interest:</h3> None declared
Drug-delivering-drug platform-mediated potent protein therapeutics <i>via</i> a non-endo-lysosomal route
Authors: Xiaofei Xin, Chao Teng, Xiaoqing Du, Yaiqi Lv, Qingqing Xiao, Yubing Wu, Wei He, Lifang Yin
Journal: Theranostics (2018)

Protein therapeutics is playing an increasingly critical role in treatment of human diseases.However, current vectors are captured by the digestive endo-lysosomal system, which results in an extremely low fraction (<2%) of protein being released in the cytoplasm.This paper reports a drug-delivering-drug platform (HA-PNPplex, 200 nm) for potent intracellular delivery of protein and combined treatment of cancer.Methods: The platform was prepared by loading functional protein on pure drug nanoparticles (PNPs) followed by hyaluronic acid coating and was characterized by dynamic light scattering, transmission electron microscopy, and gel electrophoresis.In vitro, cellular uptake, trafficking, and cytotoxicity were evaluated by flow cytometry and confocal laser microscopy.Protein expression was assayed by western blot.In vivo, blood circulation and biodistribution were studied using a fluorescence imaging system, antitumor efficacy was assessed in a caspase 3-deficient tumor model, and biocompatibility was determined by comparison of hemolytic activity and proinflammatory cytokines and tissue histology.Results: HA-PNPplex delivered the functional protein, caspase 3, to cells via bypassing endo-lysosomes and raised the caspase-3 level 6.5-fold in caspase 3-deficient cells.Promoted tumor accumulation (1.5-fold) and penetration were exhibited, demonstrating a high tumor-targeting ability of HA-PNPplex.HA-PNPplex rendered a 7-fold increase in caspase 3 in tumor and allowed for a 100% tumor growth inhibition and >60% apoptosis, implying significant antitumor activities.Conclusions: This platform gains cellular entry without entrapment in the endo-lysosomes and enables efficient intracellular protein delivery and resultant profound cancer treatment.This platform, with extremely high drug-loading, is a valuable platform for combined cancer therapy with small-molecule drugs and proteins.More importantly, this work offers a robust and safe approach for protein therapeutics and intracellular delivery of other functional peptides, as well as gene-based therapy.
AB1077 Investigation of fraility, mobility and daily life activity in elderly
Authors: U.K. Sahin, A. Demircioglu, N. Kirdi
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> There are many factors that affect negatively mobility and daily life activity of older people. Fraility is one of these. frailty is a state of decline in physiologic reserve capacity and resiliency due to impairment in multiple physiological systems, thereby causing vulnerability to death and adverse health outcomes. <h3>Objectives</h3> The aim of this study was to analyse gender differences in frailty, mobility and daily life activity score. <h3>Methods</h3> The study included 173 women, 124 men total 197 persons aged 65 years and older. The demographic information including age, height and weight, the individuals marital status, educational state, chronic diseases were taken. Elderly Mobility Scale (EMS), Edmonton Frail Scale (EFS) and KATZ were used to evaluate mobility, fraility and daily life activities level, respectively. Individuals were divided into groups according to their gender. <h3>Results</h3> There was significant difference between women and men in EMS (p=0.001), EFS (p&lt;0.001) and KATZ scores (0.048). Fraility score were lower, mobility score and daily life activity score higher than women in men. In both men and women were found positively a relation between mobility and daily life activity (p&lt;0.001), were found negatively a relation between fraility and mobility, daily life activity (p&lt;0.001). <h3>Conclusions</h3> It was seen that female gender affected mobility, fraility and daily life activity. It is important that Strategies for preventing or delaying the predisposing factor of frailty need to address gender differences and determinants among women. <h3>References</h3> [1] Fried, L.P., Ferrucci, L., Darer, J., Williamson, J.D., &amp; Anderson, G. (2004). Untangling the concepts of disability, frailty, and co-morbidity: Implications for improved targeting and care. Journal of Gerontology<i>, Series A: Biological Sciences and Medical Sciences</i>, 59(3), 255–63. [2] Alexandre, Tiago da S., et al. "Gender differences in the incidence and determinants of components of the fraility phenotype among older adults: findings from the SABE study."Journal of aging and health30.2 (2018): 190–212. <h3>Disclosure of Interest</h3> None declared
Endoscopic gastric reduction with an endoluminal suturing device: a multicenter prospective trial with 1-year follow-up
Authors: Vincent Huberty, Evzen Machytka, Ivo Boškoski, Marie Barea, Guido Costamagna, Jacques Deviere
Journal: Endoscopy (2018)

Obesity is the pandemic disease of this century. Surgery is the only effective treatment but cannot be offered to every patient. Endoscopic sutured gastroplasty is a minimally invasive technique that may potentially fill the gap between surgery and behavioral therapy. In this study, we prospectively investigated the efficacy and safety of a novel suturing device.After a pre-bariatric multidisciplinary work-up, class 1 and 2 obese patients were included. Using a simple triangulation platform, transmural sutures with serosa-to-serosa apposition were performed in the gastric cavity. Patients were followed according to the same routines as those performed for bariatric procedures.Between November 2015 and December 2016, 51 patients were included across three European Centers. Mean body mass index at baseline was 35.1 kg/m2 (SD 3.0). Excess weight loss and total body weight loss at 1 year were 29 % (SD 28) and 7.4 % (SD 7), respectively, for the whole cohort (45 patients). At follow-up gastroscopy, 88 % of sutures were still in place (30 patients). No severe adverse events were observed.Endoscopic sutured gastroplasty using this novel device is safe and achieved weight loss results in line with criteria expected for these endoluminal techniques. Further prospective studies vs. placebo or nutritional support are needed.
Association of T-Cell Receptor Repertoire Use With Response to Combined Trastuzumab-Lapatinib Treatment of HER2-Positive Breast Cancer
Authors: Ryan L. Powles, David Redmond, Christos Sotiriou, Sherene Loi, Debora Fumagalli, Paolo Nuciforo, Nadia Harbeck, Evandro de Azambuja, Severine Sarp, Serena Di Cosimo, Jens Huober, Jose Baselga, Martine Piccart-Gebhart, Olivier Elemento, Lajos Pusztai, Christos Hatzis
Journal: JAMA Oncology (2018)

Dual anti-HER2 blockade increased the rate of pathologic complete response (pCR) in the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALTTO) trial, and high immune gene expression was associated with pCR in all treatment arms. So far, no marker has been identified that is specifically associated with the benefit from dual HER2 blockade.To examine if use of the T-cell β chain variable genes adds to the potential association of immune gene signatures with response to dual HER2 blockade.In the NeoALTTO trial, HER2-positive patients recruited between January 5, 2008, and May 27, 2010, were treated with paclitaxel plus either lapatinib or trastuzumab or both as neoadjuvant therapy. In this study, RNA sequencing data from baseline tumor specimens of 245 patients in the NeoALTTO trial were analyzed and reads were aligned to TRBV gene reference sequences using a previously published Basic Local Alignment Search Tool T-cell receptor mapping pipeline. Total TRBV gene use, Shannon entropy, and gene richness were calculated for each tumor, and nonnegative matrix factorization was used to define TRBV co-use metagenes (TMGs). The association between TRBV metrics, tumor genomic metrics, and response was assessed with multivariable logistic regression. Statistical analysis was performed from January 23 to December 2, 2017.The association between TRBV use metrics and pCR.Among the 245 women with available data (mean [SD] age, 49 [11] years), total TRBV use correlated positively with a gene expression signature for immune activity (Spearman ρ = 0.93; P < .001). High use of TRBV11-3 and TMG2, characterized by high use of TRBV4.3, TRBV6.3, and TRBV7.2, was associated with a higher rate of pCR to dual HER2-targeted therapy (TRBV11-3 interaction: odds ratio, 2.63 [95% CI, 1.22-6.47]; P = .02; TMG2 interaction: odds ratio, 3.39 [95% CI, 1.57-8.27]; P = .004). Immune-rich cancers with high TMG2 levels (n = 92) had significantly better response to dual HER2-targeted treatment compared with the single therapy arms (rate of pCR, 68% [95% CI, 52%-83%] vs 21% [95% CI, 10%-31%]; P < .001), whereas those with low TMG2 levels did not benefit from dual therapy. High TMG2 levels were also associated with a higher rate of pCR to the combined therapy in immune-poor tumors (n = 30; pCR, 50% [95% CI, 22%-78%] vs 6% [95% CI, 0%-16%]; P = .009).Use patterns of TRBV genes potentially provide information about the association with response to dual HER2 blockade beyond immune gene signatures. High use of TRBV11.3 or TRBV4.3, TRBV6.3, and TRBV7.2 identifies patients who have a better response to dual HER2 targeted therapy.ClinicalTrials.gov Identifier: NCT00553358.
Pitfalls and Pearls for 3-Dimensional Printing of the Tricuspid Valve in the Procedural Planning of Percutaneous Transcatheter Therapies
Authors: Serge C. Harb, Leonardo L. Rodriguez, Lars G. Svensson, Bo Xu, Haytham Elgharably, Ryan Klatte, Amar Krishnaswamy, Richard A. Grimm, Brian P. Griffin, Samir R. Kapadia, Jose L. Navia
Journal: JACC. Cardiovascular imaging (2018)
SAT0110 Trajectories of functional disability in patients with early inflammatory polyarthritis and moderate disease activity: results from the early rheumatoid arthritis network and norfolk arthritis register
Authors: S. Norton, J. Gwinnutt, Y. Pan, D. Symmons, A. MacGregor, A. Young, P. Kiely, D. Walsh, S. Verstappen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> A large group of patients with inflammatory polyarthritis (IP), and its subset rheumatoid arthritis (RA), have moderate disease activity, despite disease modifying therapy. Identifying patients with moderate disease who are likely to have subsequent high disability may prompt different treatment strategies for these patients. <h3>Objectives</h3> To identify common trajectories of disability progression in patients with moderate disease in two large prospective observational studies. <h3>Methods</h3> The Early Rheumatoid Arthritis Network (ERAN) recruited 1236 patients with RA (&lt;36 months symptoms) from 23 centres in England from 2002-11. The Norfolk Arthritis Register (NOAR) recruited 1054 IP patients (&lt;24 months symptoms) from Norfolk, England, from 2000-8. At baseline and subsequent follow-ups, functional disability was assessed using the Health Assessment Questionnaire (HAQ). Included patients scored ≥3.2 and &lt;5.1 on the Disease Activity Score (DAS28) at either baseline, year 1 or year 2, and had previously received csDMARDS (N<sub>ERAN</sub>=605; N<sub>NOAR</sub>=407). Latent class growth models (LCGMs) were used to identify HAQ trajectories independently in each cohort. Age, sex, fulfilment of ACR RA criteria, symptom duration, DMARDs at baseline, and baseline DAS28 were included as predictors of trajectory group membership using multinomial logistic regression. <h3>Results</h3> Baseline characteristics of the cohorts were similar (ERAN vs NOAR: mean age = 57 vs 56 years; female = 70% vs 69%; met ACR criteria = 88% vs 77%; mean DAS28 = 4.7 vs 4.2). For both cohorts, LCGM analysis indicated 4 subgroups provided best fit (Bayesian Information Criterion), with similar shaped trajectories (figure 1). Multinomial logistic regression indicated that older age (ERAN &amp; NOAR, p&lt;0.005), female gender (ERAN &amp; NOAR, p&lt;0.01), meeting ACR criteria (NOAR only, p&lt;0.05), use of DMARD (ERAN &amp; NOAR, p&lt;0.01), and baseline DAS28 (ERAN &amp; NOAR, p&lt;0.005) were related to an increased likelihood of being in a subgroup with higher disability (vs. lowest disability subgroup). <h3>Conclusions</h3> Four disability trajectories were observed in both the ERAN and NOAR cohort of patients with moderate disease activity. Patients on a worse trajectory who may benefit from more intensive treatment could potentially be identified earlier in the disease the group of patients with moderate disease activity. <h3>Reference:</h3> [1] This research was funded by Arthritis Research UK. <h3>Disclosure of Interest:</h3> None declared
Hydrocortisone did not reduce mortality at 90 days in patients with septic shock
Authors: Brent A. Duran, Robert G. Badgett, Steven Q. Simpson
Journal: Annals of Internal Medicine (2018)

Source Citation Venkatesh B, Finfer S, Cohen J, et al; ADRENAL Trial Investigators, Australian–New Zealand Intensive Care Society Clinical Trials Group. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378:797-808. 29347874
REsect: Blinded assessment of amenability to potentially curative treatment of previously unresectable colorectal cancer liver metastases (CRC LM) after chemotherapy ± RadioEmbolization (SIRT) in the randomized SIRFLOX trial.
Authors: Benjamin Garlipp, Peter Gibbs, Guy A. Van Hazel, Rohan Jeyarajah, Robert C. G. Martin, Christiane J. Bruns, Hauke Lang, Derek M. Manas, Giuseppe Maria Ettorre, Fernando Pardo, Vincent Donckier, Christoph Benckert, Thomas M van Gulik, Diane Goere, Michael Schoen, Johann Pratschke, Wolf O. Bechstein, Antonio Martínez de la Cuesta, Shola Adeyemi, Max Seidensticker
Journal: Journal of Clinical Oncology (2017)

3532 Background: Secondary resection and radiofrequency ablation (RFA) of primarily unresectable LM from CRC can prolong survival and cure some patients (pts). Effective downsizing treatments are needed but their impact on secondary amenability to surgery/RFA is difficult to evaluate objectively. The added value of SIRT is not well established. Methods: Baseline (BL) and follow-up (FU) imaging at best response for CRC pts treated with FOLFOX chemotherapy±bevacizumab (bev) (CT) vs. CT+SIRT in the phase III SIRFLOX RCT were reviewed by 3−5 expert HPB surgeons (from a panel of 15) for resectability of LM. Reviewers were blinded to each other and to all clinical information incl. time of imaging (BL/FU). Resectability was defined as ≥60% of reviewers assessing a pt as resectable. For non-resectable cases, surgeons indicated whether a combination of surgery and RFA could completely remove all LM. Lesions deemed suitable for RFA by a surgeon needed to be confirmed by an interventional radiologist. Pts were defined as “clearable” if ≥60% of reviewers assessed them as amenable to complete removal of LM by surgery alone or surgery+RFA. Results: 472 pts were evaluable (CT, n = 228; CT+SIRT, n = 244). There was no significant difference in LM resectability at BL (CT, n = 25, 10.96%; CT+SIRT, n = 29, 11.89%; p = 0.77). At FU, significantly more pts in the SIRT arm had resectable LM (CT, n = 66, 28.95%; CT+SIRT, n = 93, 38.11%; p &lt; 0.0001). Of 203 pts in the CT arm and 215 pts in the CT+SIRT arm deemed unresectable at BL, 46 (22.66%) and 67 (31.16%), respectively, were converted to resectability (p &lt; 0.0001). Assessing “clearability” using surgery and RFA, again no difference was noted at BL (CT, n = 31, 13.60%; CT+SIRT, n = 42, 17.21%; p = 0.309). At FU, a trend in favor of CT+SIRT was seen (CT, n = 79, 34.65%; CT+SIRT, n = 102, 41.80%; p = 0.1296). Conclusions: The addition of SIRT to FOLFOX(±bev) based CT significantly increased the gain in resectability of primarily unresectable CRC LM compared with CT alone. For amenability to the combination of surgery+RFA, this effect was still seen, albeit attenuated. Subgroup analyses are ongoing. Clinical trial information: NCT00724503.