tbuckley/cabot-search huggingface dataset:
Routine Preoperative Laboratory Tests for Elective Surgery
Authors: Shannon K. Martin, Adam S. Cifu
Journal: JAMA (2017)

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T-cell receptor αβ+ and CD19+ cell–depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency
Authors: Ravi M. Shah, Reem Elfeky, Zohreh Nademi, Waseem Qasim, Persis Amrolia, Robert Chiesa, Kanchan Rao, Giovanna Lucchini, Juliana M.F. Silva, Austen Worth, Dawn Barge, David Ryan, Jane Conn, Andrew J. Cant, Roderick Skinner, Intan Juliana Abd Hamid, Terence Flood, Mario Abinun, Sophie Hambleton, Andrew R. Gennery, Paul Veys, Mary Slatter
Journal: Journal of Allergy and Clinical Immunology (2017)
Factors associated with receipt of adjuvant radioactive iodine in node-negative versus node-positive papillary thyroid cancer.
Authors: Ryaz Chagpar, Eren Berber, Jamie Mitchell, Joyce Shin, Judy Jin, Rosemarie Metzger, Allan Siperstein
Journal: Journal of Clinical Oncology (2014)

e17695 Background: The administration of adjuvant radioactive iodine (RAI) for patients with papillary thyroid cancer (PTC) is controversial. Current guidelines recommend RAI for patients at high risk of recurrence, including those with nodal disease. We sought to determine factors associated with receipt of RAI for patients with either node negative or node positive PTC. Methods: The Surveillance, Epidemiology, and End Results (SEER) Database was queried to identify patients with non-metastatic PTC who received total thyroidectomy with assessment of nodal status (2004-2010). A stratified analysis using multivariate logistic regression of node positive versus node negative patients was performed to determine tumor and patient factors that were associated with the receipt of adjuvant RAI. Results: Among the 42,554 patients meeting inclusion criteria, 31,735 (74.6%) were clinically or pathologically node negative, and 10,819 (25.4%) were node positive. Patients with node positive disease were more likely to receive RAI than those who were node negative (76.2% vs. 52.3%, p<0.0005). Amongst node positive patients, however, lymph node ratio, defined as the number of positive nodes/number of nodes excised, did not correlate with receipt of RAI. On univariate analysis, in both node positive and node negative cohorts, younger males with larger, high grade or multifocal tumors, that demonstrate evidence of extrathyroidal invasion, or have insular or columnar histologic features were more likely to receive RAI (p<0.0005 for all). On multivariate analysis, age, tumor size, multifocality and depth of tumor extension remained independent predictors for receipt of RAI in both the cohorts. Conclusions: There is variation in the administration of adjuvant RAI for PTC. While patients with node positive disease are more likely to receive RAI, age, tumor size, multifocality and depth of tumor extension are independently associated with the receipt of RAI regardless of lymph node status. Among node positive patients, however, a higher burden of nodal disease is not associated with receipt of RAI, despite current guidelines advocating its use in this patient cohort.
Amiloride, An Old Diuretic Drug, Is a Potential Therapeutic Agent for Multiple Myeloma
Authors: Elizabeta A. Rojas, Luis Antonio Corchete, Laura San-Segundo, Juan F. Martínez-Blanch, Francisco M. Codoñer, Teresa Paíno, Noemí Puig, Ramón García-Sanz, María Victoria Mateos, Enrique M. Ocio, Irena Misiewicz-Krzeminska, Norma C. Gutiérrez
Journal: Clinical Cancer Research (2017)

Abstract Purpose: The search for new drugs that control the continuous relapses of multiple myeloma is still required. Here, we report for the first time the potent antimyeloma activity of amiloride, an old potassium-sparing diuretic approved for the treatment of hypertension and edema due to heart failure. Experimental Design: Myeloma cell lines and primary samples were used to evaluate cytotoxicity of amiloride. In vivo studies were carried out in a xenograft mouse model. The mechanisms of action were investigated using RNA-Seq experiments, qRT-PCR, immunoblotting, and immunofluorescence assays. Results: Amiloride-induced apoptosis was observed in a broad panel of multiple myeloma cell lines and in a xenograft mouse model. Moreover, amiloride also had a synergistic effect when combined with dexamethasone, melphalan, lenalidomide, and pomalidomide. RNA-Seq experiments showed that amiloride not only significantly altered the level of transcript isoforms and alternative splicing events, but also deregulated the spliceosomal machinery. In addition, disruption of the splicing machinery in immunofluorescence studies was associated with the inhibition of myeloma cell viability after amiloride exposure. Although amiloride was able to induce apoptosis in myeloma cells lacking p53 expression, activation of p53 signaling was observed in wild-type and mutated TP53 cells after amiloride exposure. On the other hand, we did not find a significant systemic toxicity in mice treated with amiloride. Conclusions: Overall, our results demonstrate the antimyeloma activity of amiloride and provide a mechanistic rationale for its use as an alternative treatment option for relapsed multiple myeloma patients, especially those with 17p deletion or TP53 mutations that are resistant to current therapies. Clin Cancer Res; 23(21); 6602–15. ©2017 AACR.
Functional Na <sub>V</sub> 1.8 Channels in Intracardiac Neurons
Authors: Arie O. Verkerk, Carol Ann Remme, Cees A. Schumacher, Brendon P. Scicluna, Rianne Wolswinkel, Berend de Jonge, Connie R. Bezzina, Marieke W. Veldkamp
Journal: Circulation Research (2012)

The SCN10A gene encodes the neuronal sodium channel isoform Na(V)1.8. Several recent genome-wide association studies have linked SCN10A to PR interval and QRS duration, strongly suggesting an as-yet unknown role for Na(V)1.8 in cardiac electrophysiology.To demonstrate the functional presence of SCN10A/Nav1.8 in intracardiac neurons of the mouse heart.Immunohistochemistry on mouse tissue sections showed intense Na(V)1.8 labeling in dorsal root ganglia and intracardiac ganglia and only modest Na(V)1.8 expression within the myocardium. Immunocytochemistry further revealed substantial Na(V)1.8 staining in isolated neurons from murine intracardiac ganglia but no Na(V)1.8 expression in isolated ventricular myocytes. Patch-clamp studies demonstrated that the Na(V)1.8 blocker A-803467 (0.5-2 μmol/L) had no effect on either mean sodium current (I(Na)) density or I(Na) gating kinetics in isolated myocytes but significantly reduced I(Na) density in intracardiac neurons. Furthermore, A-803467 accelerated the slow component of current decay and shifted voltage dependence of inactivation toward more negative voltages, as expected for blockade of Na(V)1.8-based I(Na). In line with these findings, A-803467 did not affect cardiomyocyte action potential upstroke velocity but markedly reduced action potential firing frequency in intracardiac neurons, confirming a functional role for Na(V)1.8 in cardiac neural activity.Our findings demonstrate the functional presence of SCN10A/Na(V)1.8 in intracardiac neurons, indicating a novel role for this neuronal sodium channel in regulation of cardiac electric activity.
The potential of a portable, point-of-care electronic nose to diagnose tuberculosis
Authors: Rosarito Coronel Teixeira, Mabel Rodríguez, Nilda Jiménez de Romero, Marcel Bruins, Roscio Gómez, Jan Bart Yntema, Gilberto Chaparro Abente, Jan Willem Gerritsen, Wim Wiegerinck, Domingo Pérez Bejerano, Cecile Magis-Escurra
Journal: Journal of Infection (2017)
Neoadjuvant enzalutamide (ENZA) and abiraterone acetate (AA) plus leuprolide acetate (LHRHa) versus AA+ LHRHa in localized high-risk prostate cancer (LHRPC).
Authors: Eleni Efstathiou, John W. Davis, Mark Anton Titus, Brian Francis Chapin, Amado J. Zurita, Sijin Wen, Elsa M. Li Ning Tapia, Anh Hoang, Paul Gettys Corn, Xuemei Wang, Francine Whittington, Patricia Troncoso, Christopher Logothetis
Journal: Journal of Clinical Oncology (2016)

5002 Background: AA added to medical castration augments cytoreduction in LHRPC though wide range of persistent cancer is observed. To build on these findings we conducted a study examining AA+ LHRHa with or without ENZA. Methods: We performeda neoadjuvant study of 24 wks of AA+ENZA +LHRHa vs AA+LHRHa (randomized 2:1) in pts with LHRPC (clinical stage T1c/T2 with biopsy Gleason ≥ 8, or ≥ T2b with Gleason ≥ 7 and PSA > 10 ng/mL). We primarily studied treatment effect on pathologic stage. Secondary endpoints include: residual tumor measures; tumor volume, cellularity, tumor epithelial volume (TEV: epithelial component [cellularity %] tumor volume), steroid metabolites (LCMS) and key protein/RNA markers(AR signaling [AR-N ARC19, ARV7, CYP17, PSA], glucocorticoid receptor [GR], neuroendocrine [CD56, CgA], Ki67,p53, RB). Sample size provided 80% power for difference in ≤ pT2N0 per chi-square test at significance of 0.1. Results: Sixty-five treated pts underwent prostatectomy No Grade ≥ 4 adverse event (AE) reported. Main Grade 3 AEs: LFT increase 19 pts (13 AA+ENZA), hypertension 13 AA+ENZA. PSA nadir ≤ 0.1 ng/mL: 40/44 (91%) in ENZA+ AA+LHRHa vs 17/21 (81%). Pathologic downstaging ( ≤ pT2N0) occurred in 13/44 (30%) AA+ENZA+ LHRHa pts vs 11/21 (52 %) AA+LHRHa (p = 0.07) including 2 pCR. TEV and stage were aligned. Despite high rates of PSA ≤ 0.1, wide range of viable tumor was observed: volume (0-8.64cc), cellularity (0-90%), TEV (0-5.58cc) Metabolomic data in line with previous report. Stage ≤ pT2N0 was associated with lower Ki67 (p 0.005) and increased expression of canonical AR signaling components AR-N, ARC19, CYP17 (p 0.005) but not PSA (p 0.17). ARV7 presence was more frequent in ENZA+AA+LHRH treated tumors (p 0.05). Four CD56/CgA, 1 Rb- and 1 p53 altered, tumors identified. Conclusions: Findings do not favor adding ENZA to augment AA+LHRHa efficacy in LHRPC. Expression of neuroendocrine markers, p53, loss of RB, are infrequent in persistent cancers. Canonical AR signaling and low Ki67 correlate with lower stage. ARV7 was detected more frequently in the combination arm. Study results emphasize need to consider biologic heterogeneity when applying AR targeting therapies. Clinical trial information: NCT01946165.
THE EFFECT OF REPETITIVE KICKING ON KNEE FLEXOR NEUROMUSCULAR FUNCTION
Authors: Steven Duhig, Morgan Williams, Geoffrey Minett, David Opar, Anthony Shield
Journal: British Journal of Sports Medicine (2017)

Background The primary mechanism for hamstring strain injury is high speed running however insults also occur during kicking in which they are more severe. Objective To examine the effect of 100 drop punt kicks on isokinetic knee flexor strength and surface electromyographic (sEMG) activity of biceps femoris (BF) and medial hamstrings (MH). Design Randomised control study. Setting Community level Australian football. Participants Thirty-six recreational footballers were recruited. Interventions Participants were randomly assigned to kicking or control groups. Dynamometry was conducted immediately before and after the kicking or 10 minutes of sitting (control). Main Outcome Measurements Knee flexor strength and biceps femoris and medial hamstring surface electromyography. Results Eccentric strength declined more in the kicking than the control group (p&lt;0.001; d =1.60), with greater reductions in eccentric than concentric strength after kicking (p=0.001; d= 0.92). No significant between group differences in concentric strength change were observed (p=0.089; d= 0.60). The decline in normalized eccentric hamstring sEMG (BF and MH combined) was greater in the kicking than the control group (p&lt;0.001; d= 1.78), while changes in concentric hamstring sEMG did not differ between groups (p=0.863; d =0.04). Post-kicking reductions in sEMG were greater in eccentric than concentric actions for both BF (p=0.008; d =0.77) and MH (p&lt;0.001; d =1.11). In contrast, the control group exhibited smaller reductions in eccentric than concentric hamstring sEMG for BF (p=0.026; d =0.64) and MH (p=0.032; d =0.53). Reductions in BF sEMG were correlated with eccentric strength decline (R=0.645; p=0.007). Conclusions Reductions in knee flexor strength and hamstring sEMG are largely limited to eccentric contractions and this should be considered when planning training loads in Australian Football.
04.23 Identification of a novel subset of pathogenic stromal cells with key effector functions in tissue inflammation and damage
Authors: Adam P Croft, Joana Campos, Saba Nayar, Alice E Denton, Loriane Savary, Atif Saghir, Doug T Fearon, Andrew Filer, Francesca Barone, Christopher D Buckley
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Stromal cells are key effector cells in tissue inflammation and damage. Despite their importance these cells are yet to be targeted therapeutically. We have previously identified a distinct subset of stromal cells defined by their expression of a cassette of cell surface proteins including Podoplanin/gp38 (PDPN), Fibroblast activation protein (FAP) and Cadherin-11. The aim of this study was to determine the pathogenic role of these cells in tissue inflammation. <h3>Methods</h3> Salivary gland inflammation was induced by intra-ductal administration of a replication-deficient adenovirus resulting in tertiary lymphoid structure (TLS) formation as previously described.<sup>1</sup> Polyarthritis was induced using the KRN serum transfer model as previously described.<sup>2</sup> To delete FAP-expressing cells we used a model of conditional depletion of FAP-expressing cells, in which FAP-DTR mice were treated with Diphtheria Toxin Disease severity was assessed clinically, histologically and by MicroCT and a combination of immunofluorescence, quantitative RT-PCR and flow cytometry was performed on digested salivary glands and synovial membrane tissue. <h3>Results</h3> Tissue resident stromal cells dynamically express FAP, PDPN and cadherin-11 during inflammation. This cassette of cell surface markers defined a population of stromal cells that expand during inflammation by <i>in situ</i> proliferation. In the salivary gland, these pathogeneic cells are found surrounding ectopic lymphoid aggregates where they produce lymphoid chemokines and survival factors. In the synovium, they are localised to the synovial lining layer and pannus tissue where they invade articular cartilage and bone. Selective deletion of FAP expressing cells resulted in a defect in lymphoid chemokine production, decreased number of infiltrating lymphocytes and severely inhibited TLO formation in the salivary gland. In the joint, therapeutic deletion significantly attenuated synovial inflammation, inflammatory cell infiltration, reduced the severity of arthritis and protected against joint damage. <h3>Conclusions</h3> We have identified a pathogenic subset of stromal cells defined by their expression of common cassette of cell surface markers. Whilst the phenotype of these cells is common to inflammation our data suggests their function is both tissue and disease specific. <h3>References</h3> 1. Bombardieri, Barone, et al. JI. 2012. 2. Huang, et al. Arthrits Rheumatol2014.
Evolution of the IgE and IgG repertoire to a comprehensive array of allergen molecules in the first decade of life
Authors: X. Huang, O. Tsilochristou, S. Perna, S. Hofmaier, A. Cappella, C.‐P. Bauer, U. Hoffman, J. Forster, F. Zepp, A. Schuster, R. D'Amelio, U. Wahn, T. Keil, S. Lau, P. M. Matricardi
Journal: Allergy (2017)

Abstract Background In early childhood, the allergen‐specific IgG repertoire is mainly directed to animal and vegetable food molecules and infrequently to airborne molecules. It is unknown whether this early pattern is maintained throughout childhood. Objective To investigate the evolution of IgG and IgE responses to a broad panel of allergenic molecules from birth to age 10 years. Methods We examined the sera collected between birth and age 10 years from participants in the German Multicentre Allergy Study, a birth cohort born in 1990. The IgE (cutoff ≥0.30 ISU ) and IgG (cutoff ≥0.10 ISU ) responses to 35 genuine allergenic molecules were measured with a multiplex microarray approach (Immuno CAP ISAC ™). Results IgE responses were mostly directed against a restricted group of airborne molecules, with a sequence and prevalence hierarchy (Phl p 1&gt; Bet v 1&gt; Fel d 1&gt; Phl p 5&gt; Der p 2&gt; Der p 1) largely maintained over time. Conversely, the IgG repertoire was much broader, starting with animal foodborne, then spreading to vegetable foodborne and finally to airborne molecules. A strong and persistent IgG response to a given airborne molecule almost invariably preceded or accompanied an IgE response to that molecule. Conclusions The evolution of IgG and IgE responses throughout childhood differs widely at population level. IgG responses are mostly directed to animal food allergens, while IgE responses are dominated by airborne allergens. However, a strong IgG response almost invariably precedes or accompanies the appearance of IgE to the same molecule in specifically sensitized subjects.
Translational Considerations for Cancer Nanomedicine
Authors: Stephen T. Stern, Jennifer B. Hall, Lee L. Yu, Laura J. Wood, Giulio F. Paciotti, Lawrence Tamarkin, Stephen E. Long, Scott E. McNeil
Journal: Clinical Cancer Research (2010)

There are many important considerations during preclinical development of cancer nanomedicines, including: 1) unique aspects of animal study design; 2) the difficulties in evaluating biological potency, especially for complex formulations; 3) the importance of analytical methods that can determine platform stability in vivo, and differentiate bound and free active pharmaceutical ingredient (API) in biological matrices; and 4) the appropriateness of current dose scaling techniques for estimation of clinical first-in-man dose from preclinical data. Biologics share many commonalities with nanotechnology products with regard to complexity and biological attributes, and can, in some cases, provide context for dealing with these preclinical issues. In other instances, such as the case of in vivo stability analysis, new approaches are required. This paper will discuss the significance of these preclinical issues, and present examples of current methods and best practices for addressing them. Where possible, these recommendations are justified using the existing regulatory guidance literature.
Doctors in India demand stricter rules over drug industry gifts
Authors: Sumi S Dutta
Journal: BMJ (2017)

A group of doctors in India have criticised a proposed government order that bans health professionals from accepting gifts, travel, and hospitality from the drug industry but allows doctors’ associations and hospitals to continue accepting money from them.

The Alliance of Doctors for Ethical Healthcare has asked the government to rewrite the new rules so as to stop associations from receiving industry funds and to end the practice of drug companies offering hospitals large discounts on drugs that they sell to patients at a profit.

India’s department of pharmaceuticals is shortly due to finalise the new rules on the drug industry in India, although no date has been …
08.39 Clinical evolution of patients diagnosed of rheumatoid arthritis (ra) in treatment with optimisedoptimized doses of biological therapies (bt)
Authors: Julia Uceda Montañez, Raquel Hernández Sánchez, Jose L Marenco de la Fuente
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> RA is the most common chronic inflammatory arthropathy. About 30% of patients are treated with BT. The optimisation of TB doses in patients in clinical remission of the disease is a strategy used in clinical practice. Primary endpoint was evaluate the clinical behaviour of RA in patients of the Rheumatology Unit of Valme University Hospital, who receive BT at optimised doses, according to the BT dose optimisation protocol elaborated in our unit. <h3>Materials and methods</h3> Observational, descriptive, longitudinal and retrospective study in a cohort of 32 patients diagnosed with RA, who are treated at optimised doses of TB (2008 −2014). A description of the baseline characteristics was made. The clinical evolution was measured by the DAS 28 at different times: prior to the initial reduction and subsequent reductions, at the end of the reduction and at the data collection visit. <h3>Result</h3> 62.5% are women, mean age at diagnosis of 42.6 years. The duration of RA at the start of BT was 98.63 months and the biological treatment time at the beginning of the optimisation was 160.66 months. The 75% of the sample was FR positive and 56.7% ACPA positive. The 59.4% were with etanercept. The mean DAS28 before the reduction of BT was 2.47. At the time of analysis 21 continued with optimised doses with DAS 28: 2.67 and 11 had discontinued the dose reduction régimen, 80% by increase of the activity <h3>Conclusions</h3> All the patients in our study were in clinical remission at the beginning of TB optimisation. The optimised TB can maintain a high percentage of patients in clinical remission. One-third of our patients are maintained in optimised doses for a long period. The main reason to finalise the optimisation regimen was an increase in the activity of the disease.