tbuckley/cabot-search huggingface dataset:
Enhanced human hematopoietic stem and progenitor cell engraftment by blocking donor T cell–mediated TNFα signaling
Authors: Weijia Wang, Hisaki Fujii, Hye Jin Kim, Karin Hermans, Tatiana Usenko, Stephanie Xie, Zhi-Juan Luo, Jennifer Ma, Cristina Lo Celso, John E. Dick, Timm Schroeder, Joerg Krueger, Donna Wall, R. Maarten Egeler, Peter W. Zandstra
Journal: Science Translational Medicine (2017)

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy, but the large number of HSCs required limits its widespread use. Host conditioning and donor cell composition are known to affect HSCT outcomes. However, the specific role that the posttransplantation signaling environment plays in donor HSC fate is poorly understood. To mimic clinical HSCT, we injected human umbilical cord blood (UCB) cells at different doses and compositions into immunodeficient NOD/SCID/IL-2Rgc-null (NSG) mice. Surprisingly, higher UCB cell doses inversely correlated with stem and progenitor cell engraftment. This observation was attributable to increased donor cell-derived inflammatory signals. Donor T cell-derived tumor necrosis factor-α (TNFα) was specifically found to directly impair the survival and division of transplanted HSCs and progenitor cells. Neutralizing donor T cell-derived TNFα in vivo increased short-term stem and progenitor cell engraftment, accelerated hematopoietic recovery, and altered donor immune cell compositions. This direct effect of TNFα on transplanted cells could be decoupled from the indirect effect of alleviating graft-versus-host disease (GVHD) by interleukin-6 (IL-6) blockade. Our study demonstrates that donor immune cell-derived inflammatory signals directly influence HSC fate, and provides new clinically relevant strategies to improve engraftment efficiency during HSCT.
Stylet slow-pull versus standard suction for endoscopic ultrasound-guided fine-needle aspiration of solid pancreatic lesions: a multicenter randomized trial
Authors: Payal Saxena, Mohamad El Zein, Tyler Stevens, Ahmed Abdelgelil, Sepideh Besharati, Ahmed Messallam, Vivek Kumbhari, Alba Azola, Jennifer Brainard, Eun Shin, Anne Lennon, Marcia Canto, Vikesh Singh, Mouen Khashab
Journal: Endoscopy (2017)

Abstract Background and study aim Standard endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) procedures involve use of no-suction or suction aspiration techniques. A new aspiration method, the stylet slow-pull technique, involves slow withdrawal of the needle stylet to create minimum negative pressure. The aim of this study was to compare the sensitivity of EUS-FNA using stylet slow-pull or suction techniques for malignant solid pancreatic lesions using a standard 22-gauge needle. Patients and methods Consecutive patients presenting for EUS-FNA of pancreatic mass lesions were randomized to the stylet slow-pull or suction techniques using a 22-gauge needle. Both techniques were standardized for each pass until an adequate specimen was obtained, as determined by rapid on-site cytology examination. Patients were crossed over to the alternative technique after four nondiagnostic passes. Results Of 147 patients screened, 121 (mean age 64 ± 13.8 years) met inclusion criteria and were randomized to the stylet slow-pull technique (n = 61) or the suction technique (n = 60). Technical success rates were 96.7 % and 98.3 % in the slow-pull and suction groups, respectively (P &gt; 0.99). The sensitivity for malignancy of EUS-FNA was 82 % in the slow-pull group and 69 % in the suction group (P = 0.10). The first-pass diagnostic rate (42.6 % vs. 38.3 %; P = 0.71), acquisition of core tissue (60.6 % vs. 46.7 %; P = 0.14), and the median (range) number of passes to diagnosis (2 1 2 3 vs. 1 1 2; P = 0.71) were similar in the slow-pull and suction groups, respectively. Conclusions The stylet slow-pull and suction techniques both offered high and comparable diagnostic sensitivity with a mean of 2 passes required for diagnosis of solid pancreatic lesions. The endosonographer may choose either technique during FNA.
Novel Method for Noninvasive Sampling of the Distal Airspace in Acute Respiratory Distress Syndrome
Authors: J. Brennan McNeil, Ciara M. Shaver, V. Eric Kerchberger, Derek W. Russell, Brandon S. Grove, Melissa A. Warren, Nancy E. Wickersham, Lorraine B. Ware, W. Hayes McDonald, Julie A. Bastarache
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

A major barrier to a more complete understanding of acute respiratory distress syndrome (ARDS) pathophysiology is the inability to sample the distal airspace of patients with ARDS. The heat moisture exchanger (HME) filter is an inline bacteriostatic sponge that collects exhaled moisture from the lungs of mechanically ventilated patients.To test the hypothesis that HME filter fluid (HMEF) represents the distal airspace fluid in patients with ARDS.Samples of HMEF were collected from 37 patients with acute pulmonary edema (either from ARDS or hydrostatic causes [HYDRO; control subjects]). Concurrent undiluted pulmonary edema fluid (EF) and HMEF were collected from six patients. HMEF from 11 patients (8 ARDS and 3 HYDRO) were analyzed by liquid chromatography-coupled tandem mass spectometry. Total protein (bicinchoninic acid assay), MMP-9 (matrix metalloproteinase-9), and MPO (myeloperoxidase) (ELISA) were measured in 29 subjects with ARDS and 5 subjects with HYDRO. SP-D (surfactant protein-D), RAGE (receptor for advanced glycation end-products) (ELISA), and cytokines (IL-1β, IL-6, IL-8, and tumor necrosis factor-α) (electrochemiluminescent assays) were measured in six concurrent HMEF and EF samples.Liquid chromatography-coupled tandem mass spectrometry on concurrent EF and HMEF samples from four patients revealed similar base peak intensities and m/z values indicating similar protein composition. There were 21 significantly elevated proteins in HMEF from patients with ARDS versus HYDRO. Eight proteins measured in concurrent EF and HMEF from six patients were highly correlated. In HMEF, total protein and MMP-9 were significantly higher in ARDS than in HYDRO.These data suggest that HMEF is a novel, noninvasive method to accurately sample the distal airspace in patients with ARDS.
Abstract 12238: Is Myocardial F-!8 Flurodeoxyglucose Uptake on PET-CT Predictive of Cardiac Toxicity Following Radiation Treatment?
Authors: Nael H Aldweib, Gurleen Pasricha, Vijay Kudithipudi, Mark Trombetta, Dulabh Monga, Indu Poornima
Journal: Circulation (2014)

Background:  Myocardial imaging with FDG-PET, in the fasting state is used to image inflammatory diseases such as sarcoidosis. A proposed pathophysiology for cardiac complications following chest radiotherapy (XRT) includes inflammation and a relationship between post-XRT myocardial FDG uptake and cardiac complications has been reported. We studied the incidence of cardiac complications post-XRT in patients with lung or esophageal cancer and examined possible predictors including radiation dosimetry and changes in myocardial FDG uptake after XRT.   Methods:  We retrospectively identified patients with lung or esophageal cancer who received chest XRT and had pre-XRT and post-XRT FDG-PET scan. Myocardial FDG uptake in the lateral wall and interventricular septum was quantified as maximum standardized uptake value (mSUV) units. Change in mSUV was designated as >1 or    Results:  A total of 82 patients (68.3 ± 12.8 years; 54% male; 76% lung cancer) formed the study group. Mean follow-up was 722± 588 days. An increase in mSUV >1 was noted in 50% of patients between pre-XRT and post-XRT PET albeit, not statistically significant (p=0.12). The incidence of complications post- XRT was as follows: Congestive heart failure 7.3%; LV systolic dysfunction 11%; myocardial infarction 1.2%; arrhythmia 23.2%, pericardial effusion 15.9%; typical angina chest pain 2.4%; and non-anginal chest pain 13.4%. Pre-XRT, post-XRT or change in FDG uptake was not a predictor of cardiac complications. However extent of radiation defined by PTV correlated with the number of cardiac complications (Spearman’s rho=0.31, p=0.01). Radiation dose or FDG uptake and standard clinical variables such as hypertension, age and coronary artery disease were not predictive of the most common complication which was atrial arrhythmias (23%).   Conclusions:  Cardiac complications occur in a quarter of patients following XRT for treatment of lung or esophageal cancer and correlates with extent of radiation (PTV) but not with change in myocardial FDG uptake or radiation dose. These findings require further study in large population.
Abstract 13425: Low Income Patients With Myocardial Infarction Are Less Likely to Receive a Drug Eluting Stent Than Patients From High Income Areas
Authors: Wesley Fiser, Ramesh Mazhari, Christian Nagy, Heather Young, Jonathan Reiner
Journal: Circulation (2015)

Introduction: Choosing a bare metal stent (BMS) vs a drug eluting stent (DES) during STEMI intervention is an important and complex decision that must be made quickly. The on-call physician who is often unfamiliar with the patient (pt) must incorporate both qualitative and quantitative medical factors, as well as estimate the pt's ability to adhere to a prolonged dual antiplatelet strategy. We examined disparities between device allocation (BMS vs DES) and pt socio-demographic factors in a diverse population treated at an urban hospital. Hypothesis: Patient socioeconomic status is an influential factor in stent selection during STEMI. Methods: Records from 332 consecutive pts undergoing percutaneous coronary intervention for STEMI were retrospectively reviewed. Demographic data included: age, gender, ZIP code, stent type, self-identified race, and health insurance status. Logistical regression models were used to identify significant co-variables. Results: The mean age was 55.5 yrs (42% African American (AA), 45% White (W), 13% other). Of the 332 pts, 176 (53%) received BMS and 140 (42%) received DES; and 49% of W pts received DES vs 33% AA (adj OR 0.74, CI 0.41-1.31). Using 2010 U.S. Census Bureau data, median household income (inc) was estimated using home ZIP code (range $21,633-$214,219), and pts were then stratified into inc quartiles. Compared to the highest inc quartile, pts in the lowest quartile were more likely to be AA (72% vs 20%, p &lt;0.0001) and female (34% vs 16%, p =0.01). Nearly all patients were insured (93%), with no differences among inc groups. Strikingly, pts residing in the highest inc quartile were significantly more likely to receive a DES than those residing in the lowest inc quartile (57% vs 33%, adj. OR 2.67, 95% CI 1.27-5.63, p =0.004). The impact of inc on stent choice was strongest with AA (adj. OR 4.37, 95% CI 1.20-15.93, p =0.008), compared to W (adj. OR 1.15, 95% CI 0.34-3.92, p =0.32). Gender, age, and insurance status did not influence stent choice. Conclusions: DES were less frequently implanted in STEMI pts residing in low inc areas, suggesting that quickly made, non-quantitative, socioeconomic assessments may have important ramifications in stent selection. The fact that this effect was primarily seen in AA pts warrants further evaluation.
Role of the Nucleus as a Sensor of Cell Environment Topography
Authors: Karine Anselme, Nayana Tusamda Wakhloo, Pablo Rougerie, Laurent Pieuchot
Journal: Advanced Healthcare Materials (2017)

Abstract The proper integration of biophysical cues from the cell vicinity is crucial for cells to maintain homeostasis, cooperate with other cells within the tissues, and properly fulfill their biological function. It is therefore crucial to fully understand how cells integrate these extracellular signals for tissue engineering and regenerative medicine. Topography has emerged as a prominent component of the cellular microenvironment that has pleiotropic effects on cell behavior. This progress report focuses on the recent advances in the understanding of the topography sensing mechanism with a special emphasis on the role of the nucleus. Here, recent techniques developed for monitoring the nuclear mechanics are reviewed and the impact of various topographies and their consequences on nuclear organization, gene regulation, and stem cell fate is summarized. The role of the cell nucleus as a sensor of cell‐scale topography is further discussed.
First-in-human phase 1 study of ETC-159 an oral PORCN inhbitor in patients with advanced solid tumours.
Authors: Matthew Ng, David SP Tan, Vivek Subbiah, Colin D. Weekes, Vincenzo Teneggi, Veronica Diermayr, Kantharaj Ethirajulu, Pauline Yeo, Deborah Chen, Stephanie Blanchard, Ranjani Nellore, Bong Hwa Gan, Maryam Yasin, Lay Hoon Lee, May Ann Lee, Jeffrey Hill, Babita Madan, David Virshup, Alex Matter
Journal: Journal of Clinical Oncology (2017)

2584 Background: The Wnt signalling pathway is involved in cellular proliferation, differentiation, migration and implicated in stem cell function in several cancers. ETC-159 is a selective small molecule inhibitor of porcupine, an enzyme required for palmitoylation and secretion of all Wnt ligands. In preclinical studies, ETC-159 induced tumour regression in patient-derived xenograft models. Methods: Open-label, multi-centre study to determine safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics (PD) of ETC-159 given orally, once every other day in a 28d cycle. PD was evaluated by AXIN2 mRNA levels in whole blood and hair follicles and bone turnover by radiological and serum markers. Dose escalation was by ordinal continual reassessment method with a dose-limiting toxicity (DLT) period of 28d. Results: As of 18 Jan 2017, 16 patients (pts) were treated in 6 cohorts at 1 mg (2pts), 2 mg (2pts), 4 mg (3pts), 8 mg (4pts); 16 mg (3pts), and 30 mg (2pts). 80% were male, median age (range) was 55yr (19-68). One DLT was seen at 16 mg due to hyperbilirubinaemia. Adverse events (≥ 20%) were vomiting (32%); anorexia and fatigue (31%); dysgeusia and constipation (25%). ETC-159 C max increased with dose with a mean t 1/2 of 14 hr. Plasma levels of ETC-159 that inhibited colony formation in vitro were attained from 4 mg onwards. Reduction of whole blood and hair follicle AXIN2 mRNA levels and doubling of serum β-CTX levels was first observed at 4 mg and at C1D15 in some patients. PD modulation increased with dose, consistent with on-target modulation of Wnt signalling. Two pts had β-CTX rise &gt; 1000 pg/mL (reference limit) and a ≥ 5% reduction in bone density by C3D1. Both took vitamin D and calcium supplements and were given i.v. bisphosphonates. No responses were seen but 2 pts (2 mg: colorectal and 4 mg: peritoneal carcinoma) had stable disease for 6 and 8 cycles respectively. Dose-escalation is ongoing at 30 mg. Conclusions: ETC-159 inhibits Wnt signalling at doses that are well tolerated. β-CTX levels increased early on, and in two pts were associated with reduced bone mineral density. Early and regular monitoring of bone turnover is indicated. This study was sponsored by D3 which is funded by NMRC, NRF and BMRC Singapore. Clinical trial information: NCT02521844.
Repeated Amblyomma testudinarium tick bites are associated with increased galactose-α-1,3-galactose carbohydrate IgE antibody levels: A retrospective cohort study in a single institution
Authors: Hideo Hashizume, Toshiharu Fujiyama, Takatsune Umayahara, Reiko Kageyama, Andrew F. Walls, Takahiro Satoh
Journal: Journal of the American Academy of Dermatology (2017)
Surface modification of PGP for a neutrophil–nanoparticle co-vehicle to enhance the anti-depressant effect of baicalein
Authors: Baoyu Chen, Man Luo, Jianming Liang, Chun Zhang, Caifang Gao, Jue Wang, Jianxin Wang, Yongji Li, Desheng Xu, Lina Liu, Ning Zhang, Huijun Chen, Jing Qin
Journal: Acta Pharmaceutica Sinica B (2017)

Exploiting cells as vehicles combined with nanoparticles combined with therapy has attracted increasing attention in the world recently. Red blood cells, leukocytes and stem cells have been used for tumor immunotherapy, tissue regeneration and inflammatory disorders, and it is known that neutrophils can accumulate in brain lesions in many brain diseases including depression. N-Acetyl Pro-Gly-Pro (PGP) peptide shows high specific binding affinity to neutrophils through the CXCR2 receptor. In this study, PGP was used to modify baicalein-loaded solid lipid nanoparticles (PGP-SLNs) to facilitate binding to neutrophils in vivo. Brain-targeted delivery to the basolateral amygdala (BLA) was demonstrated by enhanced concentration of baicalein in the BLA. An enhanced anti-depressant effect was observed in vitro and in vivo. The mechanism involved inhibition of apoptosis and a decrease in lactate dehydrogenase release. Behavioral evaluation carried out with rats demonstrated that anti-depression outcomes were achieved. The results indicate that PGP-SLNs decrease immobility time, increase swimming time and climbing time and attenuate locomotion in olfactory-bulbectomized (OB) rats. In conclusion, PGP modification is a strategy for targeting the brain with a cell-nanoparticle delivery system for depression therapy.
A pilot study of the modulation of sirtuins on arylamine N-acetyltransferase 1 and 2 enzymatic activity
Authors: Eneida Turiján-Espinoza, Rául Alejandro Salazar-González, Edith Elena Uresti-Rivera, Gloria Estela Hernández-Hernández, Montserrat Ortega-Juárez, Rosa Milán, Diana Portales-Pérez
Journal: Acta Pharmaceutica Sinica B (2017)

Arylamine
Abstract 11004: Prediction of Clinical Outcome in Patients With Aortic Stenosis by Left Ventricular Mechanical Dispersion
Authors: Lars G Klaeboe
Journal: Circulation (2015)

Introduction: There is a need for new parameters to improve risk stratification and assess outcome in patients with aortic stenosis (AS). Left ventricular (LV) mechanical dispersion by strain echocardiography reflects heterogeneous myocardial contraction and is a novel marker of sudden cardiac death in structural and primary electrical heart disease. We hypothesized that mechanical dispersion provides valuable prognostic information in patients with AS, and that mechanical dispersion can be used as a clinical tool for risk stratification in these patients Methods: We included 55 patients (56% women,75±9 years) with moderate to severe AS. Global longitudinal strain (GLS) was assessed by speckle tracking echocardiography from a 16 LV segments model. Mechanical dispersion was calculated as standard deviation of time from Q/R on ECG to peak strain in 16 LV segments. Results: Average aortic valve area was 0.7±0.2 cm2. Most patients had LV septal hypertrophy (12±2 mm) and preserved LV ejection fraction (EF) (57±10%). Aortic valve replacement (AVR) was performed in 37 (67%) patients. During 38±14 months follow-up, 15(27%) patients died (no 30-day mortality after AVR). LV ejection fraction (EF) and GLS were similar in the survival and non-survival group (58±9% vs. 54±13%, p=0.16, and -17.0±3.4% vs. -16.7±4.0%, p=0.78, respectively). Mechanical dispersion was the only echocardiographic parameter that differed between survivors and non-survivors (56±18ms vs. 69±19ms, p=0.02). C-statistics for mechanical dispersion showed an AUC of 0.70 (0.55-0.86) and a value of &gt; 67 ms indicated worse survival (log rank &lt; 0.01) (Fig.1) Conclusions: LV mechanical dispersion was significantly higher in the AS non-survivors. Increased mechanical dispersion may be an additional risk marker and could give valuable prognostic information in patients with AS and preserved LVEF.
Cell salvage and donor blood transfusion during cesarean section: A pragmatic, multicentre randomised controlled trial (SALVO)
Authors: Khalid S. Khan, Philip A. S. Moore, Matthew J. Wilson, Richard Hooper, Shubha Allard, Ian Wrench, Lee Beresford, Tracy E. Roberts, Carol McLoughlin, James Geoghegan, Jane P. Daniels, Sue Catling, Vicki A. Clark, Paul Ayuk, Stephen Robson, Fang Gao-Smith, Matthew Hogg, Doris Lanz, Julie Dodds
Journal: PLoS Medicine (2017)

Excessive haemorrhage at cesarean section requires donor (allogeneic) blood transfusion. Cell salvage may reduce this requirement.We conducted a pragmatic randomised controlled trial (at 26 obstetric units; participants recruited from 4 June 2013 to 17 April 2016) of routine cell salvage use (intervention) versus current standard of care without routine salvage use (control) in cesarean section among women at risk of haemorrhage. Randomisation was stratified, using random permuted blocks of variable sizes. In an intention-to-treat analysis, we used multivariable models, adjusting for stratification variables and prognostic factors identified a priori, to compare rates of donor blood transfusion (primary outcome) and fetomaternal haemorrhage ≥2 ml in RhD-negative women with RhD-positive babies (a secondary outcome) between groups. Among 3,028 women randomised (2,990 analysed), 95.6% of 1,498 assigned to intervention had cell salvage deployed (50.8% had salvaged blood returned; mean 259.9 ml) versus 3.9% of 1,492 assigned to control. Donor blood transfusion rate was 3.5% in the control group versus 2.5% in the intervention group (adjusted odds ratio [OR] 0.65, 95% confidence interval [CI] 0.42 to 1.01, p = 0.056; adjusted risk difference -1.03, 95% CI -2.13 to 0.06). In a planned subgroup analysis, the transfusion rate was 4.6% in women assigned to control versus 3.0% in the intervention group among emergency cesareans (adjusted OR 0.58, 95% CI 0.34 to 0.99), whereas it was 2.2% versus 1.8% among elective cesareans (adjusted OR 0.83, 95% CI 0.38 to 1.83) (interaction p = 0.46). No case of amniotic fluid embolism was observed. The rate of fetomaternal haemorrhage was higher with the intervention (10.5% in the control group versus 25.6% in the intervention group, adjusted OR 5.63, 95% CI 1.43 to 22.14, p = 0.013). We are unable to comment on long-term antibody sensitisation effects.The overall reduction observed in donor blood transfusion associated with the routine use of cell salvage during cesarean section was not statistically significant.This trial was prospectively registered on ISRCTN as trial number 66118656 and can be viewed on http://www.isrctn.com/ISRCTN66118656.
Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies
Authors: Julia Oyrer, Snezana Maljevic, Ingrid E. Scheffer, Samuel F. Berkovic, Steven Petrou, Christopher A. Reid
Journal: Pharmacological Reviews (2017)

Epilepsy is a common and serious neurologic disease with a strong genetic component. Genetic studies have identified an increasing collection of disease-causing genes. The impact of these genetic discoveries is wide reaching—from precise diagnosis and classification of syndromes to the discovery and validation of new drug targets and the development of disease-targeted therapeutic strategies. About 25% of genes identified in epilepsy encode ion channels. Much of our understanding of disease mechanisms comes from work focused on this class of protein. In this study, we review the genetic, molecular, and physiologic evidence supporting the pathogenic role of a number of different voltage- and ligand-activated ion channels in genetic epilepsy. We also review proposed disease mechanisms for each ion channel and highlight targeted therapeutic strategies.