bluuebunny/crossref_metadata_2025_split huggingface dataset:
Probiotic mixture VSL#3 reduces colonic inflammation and improves intestinal barrier function in Muc2 mucin-deficient mice
Authors: Kumar Manish , Kissoon-Singh Vanessa , Coria Aralia Leon , Moreau France , Chadee Kris 
Published: November 2016

MUC2 mucin is the major glycoprotein in colonic mucus that separates intestinal microbiota from underlying host cells and serves as a food source for some eubacteria. MUC2 deficiency results in impaired epithelial barrier function, imbalance in gut microbiota, and spontaneous colitis. Probiotics have been shown to have a protective effect against colitis. In this study we used Muc2 mucin-deficient ( Muc2−/−) and Muc2+/+ littermates to test whether the probiotic mixture VSL#3 requires an intact mucin barrier to exert its beneficial effect. VSL#3 alone reduced basal colonic proinflammatory cytokine levels and improved epithelial barrier function in Muc2−/− animals. Similarly, in dextran sulfate sodium-induced colitis, VSL#3 dampened the proinflammatory chemokines KC, monocyte chemoattractant protein-1, and macrophage inflammatory protein-2 and upregulated the tissue regeneration growth factors transforming growth factor-β, fibroblast growth factor-1, and vascular endothelial growth factor-A, which accelerated resolution of colitis symptoms in Muc2−/− animals. Importantly, improved colonic health in VSL#3-treated animals was associated with attenuated reactive oxygen species production by peritoneal macrophages, restoration of antimicrobial peptide gene expression in the small intestine, and increased abundance of bacterial commensals in the gut. The beneficial effects of VSL#3 in Muc2−/− animals were mediated by acetate, an important short-chain fatty acid produced by gut bacteria. These studies provide evidence for the first time that VSL#3 can enhance epithelial barrier function by dampening the proinflammatory cytokine and chemokine response, accelerating restitution, and altering commensal microbiota in the absence of a functional mucus barrier. NEW & NOTEWORTHY It is unclear whether probiotics require an intact mucin barrier to first colonize and/or exert their protective functions. In this study we used mucin-deficient (Muc2 −/−) mice to interrogate if the multispecies probiotic mixture VSL#3 could enhance epithelial barrier function. In the absence of a mucus bilayer, VSL#3 dampened proinflammatory and chemokine production, accelerated restitution, and markedly improved gut permeability mediated by the short-chain fatty acid acetate in the colon.
Neuropeptide Y (NPY) promotes inflammation-induced tumorigenesis by enhancing epithelial cell proliferation
Authors: Jeppsson Sabrina , Srinivasan Shanthi , Chandrasekharan Bindu 
Published: November 2016

We have demonstrated that neuropeptide Y (NPY), abundantly produced by enteric neurons, is an important regulator of intestinal inflammation. However, the role of NPY in the progression of chronic inflammation to tumorigenesis is unknown. We investigated whether NPY could modulate epithelial cell proliferation and apoptosis, and thus regulate tumorigenesis. Repeated cycles of dextran sodium sulfate (DSS) were used to model inflammation-induced tumorigenesis in wild-type (WT) and NPY knockout ( NPY−/−) mice. Intestinal epithelial cell lines (T84) were used to assess the effects of NPY (0.1 µM) on epithelial proliferation and apoptosis in vitro. DSS-WT mice exhibited enhanced intestinal inflammation, polyp size, and polyp number (7.5 ± 0.8) compared with DSS- NPY−/− mice (4 ± 0.5, P < 0.01). Accordingly, DSS-WT mice also showed increased colonic epithelial proliferation (PCNA, Ki67) and reduced apoptosis (TUNEL) compared with DSS- NPY−/− mice. The apoptosis regulating microRNA, miR-375, was significantly downregulated in the colon of DSS-WT (2-fold, P < 0.01) compared with DSS- NPY−/−-mice. In vitro studies indicated that NPY promotes cell proliferation (increase in PCNA and β-catenin, P < 0.05) via phosphatidyl-inositol-3-kinase (PI3-K)-β-catenin signaling, suppressed miR-375 expression, and reduced apoptosis (increase in phospho-Bad). NPY-treated cells also displayed increased c-Myc and cyclin D1, and reduction in p21 ( P < 0.05). Addition of miR-375 inhibitor to cells already treated with NPY did not further enhance the effects induced by NPY alone. Our findings demonstrate a novel regulation of inflammation-induced tumorigenesis by NPY-epithelial cross talk as mediated by activation of PI3-K signaling and downregulation of miR-375. NEW & NOTEWORTHY Our work exemplifies a novel role of neuropeptide Y (NPY) in regulating inflammation-induced tumorigenesis via two modalities: first by enhanced proliferation (PI3-K/pAkt), and second by downregulation of microRNA-375 (miR-375)-dependent apoptosis in intestinal epithelial cells. Our data establish the existence of a microRNA-mediated cross talk between enteric neurons producing NPY and intestinal epithelial cells, and the potential of neuropeptide-regulated miRNAs as potential therapeutic molecules for the management of inflammation-associated tumors in the gut.
Central and peripheral responses to static and dynamic stretch of skeletal muscle: mechano- and metaboreflex implications
Authors: Venturelli Massimo , Cè Emiliano , Limonta Eloisa , Bisconti Angela Valentina , Devoto Michela , Rampichini Susanna , Esposito Fabio 
Published: November 2016

Passive static stretching (SS), circulatory cuff occlusion (CCO), and the combination of both (SS + CCO) have been used to investigate the mechano- and metaboreflex, respectively. However, the effects of dynamic stretching (DS) alone or in combination with CCO (DS + CCO) on the same reflexes have never been explored. The aim of the study was to compare central and peripheral hemodynamic responses to DS, SS, DS + CCO, and SS + CCO. In 10 participants, femoral blood flow (FBF), heart rate (HR), cardiac output (CO), and mean arterial pressure (MAP) were assessed during DS and SS of the quadriceps muscle with and without CCO. Blood lactate concentration [La−] in the lower limb undergoing CCO was also measured. FBF increased significantly in DS and SS by 365 ± 98 and 377 ± 102 ml/min, respectively. Compared with baseline, hyperemia was negligible during DS + CCO and SS + CCO (+11 ± 98 and +5 ± 87 ml/min, respectively). DS generated a significant, sustained increase in HR and CO (∼40s), while SS induced a blunted and delayed cardioacceleration (∼20 s). After CCO, [La−] in the lower limb increased by 135%. Changes in HR and CO during DS + CCO and SS + CCO were similar to DS and SS alone. MAP decreased significantly by ∼5% during DS and SS, did not change in DS + CCO, and increased by 4% in SS + CCO. The present data indicate a reduced mechanoreflex response to SS compared with DS (i.e., different HR and CO changes). SS evoked a hyperemia similar to DS. The similar central hemodynamics recorded during stretching and [La−] accumulation suggest a marginal interaction between mechano- and metaboreflex. NEW & NOTEWORTHY Different modalities of passive stretching administration (dynamic or static) in combination with circulatory cuff occlusion may reduce or amplify the mechano- and metaboreflex. We showed a reduced mechanoreflex response to static compared with dynamic stretching. The lack of increase in central hemodynamics during the combined mechano- and metaboreflex stimulation implicates marginal interactions between these two pathways.
The role of retinoic acid in the formation and modulation of invertebrate central synapses
Authors: Rothwell Cailin M. , de Hoog Eric , Spencer Gaynor E. 
Published: November 2016

Trophic factors can influence many aspects of nervous system function, such as neurite outgrowth, synapse formation, and synapse modulation. The vitamin A metabolite, retinoic acid, can exert trophic effects to promote neuronal survival and outgrowth in many species and is also known to modulate vertebrate hippocampal synapses. However, its role in synaptogenesis has not been well studied, and whether it can modulate existing invertebrate synapses is also not known. In this study, we first examined a potential trophic effect of retinoic acid on the formation of excitatory synapses, independently of its role in neurite outgrowth, using cultured neurons of the mollusc Lymnaea stagnalis. We also investigated its role in modulating both chemical and electrical synapses between various Lymnaea neurons in cell culture. Although we found no evidence to suggest retinoic acid affected short-term synaptic plasticity in the form of post-tetanic potentiation, we did find a significant cell type-specific modulation of electrical synapses. Given the prevalence of electrical synapses in invertebrate nervous systems, these findings highlight the potential for retinoic acid to modulate network function in the central nervous system of at least some invertebrates.NEW & NOTEWORTHY This study performed the first electrophysiological analysis of the ability of the vitamin A metabolite, retinoic acid, to exert trophic influences during synaptogenesis independently of its effects in supporting neurite outgrowth. It was also the first study to examine the ability of retinoic acid to modify both chemical and electrical synapses in any invertebrate, nonchordate species. We provide evidence that all-trans retinoic acid can modify invertebrate electrical synapses of central neurons in a cell-specific manner.
Role of fructose and fructokinase in acute dehydration-induced vasopressin gene expression and secretion in mice
Authors: Song (宋志林) Zhilin , Roncal-Jimenez Carlos A. , Lanaspa-Garcia Miguel A. , Oppelt Sarah A. , Kuwabara Masanari , Jensen Thomas , Milagres Tamara , Andres-Hernando Ana , Ishimoto Takuji , Garcia Gabriela E. , Johnson Ginger , MacLean Paul S. , Sanchez-Lozada Laura-Gabriela , Tolan Dean R. , Johnson Richard J. 
Published: November 2016

Fructose stimulates vasopressin in humans and can be generated endogenously by activation of the polyol pathway with hyperosmolarity. We hypothesized that fructose metabolism in the hypothalamus might partly control vasopressin responses after acute dehydration. Wild-type and fructokinase-knockout mice were deprived of water for 24 h. The supraoptic nucleus was evaluated for vasopressin and markers of the aldose reductase-fructokinase pathway. The posterior pituitary vasopressin and serum copeptin levels were examined. Hypothalamic explants were evaluated for vasopressin secretion in response to exogenous fructose. Water restriction increased serum and urine osmolality and serum copeptin in both groups of mice, although the increase in copeptin in wild-type mice was larger than that in fructokinase-knockout mice. Water-restricted, wild-type mice showed an increase in vasopressin and aldose reductase mRNA, sorbitol, fructose and uric acid in the supraoptic nucleus. In contrast, fructokinase-knockout mice showed no change in vasopressin or aldose reductase mRNA, and no changes in sorbitol or uric acid, although fructose levels increased. With water restriction, vasopressin in the pituitary of wild-type mice was significantly less than that of fructokinase-knockout mice, indicating that fructokinase-driven vasopressin secretion overrode synthesis. Fructose increased vasopressin release in hypothalamic explants that was not observed in fructokinase-knockout mice. In situ hybridization documented fructokinase mRNA in the supraoptic nucleus, paraventricular nucleus and suprachiasmatic nucleus. Acute dehydration activates the aldose reductase-fructokinase pathway in the hypothalamus and partly drives the vasopressin response. Exogenous fructose increases vasopressin release in hypothalamic explants dependent on fructokinase. Nevertheless, circulating vasopressin is maintained and urinary concentrating is not impaired. NEW & NOTEWORTHY This study increases our understanding of the mechanisms leading to vasopressin release under conditions of water restriction (acute dehydration). Specifically, these studies suggest that the aldose reductase-fructokinase pathways may be involved in vasopressin synthesis in the hypothalamus and secretion by the pituitary in response to acute dehydration. Nevertheless, mice undergoing water restriction remain capable of maintaining sufficient vasopressin (copeptin) levels to allow normal urinary concentration. Further studies of the aldose reductase-fructokinase system in vasopressin regulation appear indicated.
Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues
Authors: Balakrishnan Ashwini , Goodpaster Tracy , Randolph-Habecker Julie , Hoffstrom Benjamin G. , Jalikis Florencia G. , Koch Lisa K. , Berger Carolina , Kosasih Paula L. , Rajan Anusha , Sommermeyer Daniel , Porter Peggy L. , Riddell Stanley R. 
Published: November 2016

Abstract
Purpose: This study examines cell surface ROR1 expression in human tumors and normal tissues. ROR1 is considered a promising target for cancer therapy due to putative tumor-specific expression, and multiple groups are developing antibodies and/or chimeric antigen receptor–modified T cells to target ROR1. On-target, off-tumor toxicity is a challenge for most nonmutated tumor antigens; however, prior studies suggest that ROR1 is absent on most normal tissues.
Experimental Design: Our studies show that published antibodies lack sensitivity to detect endogenous levels of cell surface ROR1 by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded tissues. We developed a ROR1-specific monoclonal antibody (mAb) targeting the carboxy-terminus of ROR1 and evaluated its specificity and sensitivity in IHC.
Results: The 6D4 mAb is a sensitive and specific reagent to detect cell surface ROR1 by IHC. The data show that ROR1 is homogenously expressed on a subset of ovarian cancer, triple-negative breast cancer, and lung adenocarcinomas. Contrary to previous findings, we found ROR1 is expressed on several normal tissues, including parathyroid; pancreatic islets; and regions of the esophagus, stomach, and duodenum. The 6D4 mAb recognizes rhesus ROR1, and ROR1 expression was similar in human and macaque tissues, suggesting that the macaque is a suitable model to evaluate safety of ROR1-targeted therapies.
Conclusions: ROR1 is a promising immunotherapeutic target in many epithelial tumors; however, high cell surface ROR1 expression in multiple normal tissues raises concerns for on-target off-tumor toxicities. Clinical translation of ROR1-targeted therapies warrants careful monitoring of toxicities to normal organs and may require strategies to ensure patient safety. Clin Cancer Res; 23(12); 3061–71. ©2016 AACR.
Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban
Authors: Ansell Jack E. , Bakhru Sasha H. , Laulicht Bryan E. , Steiner Solomon S. , Grosso Michael A. , Brown Karen , Dishy Victor , Lanz Hans J. , Mercuri Michele F. , Noveck Robert J. , Costin James C. 
Published: November 2016

SummaryOf the new direct oral anticoagulants, direct factor Xa inhibitors are limited by the absence of a proven reversal agent. We assessed the safety, tolerability and impact on anticoagulation reversal of ciraparantag (PER977) alone and following a 60 mg dose of the FXa inhibitor edoxaban. Escalating, single IV doses of ciraparantag were administered alone and following a 60 mg oral dose of edoxaban in a double-blind, placebo-controlled fashion to healthy subjects. Serial assessments of the pharmacokinetics and pharmacodynamic effects of ciraparantag were performed. Eighty male subjects completed the study. Following edoxaban (60 mg), a single IV dose of ciraparantag (100 to 300 mg) demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours. Fibrin diameter within clots was restored to normal 30 minutes after a single dose of 100 to 300 mg ciraparantag as determined by scanning electron microscopy and change in fibrin diameter quantified by automated image analysis. Potentially related adverse events were periorbital and facial flushing and cool sensation following IV injection of ciraparantag. Renal excretion of ciraparantag metabolite was the main elimination route. There was no evidence of procoagulant activity following ciraparantag as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels. In conclusion, ciraparantag in healthy subjects is safe and well tolerated with minor, non-dose limiting adverse events. Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10–30 minutes of administration and sustained for at least 24 hours.Institution where the work was performed: Duke University Clinical Research Unit, Duke University Medical Center, Durham, NC USA
One-Year Outcomes After Transcatheter Insertion of an Interatrial Shunt Device for the Management of Heart Failure With Preserved Ejection Fraction
Authors: Kaye David M. , Hasenfuß Gerd , Neuzil Petr , Post Martijn C. , Doughty Robert , Trochu Jean-Noël , Kolodziej Adam , Westenfeld Ralf , Penicka Martin , Rosenberg Mark , Walton Antony , Muller David , Walters Darren , Hausleiter Jorg , Raake Philip , Petrie Mark C. , Bergmann Martin , Jondeau Guillaume , Feldman Ted , Veldhuisen Dirk J. van , Ponikowski Piotr , Silvestry Frank E. , Burkhoff Dan , Hayward Christopher 
Published: November 2016

Background—
Heart failure with preserved ejection fraction has a complex pathophysiology and remains a therapeutic challenge. Elevated left atrial pressure, particularly during exercise, is a key contributor to morbidity and mortality. Preliminary analyses have demonstrated that a novel interatrial septal shunt device that allows shunting to reduce the left atrial pressure provides clinical and hemodynamic benefit at 6 months. Given the chronicity of heart failure with preserved ejection fraction, evidence of longer-term benefit is required.

Methods and Results—

Patients (n=64) with left ventricular ejection fraction ≥40%, New York Heart Association class II–IV, elevated pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during supine bicycle exercise) participated in the open-label study of the interatrial septal shunt device. One year after interatrial septal shunt device implantation, there were sustained improvements in New York Heart Association class (
P
<0.001), quality of life (Minnesota Living with Heart Failure score,
P
<0.001), and 6-minute walk distance (
P
<0.01). Echocardiography showed a small, stable reduction in left ventricular end-diastolic volume index (
P
<0.001), with a concomitant small stable increase in the right ventricular end-diastolic volume index (
P
<0.001). Invasive hemodynamic studies performed in a subset of patients demonstrated a sustained reduction in the workload corrected exercise pulmonary capillary wedge pressure (
P
<0.01). Survival at 1 year was 95%, and there was no evidence of device-related complications.

Conclusions—
These results provide evidence of safety and sustained clinical benefit in heart failure with preserved ejection fraction patients 1 year after interatrial septal shunt device implantation. Randomized, blinded studies are underway to confirm these observations.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01913613.
Mesonets: Mesoscale Weather and Climate Observations for the United States
Authors: Mahmood Rezaul , Boyles Ryan , Brinson Kevin , Fiebrich Christopher , Foster Stuart , Hubbard Ken , Robinson David , Andresen Jeff , Leathers Dan 
Published: November 2016

Abstract
Mesoscale in situ meteorological observations are essential for better understanding and forecasting the weather and climate and to aid in decision-making by a myriad of stakeholder communities. They include, for example, state environmental and emergency management agencies, the commercial sector, media, agriculture, and the general public. Over the last three decades, a number of mesoscale weather and climate observation networks have become operational. These networks are known as mesonets. Most are operated by universities and receive different levels of funding. It is important to communicate the current status and critical roles the mesonets play.
Most mesonets collect standard meteorological data and in many cases ancillary near-surface data within both soil and water bodies. Observations are made by a relatively spatially dense array of stations, mostly at subhourly time scales. Data are relayed via various means of communication to mesonet offices, with derived products typically distributed in tabular, graph, and map formats in near–real time via the World Wide Web. Observed data and detailed metadata are also carefully archived.
To ensure the highest-quality data, mesonets conduct regular testing and calibration of instruments and field technicians make site visits based on “maintenance tickets” and prescheduled frequencies. Most mesonets have developed close partnerships with a variety of local, state, and federal-level entities. The overall goal is to continue to maintain these networks for high-quality meteorological and climatological data collection, distribution, and decision-support tool development for the public good, education, and research.
A Numerical Weather Model’s Ability to Predict Characteristics of Aircraft Icing Environments
Authors: Thompson Gregory , Politovich Marcia K. , Rasmussen Roy M. 
Published: November 2016

Abstract
Recent advances in high-performance computing have enabled higher-resolution numerical weather models with increasingly complex data assimilation and more accurate physical parameterizations. With respect to aircraft and ground icing applications, a weather model’s cloud physics scheme is responsible for the direct forecasts of the water phase and amount and is a critical ingredient to forecasting future icing conditions. In this paper, numerical model results are compared with aircraft observations taken during icing research flights, and the general characteristics of liquid water content, median volume diameter, droplet concentration, and temperature within aircraft icing environments are evaluated. The comparison reveals very promising skill by the model in predicting these characteristics consistent with observations. The application of model results to create explicit forecasts of ice accretion rates for an example case of aircraft and ground icing is shown.
Percutaneous CT-guided sternal biopsy: factors affecting the diagnostic yield
Authors: Song Yoonah , Kwon Jong Won 
Published: November 2016

BackgroundSternal lesions are occasionally seen in clinical practice and their diagnosis can be important, especially for oncologic patients. However, percutaneous computed tomography (CT)-guided biopsy of sternal lesions is rarely performed.PurposeTo assess the diagnostic yield of percutaneous CT-guided sternal biopsies and to analyze the factors that affect diagnostic yield.Material and MethodsA retrospective review of 34 patients who underwent CT-guided sternal biopsy was carried out at a single institution. Pre-biopsy CT density, location, penetration length of biopsy needle, number of biopsy attempts, angle of needle approach, final diagnosis, and operator experience level were recorded. A biopsy was considered as diagnostic if it provided a confident pathologic result. All variables were compared using Chi-square tests.ResultsTwenty-two of the 34 (64.7%) biopsy procedures yielded a diagnostic sample and 12 (35.3%) were non-diagnostic. Eight participants in the non-diagnostic group were clinically diagnosed with inflammatory arthritis of the manubriosternal or costosternal joints. Longer penetration distance of the tumor by the biopsy needle showed higher diagnostic yield ( P = 0.031). Osteoblastic lesions ( P < 0.001), lesions in the manubriosternal joint ( P = 0.018) and approaches using more obtuse angles ( P = 0.009) were associated with significantly lower diagnostic yields. Malignancy in the final diagnosis led to a higher diagnostic yield than benign lesions ( P < 0.001).ConclusionCT-guided percutaneous sternal biopsy has a relatively lower diagnostic yield. However, acute angle of needle approach may help increase biopsy success rate. Osteoblastic lesions and lesions in the manubriosternal joint tend to have lower diagnostic yield.