tbuckley/cabot-search huggingface dataset:
Traitement du reflux gastro-oesophagien par suture endoscopique: Résultats d’une étude multicentrique prospective
Authors: J Boyer, JC Grimaud, JC Letard, J Escourrou, F Prat, F Ducrot, JM Canard, JF Rey, T Ponchon, S Sfed
Journal: Endoscopy (2004)

Introduction: La suture endoscopique pour le traitement du reflux gastro-oesophagien (RGO) n’a été le sujet que d’une seule étude multicentrique prospective dans la littérature. Ce traitement reste très discuté et ne fait pas encore l’objet d’un remboursement ni d’une inscription à la nomenclature. Une étude prospective multicentrique a été conduite en France pour déterminer l’efficacité et les effets secondaires de la suture endoscopique Endocinch chez les patients (pts) porteurs de RGO. Patients et Méthodes: Les critères d’inclusion des patients étaient les suivants: âge > 18 ans, RGO symptomatique (GERD-HRQL > 20 sans traitement) traité efficacement par IPP depuis plus de 3 mois en continu, hernie hiatale < 2 cm, absence de Barrett, absence d’achalasie, BMI < 40. Dans les 2 mois précédant le geste, après arrêt des IPP pendant 10 jours, le patient avait une mesure du score GERD-HRQL, une pH-métrie de 24 heures, une manométrie oesophagienne. La suture (Endocinch, Bard) était réalisée sous anesthésie et après insertion d’un overtube. Deux à 4 plicatures étaient réalisées verticalement dans l’axe de la petite courbure, l’une au niveau de la ligne Z et les autres en dessous. Le suivi était ensuite le suivant: Consultation à 1, 3, 6 et 12 mois; pH-métrie, manométrie, gastroscopie à 3 mois; gastroscopie à 3 mois. Résultats: Soixante pts (âge moyen 49 ans, 20 femmes) ont été inclus. Une moyenne de 2,7 sutures a été mise en place par patient. Quatre pts ont eu deux séances de suture. Les effets secondaires suivants ont été rapidement régressifs: douleurs pharyngés ou rétrosternales (15%), dysphagie (18%), hoquet (2%). Pour l’instant, 45 patients ont été revus à 6 mois et 25 à 1 an. Le pourcentage de pts ayant arrêté les IPP était de 75% à 1 mois, 67% à 3 mois, 53% à 6 mois et 50% à 1 an. Le pourcentage de pts ayant arrêté les IPP ou ayant réduit la posologie était de 94% à 1 mois, 92% à 3 mois, 91% à 6 mois et 83% à 1 an. Une réduction du score GERD-HRQL (p < 0,05) a été observée à 1, 3, 6 mois et 1 an. Un seul patient a eu une cure chirurgical du RGO. Lors de la gastroscopie réalisée à 3 mois, toutes les sutures étaient en place dans 47% des cas, au moins une suture n’a pas été retrouvée dans 48% des cas et aucune suture n’a été retrouvée dans 5% des cas. Le temps de pH < 4 est passé de 11,2% à 9,2% à 3 mois (p < 0,05). La pression du sphincter inférieur était inchangée. Conclusion: Cette étude montre l’absence de morbidité de la suture endoscopique avec le système Endocinch pour le traitement du RGO et l’efficacité de cette technique pour réduire nettement les besoins en IPP. L’évolution des résultats sur un an rend incertain la persistance des effets à long terme.
Health Care Use by Older Adults With Acute Myeloid Leukemia at the End of Life
Authors: Rong Wang, Amer M. Zeidan, Stephanie Halene, Xiao Xu, Amy J. Davidoff, Scott F. Huntington, Nikolai A. Podoltsev, Cary P. Gross, Steven D. Gore, Xiaomei Ma
Journal: Journal of Clinical Oncology (2017)

Purpose Little is known about the patterns and predictors of the use of end-of-life health care among patients with acute myeloid leukemia (AML). End-of-life care is particularly relevant for older adults with AML because of their poor prognosis. Methods We performed a population-based, retrospective cohort study of patients with AML who were ≥ 66 years of age at diagnosis and diagnosed during the period from 1999 to 2011 and died before December 31, 2012. Medicare claims were used to assess patterns of hospice care and use of aggressive treatment. Predictors of these end points were evaluated using multivariable logistic regression analyses. Results In the overall cohort (N = 13,156), hospice care after AML diagnosis increased from 31.3% in 1999 to 56.4% in 2012, but the increase was primarily driven by late hospice enrollment that occurred in the last 7 days of life. Among the 5,847 patients who enrolled in hospice, 47.4% and 28.8% started their first hospice enrollment in the last 7 and 3 days of life, respectively. Among patients who transferred in and out of hospice care, 62% received transfusions outside hospice. Additionally, the use of chemotherapy within the last 14 days of life increased from 7.7% in 1999 to 18.8% in 2012. Patients who were male and nonwhite were less likely to enroll in hospice and more likely to receive chemotherapy or be admitted to intensive care units at the end of life. Conversely, older patients were less likely to receive chemotherapy or have intensive care unit admission at the end of life, and were more likely to enroll in hospice. Conclusion End-of-life care for older patients with AML is suboptimal. Additional research is warranted to identify reasons for their low use of hospice services and strategies to enhance end-of-life care for these patients.
06.03 Ionising radiation inhibits adipokine induced inflammation in synovial fibroblasts and differentiation of osteoclasts
Authors: Kateryna Shreder, Aljona Cucu, Daniela Kraft, Selina Lehrian, Claudia Fournier
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Musculoskeletal disorders (MSD) represent the highest cause of disability in Europe. Reduced mobility and quality of life are the consequences of cartilage and bone tissue destruction and chronic inflammation processes, driven by release of inflammatory factors including adipokines and bone destruction by osteoclasts. For the treatment of MSD primarily drugs are used. However, additional pain relieve is achieved when the patients receive low-dose radiation therapy with photons or radon spa treatment. To assess the effect of low-dose ionising radiation, we examined <i>in vitro</i> whether irradiation modifies the differentiation and activity of osteoclasts and affects the expression of inflammatory and bone destructive factors in adipokine stimulated synovial fibroblasts (SF). <h3>Material and methods</h3> Human SF from rheumatoid arthritis patients (RASF) and healthy donors (NSF) were pretreated with adipokines for 24 hour prior to irradiation with X-rays. Cell supernatants were collected 24 hour post-irradiation and inflammatory factors, known to contribute to the inflammation process (IL-6, IL-8, MMP-1), were measured. Human osteoclast precursor cells were X-irradiated and cultivated with M-CSF and RANKL either on bone slices or plastic for 21 days. Differentiated osteoclasts were defined as TRAP and F-actin positive with 3 or more nuclei (DAPI). TRAP activity was measured in cell supernatants. <h3>Results</h3> <i>In vitro</i> cultured primary NSF and RASF show an increased release of proinflammatory factors (IL-6, IL-8, MMP-1) after stimulation with adipokines. Irradiation of stimulated cells reduces the release of inflammatory factors in RASF, but not in NSF. Irradiation of osteoclast precursor cells caused an inhibition of osteoclast differentiation and changed activity of mature osteoclasts. <h3>Conclusion</h3> Synovial fibroblasts and osteoclasts play important roles in the synovial inflammation and bone degradation in arthritic joint. Our <i>in vitro</i> results suggest that the release of inflammatory factors in adipokine stimulated RASF and the number of osteoclasts can be reduced by low-dose X-ray irradiation, and therefore potentially inhibiting inflammation and bone destruction in the joint of patients with MSD.
Card9 mediates susceptibility to intestinal pathogens through microbiota modulation and control of bacterial virulence
Authors: Bruno Lamas, Marie-Laure Michel, Nadine Waldschmitt, Hang-Phuong Pham, Vassiliki Zacharioudaki, Louise Dupraz, Myriam Delacre, Jane M Natividad, Gregory Da Costa, Julien Planchais, Bruno Sovran, Chantal Bridonneau, Adrien Six, Philippe Langella, Mathias L Richard, Mathias Chamaillard, Harry Sokol
Journal: Gut (2017)

Objective In association with innate and adaptive immunity, the microbiota controls the colonisation resistance against intestinal pathogens. Caspase recruitment domain 9 ( CARD9 ), a key innate immunity gene, is required to shape a normal gut microbiota. Card9 –/– mice are more susceptible to the enteric mouse pathogen Citrobacter rodentium that mimics human infections with enteropathogenic and enterohaemorrhagic Escherichia coli . Here, we examined how CARD9 controls C. rodentium infection susceptibility through microbiota-dependent and microbiota-independent mechanisms. Design C. rodentium infection was assessed in conventional and germ-free (GF) wild-type (WT) and Card9 –/– mice. To explore the impact of Card9 –/– microbiota in infection susceptibility, GF WT mice were colonised with WT (WT→GF) or Card9 –/– ( Card9 –/– →GF) microbiota before C. rodentium infection. Microbiota composition was determined by 16S rDNA gene sequencing. Inflammation severity was determined by histology score and lipocalin level. Microbiota–host immune system interactions were assessed by quantitative PCR analysis. Results CARD9 controls pathogen virulence in a microbiota-independent manner by supporting a specific humoral response. Higher susceptibility to C. rodentium -induced colitis was observed in Card9 –/– →GF mice. The microbiota of Card9 –/– mice failed to outcompete the monosaccharide-consuming C. rodentium , worsening the infection severity. A polysaccharide-enriched diet counteracted the ecological advantage of C. rodentium and the defective pathogen-specific antibody response in Card9 –/– mice. Conclusions CARD9 modulates the susceptibility to intestinal infection by controlling the pathogen virulence in a microbiota-dependent and microbiota-independent manner. Genetic susceptibility to intestinal pathogens can be overridden by diet intervention that restores humoural immunity and a competing microbiota.
PTH-035 Splanchnic varices: do they increase the complication risk for patients undergoing eus guided drainage of pancreatic pseudocysts?
Authors: Y El-Sherif, K Courtney, M Cannon, D Lewis, J Devlin
Journal: Endoscopy (2017)

<h3>Introduction</h3> Splanchnic venous thromboses are recognised complication of acute and chronic pancreatitis. Splenic vein thrombosis (SVT), in isolation or in association with portal vein thrombosis (PVT) or superior mesenteric vein thrombosis (SMVT) can lead to collateral circulation and varices formation. Splanchnic varices are believed to be more problematic for patients with pancreatic pseudocysts (PP), although their true impact on this condition is not well described. The presence of varices within the peri-gastric operational field is potentially hazardous in patients undergoing endoscopic drainage. The aim of this study was to investigate the incidence of splanchnic varices, and evaluate their impact on clinical outcome of patients undergoing endoscopic ultrasound guided transmural drainage (EUD) of PP. <h3>Method</h3> A retrospective analysis of consecutive patients with symptomatic PP who underwent EUD between 2011 and 2016 was performed. Patients were identified from a prospectively collated database, with clinical data retrieved from patient records. Axial CT and MRI imaging performed in the four weeks prior to EUD was reviewed blindly by a specialist HPB radiologist. The primary outcome was to characterise the incidence of varices in patients with symptomatic PP. Secondary outcomes were to evaluate the technical success (ability to place the transmural stent), early and late adverse events (AE), and long term success (complete resolution of the cyst at 3 months) in patients with and without splanchnic varices. <h3>Results</h3> 117 patients (35% female; mean age 51 years) underwent EUD. Mean cyst size was 110 mm (30–220 mm). Venous thromboses were identified in 22 (18.8%) patients (isolated SVT=12, SVT+PVT=6, SVT+SMVT+PVT=3, isolated PVT=1). Splanchnic varices were present on radiological imaging in 69 (59%) patients. Anatomical distribution of varices was: gastro-splenic (72.5%), splenic (13%), gastric (1.5%), gastro-duodenal (1.5%), gastro-oesophageal (1.5%). Overall technical success rate of EUD was 76.1%. Intra-procedural complications were significantly higher in patients with varices (19% Vs 4%), p=0.02. Successful stent placement was higher in non-varices group (79% Vs 74%), however this did not reach statistical significance, p&gt;0.05. No significant difference between early AE (9% Vs 10%) or late AE (10% Vs 8%), or in complete resolution of the cyst at 3 months follow up (81% Vs 83%), in patients with and without splanchnic varices, p&gt;0.05 for all. <h3>Conclusion</h3> Patients with splanchnic varices who undergo EUD for PP have significantly higher intra-procedural complications, as compared to those patients without varices. However, long term outcome measures, in terms of AE and cyst resolution, are comparable between both groups. <h3>Disclosure of Interest</h3> None Declared
02.30 High levels of mir-451a differentiate patients with clinically suspect arthralgia from healthy controls
Authors: Klára Prajzlerová, Petra Hánová, Veronika Hrušková, Heřman Mann, Karel Pavelka, Jiří Vencovský, Ladislav Šenolt, Mária Filková
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Individuals with clinically suspect arthralgia (CSA) with positivity of anti-citrullinated protein antibodies (ACPA) are considered at high risk of developing rheumatoid arthritis (RA). The altered expression of miRNAs is involved in the development and maintenance of autoimmune diseases. We aimed to investigate differentially expressed miRNAs in peripheral blood mononuclear cells (PBMC) in CSA and healthy controls (HC). <h3>Material and methods</h3> The study included 19 CSA and 20 HC. Disease activity assessments and ultrasound of 28 small joints was performed in CSA. Total RNA from PBMC was isolated. A comprehensive analysis of miRNAs was performed using TaqMan Low Density Array (TLDA) in 5 samples per group. Single assay analysis of miR-451a, CXCL16 and IL-8 was performed in remaining samples and normalised to RNU44 or ACTB, respectively. dCt was used for relative quantification. <h3>Results</h3> TLDA analysis revealed 2.43x higher levels of miR-451a in CSA compared to HC. Further validation next confirmed 3.19x higher expression of miR-451a in CSA (p≤0.001). CXCL16 and IL-8 were predicted as miR-451a targets. Expression of miR-451 positively correlated with CXCL16 (r=0.497; p=0.030) in CSA and IL-8 in both CSA (r=0.485; p=0.035) and HC (r=0.617; p=0.004). This is suggestive of an indirect regulation by miR-451 and a specific role of CXCL16 in CSA. Moreover, the expression of both CXCL16 (1.51x; p=0.013) and IL-8 (3.17x; p=0.032) was higher in CSA compared to HC. By definition, all CSA individuals had swollen joint count 0. Ten CSA had some degree of subclinical activity on ultrasound (GC<b>&gt;</b>1/PD<b>&gt;</b>0). Levels of miR-451 significantly correlated with DAS28-CRP (r=0.575; p=0.010), SDAI (r=0.676; p=0.004) and VAS (r=0.484; p=0.036). CXCL16 correlated with tender joint count (r=0.576; p=0.010). Subclinical activity as per US had no effect on the levels of miR-451a, CXCL16 or IL-8 in PBMC. <h3>Conclusions</h3> Although CSA cannot be considered a disease itself, and is rather a clinical suspicion of a disease, high levels of miR-451a in PBMC distinguish these individuals at high risk of developing RA. Moreover, miR-451 in PBMC reflects the activity at this pre-clinical phase and correlates with CXCL16 with a role in angiogenesis and chemotaxis. <h3>Acknowledgement</h3> Projects MHCR 023728, SVV 2 60 263.
04.09 Characterisation of pde4 and mir-23a in psa synovial tissue
Authors: Sarah Wade, Trudy McGarry, Michelle Trenkman, Mary Canavan, Siobhan Wade, Douglas Veale, Ursula Fearon
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Introduction</h3> Phosphodiesterases (PDE) control the cellular concentrations of cAMP to modulate a number of cellular functions. PDE4 specific inhibitors, Apremilast and Rolipram, have demonstrated potent anti-inflammatory activity in PsA, yet their effects have not been fully elucidated in the synovium. In this study, we evaluate the effects of PDE4 inhibition on PsA synovial tissue and examine the role of miR-23a as a post-transcriptional regulator of PDE4B. <h3>Aims</h3> To examine the expression, regulation and the disease-modifying effects of PDE4 in PsA synovial tissue. <h3>Methods</h3> The anti-inflammatory effects of PDE4 inhibition, mediated by Rolipram, was examined in PsA synovial explant <i>ex vivo</i>. Synovial fibroblast outgrowths were quantified using matrigel invasion assays and pro-inflammatory mediators by ELISA and Real-time PCR. Expression of PDE4 isoforms(A-D) and miR-23a were quantified in response to TLR4 activation in ST and/or FLS. <i>In-Silico</i> analysis identified PDE4B as a potential target of miR-23a which was confirmed by gold-standard, luciferase reporter gene assay. MiR-23a expression was correlated to clinical markers to further elucidate its role in PsA pathogenic mechanisms. <h3>Results</h3> PDE4 inhibition decreased the production of pro-inflammatory cytokines IL-8, IL-6, MCP1, IL-1β while increasing IL-10 expression. Furthermore, Rolipram reduced the number of explant outgrowths from synovial tissue from day 8 through to day 21. We next wanted to investigate which PDE4 isoform could be responsible for these anti-inflammatory effects and found that PDE4B displayed the highest expression at baseline and in response to LPS. To try and understand how PDE4B expression is regulated in the joint we examined the role of miR-23a which we confirmed directly targets PDE4B. A reciprocal relationship was identified between PDE4B and miR-23a in PsA FLS in response to LPS stimulation. In line with this miR-23a was found to be significantly decreased at the site of inflammation compared to OA controls and correlated with key clinical markers such as DAS-28 CRP. <h3>Conclusions</h3> PDE4 inhibition decreases the pro-inflammatory activity of PsA synovial tissue. These actions may be mediated predominantly through the blockade of the PDE4B isoform which we found to be regulated by miR-23a. This data suggests a potential benefit for the development of PDE4B specific inhibitor for the treatment of PsA.
A multi-institutional outcomes analysis of patients with relapsed or refractory DLBCL treated with ibrutinib
Authors: Allison M. Winter, Daniel J. Landsburg, Anthony R. Mato, Krista Isaac, Francisco J. Hernandez-Ilizaliturri, Nishitha Reddy, Stephen Smith, Mazyar Shadman, Mitchell R. Smith, Paolo Caimi, Deepa Jagadeesh, Brian T. Hill
Journal: Blood (2017)
Cardiac effects of SGLT2 inhibitors: the sodium hypothesis
Authors: Edoardo Bertero, Leticia Prates Roma, Pietro Ameri, Christoph Maack
Journal: Cardiovascular Research (2017)

Abstract The effects of intense glycaemic control on macrovascular complications in patients with type 2 diabetes are incompletely resolved, and many glucose-lowering medications negatively affect cardiovascular outcomes. Recently, the EMPA-REG OUTCOME trial revealed that empagliflozin, an inhibitor of the sodium-glucose cotransporter 2 (SGLT2), substantially reduced the risk of hospitalization for heart failure, death from cardiovascular causes, and all-cause mortality in patients with type 2 diabetes mellitus at high cardiovascular risk. Although several mechanisms may explain this benefit, plasma volume contraction and a metabolic switch favouring cardiac ketone bodies oxidation have recently been proposed as the major drivers. Recent experimental work has prompted a novel and intriguing hypothesis, according to which empagliflozin may reduce intracellular sodium (Na+) load observed in failing cardiac myocytes by inhibiting the sarcolemmal Na+/H+ exchanger. Since elevated intracellular Na+ hampers mitochondrial Ca2+ handling and thereby, deteriorates energy supply and demand matching and the mitochondrial antioxidative defence systems, empagliflozin may positively affect cardiac function by restoring mitochondrial function, and redox state in the failing heart. Here, we review the current evidence for such a third mechanistic hypothesis, which may foster heart failure and diabetes research into a new direction which harbours several potential targets for therapeutic intervention.
Replication Stress Leading to Apoptosis within the S-phase Contributes to Synergism between Vorinostat and AZD1775 in HNSCC Harboring High-Risk <i>TP53</i> Mutation
Authors: Noriaki Tanaka, Ameeta A. Patel, Lin Tang, Natalie L. Silver, Antje Lindemann, Hideaki Takahashi, Roman Jaksik, Xiayu Rao, Nene N. Kalu, Tseng-Cheng Chen, Jiping Wang, Mitchell J. Frederick, Faye Johnson, Frederico O. Gleber-Netto, Siqing Fu, Marek Kimmel, Jing Wang, Walter N. Hittelman, Curtis R. Pickering, Jeffrey N. Myers, Abdullah A. Osman
Journal: Clinical Cancer Research (2017)

Purpose: The cure rate for patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor due to resistance to standard therapy primarily consisting of chemoradiation. As mutation of TP53 in HNSCC occurs in 60% to 80% of non-HPV-associated cases and is in turn associated with resistance to these treatments, more effective therapies are needed. In this study, we evaluated the efficacy of a regimen combining vorinostat and AZD1775 in HNSCC cells with a variety of p53 mutations.Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the in vitro and in vivo sensitivity of high-risk mutant p53 HNSCC cell lines to vorinostat in combination with AZD1775. Cell cycle, replication stress, homologous recombination (HR), live cell imaging, RNA sequencing, and apoptosis analyses were performed to dissect molecular mechanisms.Results: We found that vorinostat synergizes with AZD1775 in vitro to inhibit growth of HNSCC cells harboring high-risk mutp53. These drugs interact synergistically to induce DNA damage, replication stress associated with impaired Rad51-mediated HR through activation of CDK1, and inhibition of Chk1 phosphorylation, culminating in an early apoptotic cell death during the S-phase of the cell cycle. The combination of vorinostat and AZD1775 inhibits tumor growth and angiogenesis in vivo in an orthotopic mouse model of oral cancer and prolongs animal survival.Conclusions: Vorinostat synergizes with AZD1775 in HNSCC cells with mutant p53 in vitro and in vivo A strategy combining HDAC and WEE1 inhibition deserves further clinical investigation in patients with advanced HNSCC. Clin Cancer Res; 23(21); 6541-54. ©2017 AACR.