tbuckley/cabot-search huggingface dataset:
Comorbid TNF-mediated heart valve disease and chronic polyarthritis share common mesenchymal cell-mediated aetiopathogenesis
Authors: Lydia Ntari, Maria Sakkou, Panagiotis Chouvardas, Iordanis Mourouzis, Alejandro Prados, Maria C Denis, Niki Karagianni, Constantinos Pantos, George Kollias
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> Patients with rheumatoid arthritis and spondyloarthritisshow higher mortality rates, mainly caused by cardiac comorbidities. The TghuTNF (Tg197) arthritis model develops tumour necrosis factor (TNF)-driven and mesenchymalsynovial fibroblast (SF)-dependent polyarthritis. Here, we investigate whether this model develops, similarly to human patients, comorbid heart pathology and explore cellular and molecular mechanisms linking arthritis to cardiac comorbidities. <h3>Methods</h3> Histopathological analysis and echocardiographic evaluation of cardiac function were performed in the Tg197 model. Valve interstitial cells (VICs) were targeted by mice carrying the <i>ColVI-Cre</i>transgene. Tg197 <i>ColVI-Cre Tnfr1</i><sup>fl/fl</sup> and Tg197 <i>ColVI-Cre Tnfr1</i><sup>cneo/cneo</sup> mutant mice were used to explore the role of mesenchymal TNF signalling in the development of heart valve disease. Pathogenic VICs and SFs were further analysed by comparative RNA-sequencing analysis. <h3>Results</h3> Tg197 mice develop left-sided heart valve disease, characterised by valvular fibrosis with minimal signs of inflammation. Thickened valve areas consist almost entirely of hyperproliferative <i>ColVI</i>-expressing mesenchymal VICs. Development of pathology results in valve stenosis and left ventricular dysfunction, accompanied by arrhythmic episodes and, occasionally, valvular regurgitation. TNF dependency of the pathology was indicated by disease modulation following pharmacological inhibition or mesenchymal-specific genetic ablation or activation of TNF/TNFR1 signalling. Tg197-derived VICs exhibited an activated phenotype <i>ex viv</i>o, reminiscent of the activated pathogenic phenotype of Tg197-derived SFs. Significant functional similarities between SFs and VICs were revealed by RNA-seq analysis, demonstrating common cellular mechanisms underlying TNF-mediated arthritides and cardiac comorbidities. <h3>Conclusions</h3> Comorbidheart valve disease and chronic polyarthritis are efficiently modelled in the Tg197 arthritis model and share common TNF/TNFR1-mediated, mesenchymal cell-specific aetiopathogenic mechanisms.
Impairment of PPARα and the Fatty Acid Oxidation Pathway Aggravates Renal Fibrosis during Aging
Authors: Ki Wung Chung, Eun Kyeong Lee, Mi Kyung Lee, Goo Taeg Oh, Byung Pal Yu, Hae Young Chung
Journal: Journal of the American Society of Nephrology (2018)

Defects in the renal fatty acid oxidation (FAO) pathway have been implicated in the development of renal fibrosis. Although, compared with young kidneys, aged kidneys show significantly increased fibrosis with impaired kidney function, the mechanisms underlying the effects of aging on renal fibrosis have not been investigated. In this study, we investigated peroxisome proliferator–activated receptor α (PPAR α ) and the FAO pathway as regulators of age-associated renal fibrosis. The expression of PPAR α and the FAO pathway–associated proteins significantly decreased with the accumulation of lipids in the renal tubular epithelial region during aging in rats. In particular, decreased PPAR α protein expression associated with increased expression of PPAR α -targeting microRNAs. Among the microRNAs with increased expression during aging, miR-21 efficiently decreased PPAR α expression and impaired FAO when ectopically expressed in renal epithelial cells. In cells pretreated with oleic acid to induce lipid stress, miR-21 treatment further enhanced lipid accumulation. Furthermore, treatment with miR-21 significantly exacerbated the TGF- β –induced fibroblast phenotype of epithelial cells. We verified the physiologic importance of our findings in a calorie restriction model. Calorie restriction rescued the impaired FAO pathway during aging and slowed fibrosis development. Finally, compared with kidneys of aged littermate controls, kidneys of aged PPAR α −/− mice showed exaggerated lipid accumulation, with decreased activity of the FAO pathway and a severe fibrosis phenotype. Our results suggest that impaired renal PPAR α signaling during aging aggravates renal fibrosis development, and targeting PPAR α is useful for preventing age-associated CKD.
Changes in Apparent Diffusion Coefficient Across the Macroscopic Tumour Margin Correlate with Novel Tissue Measures of Infiltration in a Preclinical Glioblastoma Model
Authors: Gerard Thompson, Antoine Vallatos, Joanna Birch, Haitham Al-Mubarak, Lindsay Gallagher, Lesley Gilmour, Adam Waldman, William Holmes, Anthony Chalmers
Journal: Neuro-Oncology (2018)

A growing literature links diffusion-weighted imaging (DWI) characteristics with glioma molecular signatures, histology, and outcomes. Recent studies have explored ‘transition coefficients’ – changes in diffusion properties at the interface between macroscopic tumour and adjacent brain parenchyma – as markers of invasive or progressive phenotype, and have related these to survival, possibly reflecting the role of microinvasive disease in progression. Correspondence between ADC and cellularity is, however, confounded by necrosis, extracellular matrix composition, and vascularity. Moreover, validation of DWI markers of tumour burden has been limited to comparison of macroscopic, voxelwise ADC values with microscopic fields, at vastly different scales confounded by sampling bias. Here we examine transition coefficients by exploring relationships between a novel tissue-based quantification of tumour burden and ADC values at the infiltrating edge of a clinically-relevant, invasive, murine glioblastoma (GBM) model. Anatomical imaging and DWI of G7 orthotopic GBM xenografts in CD-1 nude mice was performed at 7T immediately preceding cull. Brains were excised, frozen, sectioned, and stained for HLA (Human Leukocyte Antigen) to determine the cellular burden of human-derived tumour at the macroscopic scale. Several slices were co-registered to imaging data and their relative HLA content was normalised and averaged. Macroscopic tumour boundary was delineated using ADC and T2w images without reference to HLA. For each tumour boundary voxel, a perpendicular profile allowed simultaneous centrifugal ADC and HLA measurement. Significant inverse correlations between ADC and HLA were demonstrated across the infiltrating tumour edge. Areas of localised non-correlation corresponded to non-parenchymal boundaries limiting infiltration e.g. ventricular margin. This work is the first relating ADC values to infiltrating glioblastoma tissue burden using a novel approach at comparable spatial resolutions. It provides novel direct validation of imaging against GBM invasion at a cellular level, and a platform for future non-invasive imaging characterisation of glioma endophenotype.
CYP3A4 mutation causes vitamin D–dependent rickets type 3
Authors: Jeffrey D. Roizen, Dong Li, Lauren O’Lear, Muhammad K. Javaid, Nicholas J. Shaw, Peter R. Ebeling, Hanh H. Nguyen, Christine P. Rodda, Kenneth E. Thummel, Tom D. Thacher, Hakon Hakonarson, Michael A. Levine
Journal: Journal of Clinical Investigation (2018)

Genetic forms of vitamin D-dependent rickets (VDDRs) are due to mutations impairing activation of vitamin D or decreasing vitamin D receptor responsiveness. Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D. Neither patient had a mutation in any genes known to cause VDDR; however, using whole exome sequencing analysis, we identified a recurrent de novo missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects that alters the conformation of substrate recognition site 4 (SRS-4). In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1, the principal inactivator of vitamin D metabolites. As CYP3A4 mutations have not previously been linked to rickets, these findings provide insight into vitamin D metabolism and demonstrate that accelerated inactivation of vitamin D metabolites represents a mechanism for vitamin D deficiency.
Role of Dicer on human melanoma progression and resistance.
Authors: Nathalia Cruz de Victo, Sandy Adjemian, Romulo dos Santos Sobreira Nunes, Rildo Aparecido Volpini, Mara Huffenbaecher Giavina-Bianchi, Cyro Festa Neto, Niels Olsen Saraiva Camara, Gustavo Pessini Amarante-Mendes, Jacqueline de Fatima Jacysyn
Journal: Clinical Cancer Research (2018)
Nonculprit Plaque Characteristics in Patients With Acute Coronary Syndrome Caused by Plaque Erosion vs Plaque Rupture
Authors: Tomoyo Sugiyama, Erika Yamamoto, Krzysztof Bryniarski, Lei Xing, Hang Lee, Mitsuaki Isobe, Peter Libby, Ik-Kyung Jang
Journal: JAMA Cardiology (2018)

<h3>Importance</h3> Patients with culprit plaque rupture are known to have pancoronary plaque vulnerability. However, the characteristics of nonculprit plaques in patients with acute coronary syndromes caused by plaque erosion are unknown. <h3>Objective</h3> To investigate the nonculprit plaque phenotype in patients with acute coronary syndrome according to culprit plaque pathology (erosion vs rupture) by 3-vessel optical coherence tomography imaging. <h3>Design, Setting, and Participants</h3> In this observational cohort study, between August 2010 and May 2014, 82 patients with acute coronary syndrome who underwent preintervention optical coherence tomography imaging of all 3 major epicardial coronary arteries were enrolled at the Massachusetts General Hospital Optical Coherence Tomography Registry database. Analysis of the data was conducted between November 2016 and July 2017. Patients were classified into 2 groups based on the culprit lesion pathology: 17 patients with culprit plaque erosion and 34 patients with culprit plaque rupture. Thirty-one patients with the absence of culprit rupture or erosion were excluded from further analysis. <h3>Exposures</h3> Preintervention 3-vessel optical coherence tomography imaging. <h3>Main Outcomes and Measures</h3> Plaque characteristics at the culprit and nonculprit lesions evaluated by optical coherence tomography. <h3>Results</h3> In 51 patients (37 men; mean age, 58.7 years), the characteristics of 51 culprit plaques and 216 nonculprit plaques were analyzed. In patients with culprit erosion, the mean (SD) number of nonculprit plaques per patient was smaller (3.4 [1.9] in erosion vs 4.7 [2.1] in rupture,<i>P</i> = .05). Patient-based analysis showed that none of 17 patients with culprit plaque erosion had nonculprit plaque rupture, whereas 26% of the patients (9 of 34) with culprit plaque rupture had nonculprit plaque rupture (<i>P</i> = .02). Plaque-based analysis showed that, compared with the culprit rupture group (n = 158), the culprit erosion group (n = 58) had lower prevalence of plaque rupture (0% vs 8%;<i>P</i> &lt; .001), macrophage accumulation (29% vs 53%;<i>P</i> = .01), microvessels (21% vs 42%;<i>P</i> = .003), and spotty calcium (5% vs 22%;<i>P</i> = .006) in the nonculprit lesions. The prevalence of lipid-rich plaque, thin-cap fibroatheroma, and thrombus did not differ between the groups. <h3>Conclusions and Relevance</h3> Compared with those with culprit plaque rupture, patients with acute coronary syndrome caused by culprit plaque erosion had a smaller number of nonculprit plaques and the lower levels of panvascular instability, affirming that distinct pathophysiologic mechanisms operate in plaque erosion and plaque rupture.
Evaluation des complications de la résection endoscopique des polypes colo-rectaux: Experience du service de gastro-entérologie du CHU Bab el oued-ALGER
Authors: Y Zmiri, H Saoula, Y Aissat, A Khaldi, H Mahiou, AF Boutaleb, R Osmane, A Mitiche, M Nakmouche
Journal: Endoscopy (2018)

La détection et la résection endoscopique des polypes du colon diminue fortement l'incidence et la mortalité par Cancer colo-rectal. C'est une alternative à la chirurgie, elle est sûre et efficace mais n'est pas dénuée de complications (perforation, hémorragie) qu'il faut savoir prévenir et gérer. Le but de ce travail est de rapporter l'expérience de notre sevice en matière de résection de polypes et d'étudier la fréquence, la prévention et la gestion des complications.
La dissection colique est possible en France en particulier en utilisant la technique de contre-traction par double-clip
Authors: J Jacques, J Albouys, R Legros, A Charissoux, J Rivory, A Tailleur, V Valgueblasse, D Sautereau, T Ponchon, M Pioche
Journal: Endoscopy (2018)

Le choix de la technique de résection endoscopique pour les lésions coliques sus-péritonéales est source de débat. Alors que la dissection sous-muqueuse est la technique de référence au Japon, les auteurs occidentaux sont plus en faveur de la mucosectomie piece-meal vu la difficulté technique et les risques de l'ESD en sus-péritonéal et les résultats publiés jusqu'ici par les équipes occidentales. Effectivement l'ESD colique est bien plus difficile que l'ESD rectale en raison des mouvements du péristaltisme, de la présence des plis, de l'inconstance de l'aide par la gravité, des mouvements respiratoires, de la finesse de la sous muqueuse et de son caractère souvent fibreux ainsi que des boucles dont la présence impacte considérablement la précision de la résection. Peu d'études occidentales se sont intéressées aux résultats de la dissection colique hors lésions rectales. Effectivement la plupart des études occidentales d'ESD colorectales sont biaisées par la présence très majoritaire de lésions rectales dont les résultats sont difficilement extrapolables au colon. Nous rapportons ici la première expérience française bicentrique en ESD colique pure.
La Fibroscopie gastroduodénale de l'enfant à Abidjan (COTE D'IVOIRE)
Authors: AD Bangoura, H Yakk, S Doffou, CD Fanou
Journal: Endoscopy (2018)

L'objectif de notre étude vise à déterminer les données démographiques, les indications, le rendement, et la sécurité de la gastroscopie chez l'enfant en côte d'ivoire.
Risque carcinologique des polypes festonnés
Authors: J Tannoury, C Cremone, C Charpy, C Gagnière, AL Rentien, F Mesli, Y Le Baleur, A Amiot, I Sobhani
Journal: Endoscopy (2018)

Le cancer colorectal (CCR) demeure une des principales causes de mortalité par cancer justifiant des actions de dépistage. Le test d'Hemocult basé sur le saignement occulte n'est pas adapté aux polypes dits «festonnés» ou serrated polyps (SP). Certains cancers d'intervalle après le test immunologique de dépistage-FIT (pourtant plus sensible) pourraient être secondaires à SPs (Gastroenterology 2017;153:439 – 447). A côté de la séquence classique adénome-adénocarcinome, le SP correspondrait à une voie de carcinogenèse alternative impliquant des mutations génétiques différentes.
Breast Cancer Diagnosis and Treatment After High-Deductible Insurance Enrollment
Authors: J. Frank Wharam, Fang Zhang, Christine Y. Lu, Anita K. Wagner, Larissa Nekhlyudov, Craig C. Earle, Stephen B. Soumerai, Dennis Ross-Degnan
Journal: Journal of Clinical Oncology (2018)

Purpose High-deductible health plans (HDHPs) require substantial out-of-pocket spending and might delay crucial health services. Breast cancer treatment delays of as little as 2 months are associated with adverse outcomes. Methods We used a controlled prepost design with survival analysis to assess timing of breast cancer care events among 273,499 women age 25 to 64 years without evidence of breast cancer before inclusion. Women were included if continuously enrolled for 1 year in a low-deductible ($0 to $500) plan followed by up to 4 years in a HDHP (at least $1,000 deductible) after an employer-mandated switch. Study inclusion was on a rolling basis, and members were followed between 2003 and 2012. The comparison group comprised 2.4 million contemporaneously matched women whose employers offered only low-deductible plans. Measures were times to first diagnostic breast imaging (diagnostic mammogram, breast ultrasound, or breast magnetic resonance imaging), breast biopsy, incident early-stage breast cancer diagnosis, and breast cancer chemotherapy. Outcomes were analyzed by using Cox models and adjusted for age-group, morbidity score, poverty level, US region, index date, and employer size. Results After the index date, HDHP members experienced delays in receipt of diagnostic imaging (adjusted hazard ratio [aHR], 0.95; 95% CI, 0.94 to 0.96), biopsy (aHR, 0.92; 95% CI, 0.89 to 0.95), early-stage breast cancer diagnosis (aHR, 0.83; 0.78 to 0.90), and chemotherapy initiation (aHR, 0.79; 95% CI, 0.72 to 0.86) compared with the control group. Conclusion Women switched to HDHPs experienced delays in diagnostic breast imaging, breast biopsy, early-stage breast cancer diagnosis, and chemotherapy initiation. Additional research should determine whether such delays cause adverse health outcomes, and policymakers should consider selectively reducing out-of-pocket costs for key breast cancer services.
Phase 2 study of the safety and efficacy of pembrolizumab (pembro) in combination with dabrafenib (D) and trametinib (T) for advanced melanoma (KEYNOTE-022).
Authors: Georgina V. Long, Omid Hamid, F. Stephen Hodi, Donald P. Lawrence, Victoria Atkinson, Alexander Starodub, Matteo S. Carlino, Rosalie Anne Fisher, Wilson H Miller, Michele Maio, Marcus Butler, Paola Queirolo, Pier Francesco Ferrucci, Teresa M. Petrella, Jacob Schachter, Yingjie Huang, Scott J. Diede, Scot Ebbinghaus, Antoni Ribas
Journal: Journal of Clinical Oncology (2016)

TPS9596 Background: The interaction between programmed death 1 (PD-1) and its ligands PD-L1 and PD-L2 represents a major pathway that tumors may use to evade immune control, enabling their survival and progression. Pembro, a highly selective and potent humanized monoclonal antibody that directly blocks PD-1, has demonstrated a manageable toxicity profile with durable responses in advanced melanoma. Inhibition of the MAPK pathway with a combination of BRAF and MEK inhibitors improves survival in BRAFV600-mutant melanoma and may be synergistic with immunotherapies. KEYNOTE-022 (NCT02130466) is a multicenter phase 1/2 study of pembro in combination with D, a selective BRAF inhibitor, and T, a highly selective MEK1/2 inhibitor. In the randomized phase 2 study described here, we will evaluate the safety, tolerability, and preliminary efficacy of this triplet combination as first-line therapy for BRAF-mutant melanoma. Methods: Patients aged ≥ 18 y with histologically confirmed unresectable or metastatic stage III/IV BRAFV600E/K- mutant melanoma and no prior therapy are to be randomized 1:1 to pembro 2 mg/kg IV Q3W with D 150 mg orally BID + T 2 mg orally daily or placebo + D + T. Randomization is to be stratified by ECOG PS (0 vs 1) and LDH level ( > 1.1× vs ≤ 1.1× ULN). Pembro is to be given for ≤ 24 mo or until confirmed disease progression, unacceptable toxicity, or pt or investigator withdrawal; pts experiencing confirmed complete response (CR) after ≥ 6 mo may discontinue pembro after receiving ≥ 2 doses beyond initial CR, but may continue treatment with D + T. AEs are to be graded by NCI CTCAE v4.0. Response is to be assessed at wk 12, then every 6 wk until mo 18, then every 12 wk thereafter by RECIST v1.1 per investigator. Primary end point is PFS; secondary end points are ORR, response duration, and OS. A data monitoring committee is to monitor safety and efficacy at a planned interim analysis (IA). Key end point for the IA is the 5-category ordinal response at wk 36 (CR, very good partial response [PR], moderate PR, stable disease, progressive disease) determined by central review. Recruitment in KEYNOTE-022 is ongoing; approximately 120 pts are expected to enroll. Clinical trial information: NCT02130466.
Un outil entièrement automatisé, performant, rapide, pour évaluer la qualité de la visualisation en vidéocapsule endoscopique de l'intestin grêle
Authors: S Oumrani, A Histace, E Abou Ali, O Pietri, A Becq, G Houist, I Nion Larmurier, M Camus, C Florent, X Dray
Journal: Endoscopy (2018)

La vidéocapsule endoscopique (VCE) est la méthode de première ligne dans l'exploration de l'intestin grêle. Sa rentabilité diagnostique peut être diminuée par une mauvaise visualisation de la muqueuse due à la présence de résidus, sécrétions (bile notamment), bulles dans la lumière digestive, ou due à un défaut de luminosité (insuffisante ou excessive). Des scores cliniques, qualitatifs et quantitatifs de qualité de visualisation de la muqueuse lors d'une VCE ont été établis, mais leur reproductibilité est médiocre, notamment du fait qu'ils portent sur des séquences de milliers d'images. Une évaluation électronique, image par image, est susceptible d'être plus performante et mieux reproductible qu'une évaluation humaine. L'objectif principal de notre étude était d'évaluer les performances diagnostiques, isolées puis combinées, de 3 méthodes d'analyse électronique de qualité de visualisation de la muqueuse d'images fixes de VCE du grêle de 3ème génération: (a) l'analyse du ratio de pixels rouges/verts de l'image; (b) un indice reflétant l'abondance des bulles, basé sur une matrice de cooccurrence en niveaux de gris (GLCM); (c) un indice reflétant la luminosité ou contraste de l'image. L'objectif secondaire était d'évaluer le temps nécessaire pour l'analyse d'une image (et d'extrapoler à une vidéo complète de 50000 images du grêle) avec la méthode la plus performante.
Emphysema and extrapulmonary tissue loss in COPD: a multi-organ loss of tissue phenotype
Authors: Bartolome R. Celli, Nicholas Locantore, Ruth Tal-Singer, John Riley, Bruce Miller, Jørgen Vestbo, Julie C. Yates, Edwin K. Silverman, Caroline A. Owen, Miguel Divo, Victor Pinto-Plata, Emiel F.M. Wouters, Rosa Faner, Alvar Agusti
Journal: European Respiratory Journal (2018)

We tested whether emphysema progression accompanies enhanced tissue loss in other body compartments in 1817 patients from the ECLIPSE chronic obstructive pulmonary disease (COPD) cohort. Clinical and selected systemic biomarker measurements were compared in subjects grouped by quantitative tomography scan emphysema quartiles using the percentage of low attenuation area (LAA%). Lowest and highest quartile patients had amino-acid metabolomic profiles. We related LAA% to 3 years decline in lung function (forced expiratory volume in 1 s (FEV 1 )), body mass index (BMI), fat-free mass index (FFMI) and exacerbations, hospitalisations and mortality rates. Participants with more baseline emphysema had lower FEV 1 , BMI and FFMI, worse functional capacity, and less cardiovascular disease but more osteoporosis. Systemic C-reactive protein and interleukin-6 levels were similar among groups, but club cell protein 16 was higher and interleukin-8, surfactant protein D and soluble receptor for advanced glycation end product were lower with more emphysema. Metabolomics differed between extreme emphysema quartiles. Patients with more emphysema had accelerated FEV 1 , BMI and FFMI decline and more exacerbations, hospitalisations and mortality. COPD patients with more emphysema undergo excessive loss of pulmonary and extrapulmonary tissue, which is probably related to abnormal tissue maintenance. Because of worse clinical outcomes, we propose this subgroup be named the multi-organ loss of tissue (MOLT) COPD phenotype.