tbuckley/cabot-search huggingface dataset:
Overall Survival in Malignant Glioma Is Significantly Prolonged by Neurosurgical Delivery of Etoposide and Temozolomide from a Thermo-Responsive Biodegradable Paste
Authors: Stuart J. Smith, Betty M. Tyler, Toby Gould, Gareth J. Veal, Noah Gorelick, Jonathan Rowlinson, Riccardo Serra, Alison Ritchie, Phillip Berry, Annette Otto, John Choi, Nicolas Skuli, Maria Estevez-Cebrero, Kevin M. Shakesheff, Henry Brem, Richard G. Grundy, Ruman Rahman
Journal: Clinical Cancer Research (2019)

Abstract Purpose: High-grade glioma (HGG) treatment is limited by the inability of otherwise potentially efficacious drugs to penetrate the blood–brain barrier. We evaluate the unique intracavity delivery mode and translational potential of a blend of poly(DL-lactic acid-co-glycolic acid; PLGA) and poly(ethylene glycol; PEG) paste combining temozolomide and etoposide to treat surgically resected HGG. Experimental Design: To prolong stability of temozolomide prodrug, combined in vitro drug release was quantitatively assessed from low pH–based PLGA/PEG using advanced analytic methods. In vitro cytotoxicity was measured against a panel of HGG cell lines and patient-derived cultures using metabolic assays. In vivo safety and efficacy was evaluated using orthotopic 9L gliosarcoma allografts, previously utilized preclinically to develop Gliadel. Results: Combined etoposide and temozolomide in vitro release (22 and 7 days, respectively) was achieved from a lactic acid–based PLGA/PEG paste, used to enhance stability of temozolomide prodrug. HGG cells from central-enhanced regions were more sensitive to each compound relative to primary lines derived from the HGG-invasive margin. Both drugs retained cytotoxic capability upon release from PLGA/PEG. In vivo studies revealed a significant overall survival benefit in postsurgery 9L orthotopic gliosarcomas, treated with intracavity delivered PLGA/PEG/temozolomide/etoposide and enhanced with adjuvant radiotherapy. Long-term survivorship was observed in over half the animals with histologic confirmation of disease-free brain. Conclusions: The significant survival benefit of intracavity chemotherapy demonstrates clinical applicability of PLGA/PEG paste-mediated delivery of temozolomide and etoposide adjuvant to radiotherapy. PLGA/PEG paste offers a future platform for combination delivery of molecular targeted compounds.
PERCUTANEOUS ENDOSCOPIC GASTOSTOMY AND JEJUNOSTOMY – ONE CENTRE REVIEW (SUMMARY DATA 2002 – 2018)
Authors: P Kohout, Z Antos, G Puskarova, M Rozmahel, M Cernik, S Summerova
Journal: Endoscopy (2019)

The aim of study was to review number of percutaneous gastrostomies (PEG) and jejunostomies (PEJ) in PEG Center of Internal Clinic 3 rd Medical Faculty of Charles University and Thomayer's Hospitalin Prague.
FUTURE KEY PERFORMANCE INDICES FOR DEVICE ASSISTED ENTEROSOCPY; WHAT WE CAN LEARN FROM CURRENT PRACTICE
Authors: MS Ismail, A O'Keefe, CJ Aylward, N Hickey, D McNamara
Journal: Endoscopy (2019)

ESGE has recommended device-assisted-enteroscopy (DAE) is used to confirm and treat small bowel lesions. DAE is relatively new and lacks Key Performance Indices (KPI). Quality of DAE would have significant impact on patient outcome; assessment of current practice could highlight important future KPIs.
CLINICAL EFFECTIVENESS OF HEMOSPRAY IN UPPER GASTROINTESTINAL BLEEDING: EXPERIENCE FROM “REAL WORLD” CLINICAL PRACTICE IN A TERTIARY REFERRAL CENTRE
Authors: M Fraile-López, W Fateen, J Ortíz Fernández-Sordo, K Ragunath
Journal: Endoscopy (2019)

Hemospray is an useful endoscopic haemostatic powder for the management of gastrointestinal bleeding. Its role within the therapeutic algorithm of upper gastrointestinal bleeding (UGIB) is not well defined. Its usage is generally aimed at immediate but temporary control of UGIB to allow time for definitive therapy, spontaneous control or for palliation. We aimed to describe:1) indications and effectiveness of endoscopic haemostasis in UGIB. 2) to describe adverse events and re-bleeding rates.
Blood Pressure–Lowering by the Antioxidant Resveratrol Is Counterintuitively Mediated by Oxidation of cGMP-Dependent Protein Kinase
Authors: Oleksandra Prysyazhna, Kathryn Wolhuter, Christopher Switzer, Celio Santos, Xiaoping Yang, Steven Lynham, Ajay M. Shah, Philip Eaton, Joseph R. Burgoyne
Journal: Circulation (2019)

Background: The health-promoting and disease-limiting abilities of resveratrol, a natural polyphenol, has led to considerable interest in understanding the mechanisms of its therapeutic actions. The polyphenolic rings of resveratrol enable it to react with and detoxify otherwise injurious oxidants. Whilst the protective actions of resveratrol are commonly ascribed to its antioxidant activity, here we show that this is a misconception. Methods: The ability of resveratrol to oxidize cGMP-dependent PKG1α (protein kinase 1α) was assessed in isolated rat aortic smooth muscle cells, and the mechanism of action of this polyphenol was characterized using in vitro experiments, mass spectrometry and electron paramagnetic resonance. The blood pressure of wild-type and C42S knock-in mice was assessed using implanted telemetry probes. Mice were made hypertensive by administration of angiotensin II via osmotic mini-pumps and blood pressure monitored during 15 days of feeding with chow diet containing vehicle or resveratrol. Results: Oxidation of the phenolic rings of resveratrol paradoxically leads to oxidative modification of proteins, explained by formation of a reactive quinone that oxidizes the thiolate side chain of cysteine residues; events that were enhanced in cells under oxidative stress. Consistent with these observations and its ability to induce vasodilation, resveratrol induced oxidative activation of PKG1α and lowered blood pressure in hypertensive wild-type mice, but not C42S PKG1α knock-in mice that are resistant to disulfide activation. Conclusions: Resveratrol mediates lowering of blood pressure by paradoxically inducing protein oxidation, especially during times of oxidative stress, a mechanism that may be a common feature of antioxidant molecules.
RISK FACTORS FOR PREDICTING EARLY VARICEAL REBLEEDING AFTER ENDOSCOPIC VARICEAL LIGATION (EVL)
Authors: R Banjira, N Lahmidani, A Lamine Sejai, M Lahlali, H Abid, M Elyousfi, DA Benajah, M Elabkari, A Ibrahimi
Journal: Endoscopy (2019)

The aim of this study is to determine the factors predicting the occurrence of post LVO bleeding and its mortality.
Abstract A34: Modeling and analysis of YAP/TAZ activity integrating mechanosensing and the Hippo pathway
Authors: Meng Sun, Fabian Spill, Muhammad Zaman
Journal: Cancer Research (2017)

Abstract With the recent enormous progress in uncovering the roles of YAP/TAZ in cell proliferation, differentiation, tissue organization and tumorgenesis, the crosstalk of YAP/TAZ mechanical regulators and the Hippo pathway regulators (the cell-cell adhesion) remains largely elusive. To bridge the current gap in our understanding, we present a computational model predicting YAP/TAZ activity depending on ECM mechanical properties, cell-cell adhesions, and more importantly, the crosstalk between the two. We propose a mechanism of the interaction between LIMK and LATS to explain the unresolved synergistic effect of YAP/TAZ activity between the mechano-sensing and the Hippo pathways. Using this computational model, we are able to analyze the synergistic effects of YAP/TAZ driven by the LIMK-LATS mechanism or by the AMOT mechanism, which is another key candidate for the crosstalk. Cancer cell lines that have downregulated E-cadherin expression overcoming the LATS-dependent YAP/TAZ contact inhibition regulation, and the mechanical sensing of YAP/TAZ serves as an important checkpoint for regulating tumor progression. We are able to quantitatively predict the YAP/TAZ activity as a function of mechanical ECM properties (stiffness response function) in these systems. Our model aims to bridge the gap by including mechano-to-biochemical signal conversion by adhesion molecules, intracellular signal transmission, cytoskeleton dynamics, and regulation of effectors relevant to directing transcriptional programs, such as YAP/TAZ activity. Such an integrated molecular model predicts effects of molecular inhibitors or changes in mechanical propertiesin silico, and the difference in 2D and 3D. For example, adhesion molecules such as FAK can shift the stiffness response function horizontally, such that FAK overexpression rescues YAP/TAZ activity in soft environments. The model also predicts that the sensitivity of YAP/TAZ activity to ECM mechanical properties is higher than the one of SRF/MAL, which is another important regulator of differentiation and regulated by cytoskeleton dynamics. Overall, our model provides a novel platform of studying YAP/TAZ activity in the context of integrating different signaling pathways. This platform can be used to gain new fundamental insights into the role of key molecular and mechanical regulators on development, tissue engineering or tumor progression. Citation Format: Meng Sun, Fabian Spill, Muhammad Zaman. Modeling and analysis of YAP/TAZ activity integrating mechanosensing and the Hippo pathway. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A34.
Place de l'écho-endoscopie recto-sigmoïdienne avec élastométrie et produit de contraste dans l'évaluation et la prise en charge de l'endométriose pelvienne profonde avec atteinte digestive
Authors: C Fortier-Beaulieu, M Chassang, M Le Marechal, C Gomercic, M Barthet, T Piche, J Delotte, G Vanbiervliet
Journal: Endoscopy (2019)

L'endométriose pelvienne profonde (EPP) est une atteinte endométriosique pénétrant l'espace sous péritonéal et/ou la paroi des organes pelviens. Il s'y associe fréquemment une atteinte digestive. L'écho-endoscopie rectale complète le bilan iconographique avec une sensibilité diagnostique de 90% pour les atteintes digestives. Aucune étude n'a évalué l'intérêt de l'écho-endoscopie avec élastométrie et contraste, outils permettant d'augmenter sa précision diagnostique, dans la caractérisation des lésions digestives d'endométriose. Le but principal de l'étude était de caractériser par élastografie et écho-endoscopie de contraste les lésions digestives d'endométriose pelvienne profonde. Les objectifs secondaires étaient d'établir une corrélation entre l'examen élastographique, la prise de contraste des lésions et: i) la sévérité clinique de la maladie, ii) l'analyse histologique des lésions et iii) la réponse thérapeutique des patientes. Le dernier objectif était de déterminer l'innocuité de ces deux techniques écho endoscopiques lors de l'évaluation de l'endométriose pelvienne profonde.
RANKL inhibition improves muscle strength and insulin sensitivity and restores bone mass
Authors: Nicolas Bonnet, Lucie Bourgoin, Emmanuel Biver, Eleni Douni, Serge Ferrari
Journal: Journal of Clinical Investigation (2019)

Receptor activator of NF-κB ligand (RANKL) activates, while osteoprotegerin (OPG) inhibits, osteoclastogenesis. A neutralizing Ab against RANKL, denosumab, improves bone strength in osteoporosis. OPG also improves muscle strength in mouse models of Duchenne's muscular dystrophy (mdx) and denervation-induced atrophy, but its role and mechanisms of action on muscle weakness in other conditions remain to be investigated. We investigated the effects of RANKL inhibitors on muscle in osteoporotic women and mice that either overexpress RANKL (HuRANKLTg+), or lack Pparb and concomitantly develop sarcopenia (Pparb–/–). In women, taking denosumab for more than 3 years improved appendicular lean mass and handgrip strength compared with no treatment, whereas bisphosphonate did not. HuRANKLTg+ mice displayed lower limb force and maximal speed, while their leg muscle mass was diminished, with a lower number of type I and II fibers. Both OPG and denosumab increased limb force proportionally to the increase in muscle mass. They markedly improved muscle insulin sensitivity and glucose uptake, and decreased antimyogenic and inflammatory gene expression in muscle, such as myostatin and protein tyrosine phosphatase receptor-γ. Similarly, in Pparb–/–, OPG increased muscle volume and force while also normalizing insulin signaling and higher expression of inflammatory genes in skeletal muscle. In conclusion, RANKL deteriorates while its inhibitors improve muscle strength and insulin sensitivity in osteoporotic mice and humans. Hence, denosumab could represent a novel therapeutic approach for sarcopenia.
Estimating the association between antibiotic exposure and colonization with extended-spectrum β-lactamase-producing Gram-negative bacteria using machine learning methods: a multicentre, prospective cohort study
Authors: E. Tacconelli, A. Górska, G. De Angelis, C. Lammens, G. Restuccia, J. Schrenzel, D.H. Huson, B. Carević, L. Preoţescu, Y. Carmeli, M. Kazma, T. Spanu, E. Carrara, S. Malhotra-Kumar, B.P. Gladstone
Journal: Clinical Microbiology and Infection (2019)
Response to: ‘Differentiating disease activity from damage in systemic sclerosis: it’s still early days!’ by Jain and Sharma
Authors: Mandana Nikpour
Journal: Annals of the Rheumatic Diseases (2019)

Disease activity and organ damage: different sides of the same coin in systemic sclerosisWe thank Drs Jain and Sharma 1 for their interest in our work. 2 We agree that what may be deemed irreversible loss of organ structure and/or function in the current therapeutic landscape of systemic sclerosis (SSc), may one day be reversible and indeed even preventable as highly effective novel therapies become available.We caution against the erroneous interpretation that the presence of damage is necessarily an indication for withdrawal or de-escalation of treatment.Unlike some other rheumatic diseases wherein relapsing remitting disease activity leads to damage, in SSc, activity and damage can occur concurrently.Therefore, therapeutic decisions must not rest solely on assessment of damage but also of concomitant activity in a particular organ.Indeed, the same working group of the Scleroderma Clinical Trials Consortium (SCTC) is currently working on the development of an Activity Index in SSc, using similar methodology to that deployed for the development of the Damage Index (DI).We emphasise that the attribution of damage to SSc is fundamentally important to the application of the SCTC-DI. 1 In the examples given by Drs Jain and Sharma, reduced forced vital capacity must be attributable to SSc interstitial lung disease, and low body mass index below 18.5 kg/m 2 must be attributable to SSc for these items to be scored.Finally, while digital pitting scars represent damage to the digital pulps and this item was included in the initial survey of experts, it was not ultimately included in the SCTC-DI as it did not correlate with morbidity and mortality endpoints independently of the digital ulceration and amputation items.
RISK OF MICROBIAL TRANSLOCATION IN PER-ORAL ENDOSCOPIC MYOTOMY (POEM) FOR ACHALASIA: ANTIBIOTIC PROPHYLAXIS OR SHORT-THERAPY? AN INTERIM ANALYSIS OF A PROSPECTIVE RANDOMIZED CLINICAL TRAIL
Authors: R Maselli, A Oliva, M Badalamenti, S Attardo, R Nicoletti, E Finati, S Vetrano, C Correale, EC Ferrara, AP Galtieri, A Fugazza, S Carrara, A Anderloni, A Repici
Journal: Endoscopy (2019)

Microbial translocation (MT) is the passage of viable/nonviable microbes across the GI-barrier. Presence of Lipopolysaccharide (LPS) of Gram-negatives and LPS-binding protein (LBP) in the plasma correlates to sepsis/septic shock through the activation of inflammation (IN) via soluble-CD14 (sCD14) and consequent cytokines production (IL-6, IL-1b, TNF-α). Considering POEM a clean-contaminated procedure it should be assessed whether the post-POEM fever/inflammation is cytokine-mediated or infection-related. Aim of the study was to evaluate markers of MT, IN and bacteremia post POEM.
HIGH DIAGNOSTIC ADEQUACY AND ACCURACY OF THE NEW 20G PROCORE NEEDLE FOR EUS-GUIDED TISSUE ACQUISITION: RESULTS OF A LARGE MULTICENTRE RETROSPECTIVE STUDY
Authors: C Fabbri, A Fornelli, L Fuccio, S Giovanelli, I Tarantino, F Antonini, R Liotta, L Frazzoni, P Gusella, M La Marca, L Barresi, G Macarri, M Traina, D De Biase, S Fiorino, E Jovine, A Larghi, V Cennamo
Journal: Endoscopy (2019)

EUS-guided fine-needle biopsy has become the standard for tissue sampling. A new 20G ProCore needle has been developed to overcome the limitations of tissue acquisition of the smaller needles (22G, 25G) and the rigidity of the larger one (19G). Aim of the study was to assess the performance of the 20G ProCore needle.
Molecular pathology of tumors of the central nervous system
Authors: B.W. Kristensen, L.P. Priesterbach-Ackley, J.K. Petersen, P. Wesseling
Journal: Annals of Oncology (2019)

Since the update of the 4th edition of the WHO Classification of Central Nervous System (CNS) Tumors published in 2016, particular molecular characteristics are part of the definition of a subset of these neoplasms. This combined ‘histo-molecular’ approach allows for a much more precise diagnosis of especially diffuse gliomas and embryonal CNS tumors. This review provides an update of the most important diagnostic and prognostic markers for state-of-the-art diagnosis of primary CNS tumors. Defining molecular markers for diffuse gliomas are IDH1/IDH2 mutations, 1p/19q codeletion and mutations in histone H3 genes. Medulloblastomas, the most frequent embryonal CNS tumors, are divided into four molecularly defined groups according to the WHO 2016 Classification: wingless/integrated (WNT) signaling pathway activated, sonic hedgehog (SHH) signaling pathway activated and tumor protein p53 gene (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH-activated. Molecular characteristics are also important for the diagnosis of several other CNS tumors, such as RELA fusion-positive subtype of ependymoma, atypical teratoid rhabdoid tumor (AT/RT), embryonal tumor with multilayered rosettes, and solitary fibrous tumor/hemangiopericytoma. Immunohistochemistry is a helpful alternative for further molecular characterization of several of these tumors. Additionally, genome-wide methylation profiling is a very promising new tool in CNS tumor diagnostics. Much progress has thus been made by translating the most relevant molecular knowledge into a more precise clinical diagnosis of CNS tumors. Hopefully, this will enable more specific and more effective therapeutic approaches for the patients suffering from these tumors.
Youth-Nominated Support Team Intervention For Suicidal Adolescents And Mortality Outcomes—Reply
Authors: Cheryl A. King, Ewa Czyz, Brenda W. Gillespie
Journal: JAMA Psychiatry (2019)

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Differences between breast cancer subtypes in developing metastatic disease
Authors: H. Wildiers, M. van Mechelen, A. van Herck, J.-P. Lobelle, A. Smeets, P. Neven, K. Punie
Journal: Annals of Oncology (2019)

Background: This large study aims to explore in depth the impact of breast cancer (BC) subtype on metastatic behavior and long term outcome. Methods: This is a retrospective single centre study of 5971 patients with newly diagnosed, unilateral first diagnosis of BC, diagnosed between 2000 and 2010. Surrogate BC subtypes were defined according to immunohistochemical criteria (estrogen receptor (ER), tumor grade, HER2), and the HER2+ subgroups were separately analyzed depending on trastuzumab (TRTZ) administration. The impact of BC subtype was evaluated in terms of first distant metastatic event behavior and breast cancer specific survival (BCSS), defined as time from first distant metastases (DM) till death due to breast cancer. Analysis was performed using the Kaplan-Meier method, logistic and Cox regression. Results: The cohort consisted of 5071 early BC pts treated with upfront surgery (EBC) of whom 621 (12,2%) developed DM, 592 early BC pts treated with neoadjuvant systemic therapy (NEO) of whom 196 (33.1%) developed DM, and 308 primary metastatic pts (META). Median FUP was 122,9 Mo (IQR 92-156). For EBC+NEO, DM rate per subtype was: LumA(grade 1-2) 8.1%, LumB(grade 3) 20.4%, ER+HER2+ without TRTZ 21.7%, ER+HER2+ with TRTZ 9.0%, ER-HER2+ without TRTZ 30.0%, ER-HER2+ with TRTZ 19.8% and Triple Neg BC (TNBC) 25.3%. Primary metastatic disease (META) rate per subtype was least common in TNBC (17,7%) and most common in ER+HER+ with TRZT (37,8%) and LumA (34,1%). There were major differences in site of first DM according to subtype. Median BCSS was worst for TNBC (12.0 mo) and best for LumA (46.7mo) and ER+HER2+ with TRZT(43.1mo). For pts with single organ DM, median BCSS was worst for brain localization (17.9mo), compared to skin (24.1mo), lung (25,0mo), liver (33,8mo), bone (38.7mo). Multiple sites of first DM had worse BCSS (³3 sites 20,5mo) compared to 2 sites (27,1mo) or 1 site (40.0mo). BCSS is longer in primary DM (META: 43,4mo) as compared to secondary DM (EBC+NEO: 27,9mo) but when looking at subtypes, this difference only seems important in LumA and LumB subtypes. Conclusions: Tumor subtype influences the metastatic behavior and survival after development of metastatic disease. Legal entity responsible for the study: University Hospitals Leuven. Funding: Has not received any funding. Disclosure: H. Wildiers: Travel support: Roche, Pfizer; His institution received consulting fees, honoraria: Roche and other companies; His institution received an unrestricted research grant: Roche. P. Neven: Speaker's fees, consulting fees, research support: Roche (all provided to his institute); Advisory board: Novartis, AstraZeneca, Lilly, Pfizer (all consulting fees are provided to his institute). K. Punie: Consulting fees, travel support: Roche (all provided to his institute). All other authors have declared no conflicts of interest.