tbuckley/cabot-search huggingface dataset:
Human glioma cell models resistant to alloreactive cytotoxic T lymphocytes
Authors: Yu-Pei Liao, Lisa H. Butterfield, Wilson S. Meng, Antoni Ribas, William H. McBride
Journal: Cancer Research (2004)

687  Radiation is a well-known immunosuppressive agent. The mechanism is generally ascribed to the high radiosensitivity of lymphocytes. We have investigated whether suppression of antigen presentation function might exist at the level of dendritic cells (DCs), which are relatively radioresistant. DCs capture, process, and load peptides on major histocompatibility complex (MHC) class I or II molecules in order to activate CD8+ or CD4+ T cells. Antigenic peptides presented on MHC class I molecules can be loaded either by the endogenous or exogenous pathway. The endogenous pathway in DCs involves antigen degradation through the proteasome. The exogenous pathway involves direct loading of peptides onto the MHC class I molecules. In this study, we used the human melanocyte/melanoma antigen MART-1 to investigate the effects of radiation on the development of class I-mediated MART-1 specific T cell responses. DCs were generated from 7-day cultures of murine bone marrow cells in GM-CSF and IL-4. Replication-deficient adenoviral vectors were used to express MART-1 (AdVMART1) in DCs for processing through the endogenous pathway. C57BL/6 mice were immunized with AdVMART1 transduced DCs, with and without prior irradiation. 10-14 days after immunization, IFN-γ production by immune splenocytes was measured by ELISPOT. Prior radiation treatment resulted in a significant decrease in MART-1-specific T cell responses. To investigate if the generation of protective anti-tumor immunity was affected, the murine B16 tumor cells which express murine MART-1 were used. AdVMART1/DC vaccination protected C57BL/6 mice against challenge with viable B16 melanoma cells while irradiation of the DCs prior to AdVMART1 transduction completely abrogated protection. Irradiation affected expression of costimulatory molecules by DC; however, this may not be the mechanism for reduced function of irradiated DC because antigen presentation through the exogenous MHC class I pathway was not inhibited and was in fact improved by irradiation. This was shown using the immunodominant antigenic peptide MART-1(27-35), presented by HLA-A2.1 MHC molecules. HLA-A2.1/Kb transgenic mice were injected with peptide pulsed DCs, with and without irradiation treatment. A significant increase in MART-1 specific T cells responses was seen by ELISPOT. To study protective immunity, HLA-A2.1/Kb transgenic mice were immunized with MART-1(27-35) pulsed DCs (MART-1/DC) with or without prior irradiation. B16/A2/Kb tumor cells had delayed tumor growth in mice immunized with radiation treated MART-1/DC immunization comparing to the non-irradiated group. These results suggest that DC antigen presentation function is affected by irradiation and this may be a possible pathway suppressing immune responses to tumor antigens released during radiation therapy.
PREDICTIVE FACTORS OF FAILURE AND COMPLICATIONS OF ENDOSCOPIC COLONIC POLYPECTOMY: A SINGLE-CENTER STUDY
Authors: K Agar, M Medhioub, S Jardak, L Hamzaoui, A Khsiba, M Msaddek Azouz
Journal: Endoscopy (2018)

Endoscopic polypectomy is a simple and effective technique which can sometimes lead to serious complications that may require surgery.
EXTRAMEDULLARYPLASMOCYTOMA OF THE ANAL CANAL AND RECTUM IN PATIENT WITH ULCERATIVE COLITIS
Authors: I Jovanovic, D Popovic, S Djuranovic, S Lukic, M Spuran, M Micev, M Perunicic, A Sokic-Milutinovic, I Jovicic, J Bila, S Zgradic, M Smiljanic, K Jankovic
Journal: Endoscopy (2018)

Plasmacytomas are clonal proliferations of plasma cells which are cytologically and immunophenotypically identical as plasma cell myeloma, but manifest a localized osseous or extraosseous growth pattern. Solitary plasmacytoma of bone (P-bone) and solitary extramedullaryplasmacytoma (P-extramedullary) are rare diseases. Extramedullaries rarely occur in the GI tract, stomach, small bowel, colon, or rectum. The lower gastrointestinal EMP represents less than 5% of all cases, and location in the anal canal is exceedingly rare. We found only few cases of common presentation of inflammatory bowel disease and extramedullaryplasmacytoma.
Abstract 15649: Open-Chest Intramyocardial Delivery of Exosomes From Cardiosphere-Derived Cells (CDCs) Mimics Cellular Postconditioning: Decreased Infarct Size and Improved Perfusion in a Pig Model of Acute Myocardial Infarction
Authors: Romain Gallet, James Dawkins, Eli Simsolo, Eleni Tseliou, Ryan Middleton, Jackelyn Valle, Michelle Kreke, Rachel Smith, Linda Marbán, Eduardo Marbán
Journal: Circulation (2015)

Background: Various lines of evidence indicate that exosomes mediate the therapeutic effects of cardiosphere-derived cells (CDCs). However, retention and efficacy of exosomes may be limited after intracoronary (IC) delivery due to their very small size (30-150 nm diameter). Objectives: We sought to assess the optimal dosing and delivery techniques for exosomes, and their ability to reduce microvascular obstruction (MVO) and infarct size (IS) in a pig model of ischemia/reperfusion. Methods: Acute myocardial infarction (AMI) was induced in 23 mini-pigs by balloon occlusion of the mid-LAD for 1.5h. Thirty minutes after reperfusion, pigs received, by prior random assignment, IC injection of CDC-derived exosomes (1.5mg [n=3] or 15mg [n=5] of exosome protein), vehicle [n=6], or transepicardial intramyocardial injection (IM) of exosomes (15mg [n=4] or 7.5mg [n=5]) via median sternotomy. Pigs were sacrificed 48 hr post-MI to measure area at risk (AAR), IS and MVO utilizing gentian violet, TTC (2,3,5-triphenyl tetrazolium chloride) and thioflavin staining respectively. Left ventricular ejection fraction (LVEF) was measured by contrast ventriculography before injection and at endpoint. Results: AAR was identical in all groups (averaging 22±4% of LV, P=0.65 among groups). Consistently, LVEF was similar in all groups before treatment. IC delivery of high-dose exosomes (15mg) decreased MVO (43±6% vs. 56±7%, P=0.02) whereas IC low-dose (1.5mg) did not (54±6%, P=0.66). However, IC exosomes failed to decrease IS regardless of dose. In contrast, both IM doses decreased MVO (43±6% for 15mg and 25±14% for 7.5mg, P=0.04 and P&lt;0.0001 respectively) and IS (67±6% for 15mg, 57±15% for 7.5mg vs. 80±6 for placebo, P=0.04 and P=0.003 respectively). At both IM doses, LVEF at endpoint was higher in exosome-injected pigs compared to vehicle (P=0.03). Conclusion: Intracoronary injection of CDC-secreted exosomes decreases MVO at high doses, but fails to reduce IS. In contrast, both low- and high-dose exosomes reduce IS and MVO after intramyocardial delivery, mimicking the cardioprotection seen with CDCs themselves (cellular postconditioning). These results indicate that IM delivery may be more suitable for exosome therapy of myocardial disease.
Pravastatin and glucose intolerance: Evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study
Authors: A Gaw, J Norrie, N Sattar, Rdg Neely, SM Cobbe, Jane B Ford, C Isles, AR Lorimer, PW Macfarlane, JH McKillop, CJ Packard, J Shepherd, DJ Freeman
Journal: Journal of the American College of Cardiology (2000)
Maintain funding to cover GPs’ indemnity costs, says BMA
Authors: Abi Rimmer
Journal: BMJ (2018)

NHS England must continue to provide the additional funding to GPs for indemnity to reduce the risk of unfilled shifts in out-of-hours care, the BMA has warned.

The association’s general practitioners committee has called for “a sustainable, long term indemnity package for general practice that covers all GPs providing out-of-hours sessions.”1

It said that NHS England should extend the winter indemnity scheme, which made £10m (€11.4m; $14.1m) available to GPs working out-of-hours shifts over the winter to …
Discovery of physiological and cancer-related regulators of 3′ UTR processing with KAPAC
Authors: Andreas J. Gruber, Ralf Schmidt, Souvik Ghosh, Georges Martin, Andreas R. Gruber, Erik van Nimwegen, Mihaela Zavolan
Journal: Genome biology (2018)

3′ Untranslated regions (3' UTRs) length is regulated in relation to cellular state. To uncover key regulators of poly(A) site use in specific conditions, we have developed PAQR, a method for quantifying poly(A) site use from RNA sequencing data and KAPAC, an approach that infers activities of oligomeric sequence motifs on poly(A) site choice. Application of PAQR and KAPAC to RNA sequencing data from normal and tumor tissue samples uncovers motifs that can explain changes in cleavage and polyadenylation in specific cancers. In particular, our analysis points to polypyrimidine tract binding protein 1 as a regulator of poly(A) site choice in glioblastoma.
PREDICTIVE FACTORS FOR TECHNICALLY DIFFICULT ENDOSCOPIC SUBMUCOSAL DISSECTION (ESD). IMPLICATIONS FOR CASE SELECTION: A SPANISH PROSPECTIVE MULTICENTER COHORT STUDY
Authors: JC Marín-Gabriel, F Ramos-Zabala, F Múgica-Aguinaga, A Herreros de Tajada-Echanojauregui, E Albéniz Arbizu, J de la Peña-García, Ó Nogales-Rincón, A Sánchez-Yagüe, G Fernández-Esparrach, C Dolz-Abadía, A Álvarez-Delgado, H Cortés-Pérez, C Guarner-Argente, AJ del Pozo-García, J Díaz-Tasende
Journal: Endoscopy (2018)

To identify the potential risk factors that are associated with a higher technical difficulty during ESD in a Western European setting.
THE MACRODILATATION OF THE SPHINCTER OF ODDI OR SPHINCTEROPLASTY IN THE TREATMENT OF LARGE STONES OF THE MAIN BILE DUCT
Authors: S Jamal, H Seddik, S Berrag, K Loubaris, F Bouhamou, S Morabit, A Aomari, H Boutallaka, R Berraida, I El Koti, A Benkirane
Journal: Endoscopy (2018)

Sphincteroplasty consists of a large dilatation of the papilla which completes an endoscopic sphincterotomy in cases of groß choledochal calculus. The aim to evaluate results and complications of sphincteroplasty and associated factors.
Valeur diagnostique de la ponction sous échoendoscopie des tumeurs pancréatiques
Authors: G Lamblin, C Ménard, M Gasmi, V Vitton, JC Grimaud, M Barthet
Journal: Endoscopy (2009)

Introduction: La ponction sous échoendoscopie de masses pancréatiques solides est souvent limitée par sa valeur prédictive négative (VPN) qui varie dans la littérature de 25 à 75%. Le but de ce travail est d'évaluer l'amélioration des performances diagnostiques apportées par la cytologie monocouche et la répétition des ponctions.
Parkinson disease-associated mutations in LRRK2 cause centrosomal defects via Rab8a phosphorylation
Authors: Jesús Madero-Pérez, Elena Fdez, Belén Fernández, Antonio J. Lara Ordóñez, Marian Blanca Ramírez, Patricia Gómez-Suaga, Dieter Waschbüsch, Evy Lobbestael, Veerle Baekelandt, Angus C. Nairn, Javier Ruiz-Martínez, Ana Aiastui, Adolfo López de Munain, Pawel Lis, Thomas Comptdaer, Jean-Marc Taymans, Marie-Christine Chartier-Harlin, Alexandria Beilina, Adriano Gonnelli, Mark R. Cookson, Elisa Greggio, Sabine Hilfiker
Journal: Molecular Neurodegeneration (2018)

Mutations in LRRK2 are a common genetic cause of Parkinson's disease (PD). LRRK2 interacts with and phosphorylates a subset of Rab proteins including Rab8a, a protein which has been implicated in various centrosome-related events. However, the cellular consequences of such phosphorylation remain elusive.Human neuroblastoma SH-SY5Y cells stably expressing wildtype or pathogenic LRRK2 were used to test for polarity defects in the context of centrosomal positioning. Centrosomal cohesion deficits were analyzed from transiently transfected HEK293T cells, as well as from two distinct peripheral cell types derived from LRRK2-PD patients. Kinase assays, coimmunoprecipitation and GTP binding/retention assays were used to address Rab8a phosphorylation by LRRK2 and its effects in vitro. Transient transfections and siRNA experiments were performed to probe for the implication of Rab8a and its phosphorylated form in the centrosomal deficits caused by pathogenic LRRK2.Here, we show that pathogenic LRRK2 causes deficits in centrosomal positioning with effects on neurite outgrowth, cell polarization and directed migration. Pathogenic LRRK2 also causes deficits in centrosome cohesion which can be detected in peripheral cells derived from LRRK2-PD patients as compared to healthy controls, and which are reversed upon LRRK2 kinase inhibition. The centrosomal cohesion and polarity deficits can be mimicked when co-expressing wildtype LRRK2 with wildtype but not phospho-deficient Rab8a. The centrosomal defects induced by pathogenic LRRK2 are associated with a kinase activity-dependent increase in the centrosomal localization of phosphorylated Rab8a, and are prominently reduced upon RNAi of Rab8a.Our findings reveal a new function of LRRK2 mediated by Rab8a phosphorylation and related to various centrosomal defects.
Loss of PDK4 switches the hepatic NF‐κB/TNF pathway from pro‐survival to pro‐apoptosis
Authors: Jianguo Wu, Yulan Zhao, Young‐Ki Park, Ji‐Young Lee, Ling Gao, Jiajun Zhao, Li Wang
Journal: Hepatology (2018)

It has been established that nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) members promote survival by upregulating antiapoptotic genes and that genetic and pharmacological inhibition of NF‐κB is required for tumor necrosis factor (TNF)‐induced hepatocyte apoptosis. In this study, we demonstrate that this pro‐survival pathway is switched to pro‐apoptosis under pyruvate dehydrogenase kinase 4 (PDK4)‐deficient conditions. PDK4‐deficiency triggered hepatic apoptosis concomitantly with increased numbers of aberrant mitochondria, reactive oxygen species (ROS) production, sustained c‐Jun N‐terminal Kinase (JNK) activation, and reduction of glutathione (GSH). Interestingly, PDK4 retained p65 in cytoplasm via a direct protein‐protein interaction. Disruption of PDK4‐p65 association promoted p65 nuclear translocation. This, in turn, facilitated p65 binding to the TNF promoter to activate TNF‐TNFR1 apoptotic pathway. Pdk4 −/− livers were sensitized to Jo2 and D‐(+)‐Galactosamine /Lipopolysaccharide (GalN/LPS)‐mediated apoptotic injury which was prevented by the inhibition of p65 or TNFR1. The pro‐survival activity of TNF was shifted, which was switched to a pro‐apoptotic activity in Pdk4 −/− hepatocytes as a result of impaired activation of pro‐survival NF‐κB targets. Conclusion : PDK4 is indispensable to dictate the fate of TNF/NF‐κB‐mediated hepatocyte apoptosis. (H epatology 2018).
A New IDEA in Adjuvant Chemotherapy for Colon Cancer
Authors: Richard L. Schilsky
Journal: New England Journal of Medicine (2018)

Prospective, randomized trials have clearly established that the relative risk of tumor recurrence or death from colon cancer is approximately 30% lower among patients who receive adjuvant fluorouracil-based chemotherapy administered for 6 months than among those who undergo surgery alone, with the benefits confined mainly to patients with stage III (lymph-node–positive) disease.1-3 The absolute improvement in the 5-year rate of disease-free survival with chemotherapy, as compared with no adjuvant therapy, is approximately 7 to 10 percentage points. The addition of the drug oxaliplatin to fluorouracil plus leucovorin in a regimen commonly known as FOLFOX results in a further improvement in . . .
Sport and exercise medicine: served three ways
Authors: Eleanor Tillett
Journal: British Journal of Sports Medicine (2018)

Welcome to the 2018 British Association of Sport & Exercise Medicine (BASEM) issue of the British Journal of Sports Medicine  (BJSM). It is always a pleasure to bring this issue together; both due to the plethora of high quality articles to choose from and the opportunity to report the positive changes that continue within BASEM.

At our AGM in 2017 our membership voted that we should go back to our roots and once again become a truly multi-disciplinary organisation. BASEM now gives all full members, whatever the type of Sports and Exercise Medicine (SEM) practitioner, equal access and rights to all that BASEM has to offer. This is a very positive stride towards collaboration and development across all SEM communities and we are looking forward to this next exciting phase. It seems collaboration is in the air internationally too with David Humphries and an international author team  (see page 490) reporting on the first stage of an International Syllabus in Sport and Exercise Medicine.

BASEM …
Hepatocyte microvesicle levels improve prediction of mortality in patients with cirrhosis
Authors: Audrey Payancé, Gilberto Silva‐Junior, Julien Bissonnette, Marion Tanguy, Blandine Pasquet, Cristina Levi, Olivier Roux, Ouardia Nekachtali, Anna Baiges, Virginia Hernández‐Gea, Cédric Laouénan, Didier Lebrec, Miguel Albuquerque, Valérie Paradis, Richard Moreau, Dominique Valla, François Durand, Chantal M. Boulanger, Juan‐Carlos Garcia‐Pagan, Pierre‐Emmanuel Rautou
Journal: Hepatology (2018)

Microvesicles (MVs) are extracellular vesicles released by cells following activation or apoptosis. Some MV subpopulations augment with cirrhosis severity and contribute to portal hypertension. This study aimed at determining if plasma MV levels can estimate the presence of hepatic venous pressure gradient (HVPG) ≥10 mm Hg and predict mortality in patients with advanced chronic liver disease. All patients with severe fibrosis or cirrhosis undergoing liver catheterization between 2013 and 2015 at two centers were prospectively included. We measured circulating levels of annexin V + , platelet, leukocyte, endothelial, and hepatocyte MVs. The test cohort included 139 patients. Hepatocyte MV levels were 4.0‐fold and 2.2‐fold higher in patients with Child‐Pugh C than in those with Child‐Pugh A or B liver disease, respectively. Levels of other MV subpopulations were not influenced by liver disease severity. Hepatocyte MV levels correlated with HVPG but could not identify patients with HVPG ≥10 mm Hg. Hepatocyte MV level &gt;65 U/L predicted 6‐month mortality independently of Child‐Pugh score and of Model for End‐Stage Liver Disease (MELD). Patients with hepatocyte MV levels &gt;65 U/L and MELD &gt;15 had a higher 6‐month mortality than other patients (23% versus 3%; P = 0.001). These findings were confirmed in a validation cohort including 103 patients. Conclusion : Circulating MV levels cannot identify patients with HVPG ≥10 mm Hg; by contrast, hepatocyte MV levels strongly improve prediction of 6‐month mortality in patients with advanced chronic liver disease; therapies associated with decreased levels of circulating hepatocyte MV might be attractive strategies in patients with severe cirrhosis. (H epatology 2018).
David Oliver: Moral distress in hospital doctors
Authors: David Oliver
Journal: BMJ (2018)

The concept of “moral distress” in nurses was described by Andrew Jameton in 1984.1 He has defined it as occurring when one knows the right thing to do for a patient but institutional constraints make it impossible to pursue that course of action.23

The medical literature has plenty on physician burnout, poor working conditions, and their effects on doctors’ wellbeing.45 We haven’t tended to discuss moral distress as much as nurses do, although we clearly experience it too.

The Point of Care Foundation6 has worked with over 180 organisations throughout the NHS, specifically supporting clinical teams. The foundation’s director, Jocelyn Cornwell, told me, “I have learned that …
MANAGEMENT OF COMPLICATED BILIARY STONES USING SPYGLASS DS PER-ORAL CHOLANGIOSCOPY-GUIDED LASER LITHOTRIPSY
Authors: P Soriani, V Giorgio Mirante, C Barbera, T Gabbani, L Miglioli, M Manno
Journal: Endoscopy (2018)

Here we report a video-case of an 88-year-old woman referred to our unit because of cholangitis in cholecysto-choledochal lithiasis, deemed unfit for surgery (cholecystectomy) due to severe co-morbidities. Endoscopic retrograde cholangiography (ERC) (TJF-160VR; Olympus Co., Tokyo, Japan), performed under deep sedation with anesthesiological assistance, showed severe dilation of biliary tree with a voluminous stone (about 35 mm) impacted in the common hepatic duct. The endoscopic approach was challenging because of the site, the size of the stone and the overall biliary tree dilation. In fact, because of similar dilation of cystic and common bile duct, it was quite difficult to reach the common hepatic duct.
Telomere length and reactive oxygen species levels are positively associated with a high risk of mortality and recurrence in hepatocellular carcinoma
Authors: Eunkyong Ko, Hyun‐Wook Seo, Guhung Jung
Journal: Hepatology (2017)

Telomeres protect chromosomal ends from deterioration and have been shown to be susceptible to shortening by reactive oxygen species (ROS)-induced damage. ROS levels increase during the progression from early to advanced hepatocellular carcinoma (HCC). An independent study found that the telomeres in most HCC tissues lengthened during carcinogenic advancement. Activated telomerase has been hypothesized to elongate telomeres during the progression of malignant HCC, but it remains unclear which signaling pathway is necessary for telomerase activation in HCC. Here, we showed using cell lines derived from human HCC that H2 O2 , which is a major component of ROS in living organisms, elongates telomeres by increasing telomerase activity through protein kinase B (AKT) activation. The AKT inhibitor, perifosine, decreased telomere length, cellular viability, and H2 O2 -mediated migration and invasion capacity in HCC cells while also inhibiting AKT activation, telomere maintenance, and tumor growth in nude mice. Advanced HCC tissues showed a positive correlation among ROS levels, phosphorylated AKT (pAKT) levels, and telomere length. Furthermore, patients with HCC tumors that have high ROS levels and long telomeres displayed poorer survival rates. These data demonstrate the significant utilities of ROS levels, pAKT levels, and telomere length for predicting a poor prognosis in patients with HCC. Taken together, AKT activation could be essential for telomere maintenance in advanced HCC tumors as well as being an important contributor to malignant HCC progression.We showed that H2 O2 contributes to telomere elongation through AKT activation in advanced HCC, suggesting that an AKT inhibitor such as perifosine may be useful for treating patients with malignant HCC. (Hepatology 2018;67:1378-1391).
EUS-guided radiofrequency ablation of porcine pancreas
Authors: Kim Hong Jun
Journal: Endoscopy (2011)

Percutaneous radiofrequency ablation (RFA) has become a widespread treatment option for primary or metastatic tumor of liver. However, there is limitation to approach pancreas by percutaneous method. EUS has emerged as an essential diagnostic and therapeutic tool in pancreatic disease. There are several important things to be considered to apply RFA through EUS. The length of delivery system, thickness and length of electrode may affect the efficacy of ablation. The purposes of this study are to evaluate in vivo feasibility, efficacy and safety of EUS-guided RFA on porcine pancreas.