tbuckley/cabot-search huggingface dataset:
Efficacy and safety of open-label etanercept on extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis and psoriatic arthritis: part 1 (week 12) of the CLIPPER study
Authors: Gerd Horneff, Ruben Burgos-Vargas, Tamas Constantin, Ivan Foeldvari, Jelena Vojinovic, Vyacheslav G Chasnyk, Joke Dehoorne, Violeta Panaviene, Gordana Susic, Valda Stanevica, Katarzyna Kobusinska, Zbigniew Zuber, Richard Mouy, Ingrida Rumba-Rozenfelde, Luciana Breda, Pavla Dolezalova, Chantal Job-Deslandre, Nico Wulffraat, Daniel Alvarez, Chuanbo Zang, Joseph Wajdula, Deborah Woodworth, Bonnie Vlahos, Alberto Martini, Nicolino Ruperto
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Abstract</h3> Antifungal resistance in pathogenic fungi is a growing global health concern. Non-pathogenic laboratory strains of <i>Saccharomyces cerevisiae</i> are a useful model for studying mechanisms of antifungal resistance that are relevant to understanding the same processes in pathogenic fungi. We developed a series of lab modules in which high school students used experimental evolution to study antifungal resistance by isolating azole-resistant <i>S. cerevisiae</i> and examining the genetic basis of resistance. All 99 sequenced clones from these experiments possessed mutations previously shown to impact azole resistance, demonstrating the efficacy of our protocols. We additionally found recurrent mutations in an mRNA degradation pathway and an uncharacterized mitochondrial protein (Csf1) that have possible mechanistic connections to azole resistance. The scale of replication in this high school-led initiative allowed us to identify epistatic interactions, as evidenced by pairs of mutations that occur in the same clone more frequently than expected by chance (positive epistasis) or less frequently (negative epistasis). We validated one of these pairs, a negative epistatic interaction between gain-of-function mutations in the multidrug resistance transcription factors Pdr1 and Pdr3. This high school-university collaboration can serve as a model for involving members of the broader public in the scientific process to make meaningful discoveries in biomedical research.
Trimming of TAP-translocated peptides in the endoplasmic reticulum and in the cytosol during recycling.
Authors: J Roelse, M Grommé, F Momburg, G Hämmerling, J Neefjes
Journal: The Journal of Experimental Medicine (1994)

Cytosolic peptides are translocated to the endoplasmic reticulum (ER) lumen by the transporters associated with antigen processing (TAP), where major histocompatibility complex (MHC) class I molecules associate with peptides of about 8-10 amino acids. TAP translocates peptides of 9-13 amino acids with the highest relative affinity but also longer and shorter peptides. The fate of the peptides that fail to associate with class I molecules because of incorrect sequence or length, is unknown. Here we show that the bulk of the translocated peptides are rapidly released from the ER by a mechanism that requires adenosine triphosphate (ATP) and that could not be inhibited by GTP gamma S. TAP does not appear to be involved in this process. Whereas free peptides are slowly trimmed in the ER lumen, they are rapidly degraded in the cytosol. A fraction of the peptides released from the ER escapes complete degradation in the cytosol and recycles back to the ER in a TAP-dependent fashion. These results suggest that peptides that are too long for binding to class I molecules in the ER can be trimmed further in the ER lumen or, alternatively, can be transported back to the cytosol where a fraction of the peptides is trimmed to a size suitable for association to MHC class I molecules and recycles back to the ER.
Synthetic Lethality by Lentiviral Short Hairpin RNA Silencing of Thymidylate Kinase and Doxorubicin in Colon Cancer Cells Regardless of the <i>p53</i> Status
Authors: Chun-Mei Hu, Zee-Fen Chang
Journal: Cancer Research (2008)

Intracellular supply of dTTP is a highly regulated process and has been a key target for chemotherapeutic drug development. Thymidylate kinase (TMPK) is the key enzyme for dTTP formation in both de novo and salvage pathways. In this study, we used lentiviral-based small hairpin RNA to silence TMPK expression in p53(+/+) and p53(-/-) HCT-116 colon cancer cells. This approach was sufficient to decrease the dTTP pool gradually without affecting p53 expression and generating cytotoxicity. TMPK knockdown significantly increased doxorubicin sensitivity dramatically in p53-proficient, p53-null HCT-116, and LoVo colon cancer cells. The decrease in the dTTP pool using this approach augmented the DNA damage response and enhanced apoptotic induction after exposure to low-dose doxorubicin, leading to cell death. In contrast, silencing of thymidylate synthase which blocks the de novo pathway was incapable of sensitizing p53-null HCT-116 cells to doxorubicin-induced apoptosis because of the compensation by the salvage pathway. Our results suggest the lentiviral delivery of small hairpin RNA targeting TMPK in combination with a low dose of doxorubicin as a new approach to kill colon cancer cells regardless of p53 status.
Meta-Analysis: Angiotensin-Receptor Blockers in Chronic Heart Failure and High-Risk Acute Myocardial Infarction
Authors: Victor C. Lee, David C. Rhew, Michelle Dylan, Enkhe Badamgarav, Glenn D. Braunstein, Scott R. Weingarten
Journal: Annals of Internal Medicine (2004)

Background: The role of angiotensin-receptor blockers (ARBs) in treating patients with chronic heart failure and high-risk acute myocardial infarction (MI) has been controversial, and recent clinical trials provide more information on this topic. Purpose: To quantify the effect of ARBs when compared with placebo (with and without background angiotensin-converting enzyme [ACE] inhibitors) and ACE inhibitors on all-cause mortality and heart failure hospitalizations in patients with chronic heart failure and high-risk acute MI. Data Sources: Data from original research published through 13 November 2003. Study Selection: Predefined criteria were used to identify 24 trials. Data Extraction: 2 reviewers independently collected information on study characteristics and data on all-cause mortality and heart failure hospitalization. Data Synthesis: 24 trials involving 38 080 patients were included. Analysis of chronic heart failure trials revealed that 1) ARBs were associated with reduced all-cause mortality (odds ratio [OR], 0.83 [95% CI, 0.69 to 1.00]) and heart failure hospitalizations (OR, 0.64 [CI, 0.53 to 0.78]) as compared with placebo; 2) for ARBs versus ACE inhibitors, all-cause mortality (OR, 1.06 [CI, 0.90 to 1.26]) and heart failure hospitalization (OR, 0.95 [CI, 0.80 to 1.13]) did not differ; 3) and for combinations of ARBs plus ACE inhibitors versus ACE inhibitors alone, all-cause mortality was not reduced (OR, 0.97 [CI, 0.87 to 1.08]) but heart failure hospitalizations were reduced (OR, 0.77 [CI, 0.69 to 0.87]). For patients with high-risk acute MI, 2 randomized trials compared ARBs with ACE inhibitors but did not reveal differences in all-cause mortality or heart failure hospitalization. Limitations: Comparative economic data between ARBs and ACE inhibitors are lacking. Conclusions: Because ACE inhibitors and ARBs do not differ in efficacy for reducing all-cause mortality and heart failure hospitalizations in patients with chronic heart failure and in patients with high-risk acute MI, ARBs should be regarded as suitable alternatives to ACE inhibitors.
Docetaxel and Cisplatin With Granulocyte Colony-Stimulating Factor (G-CSF) Versus MVAC With G-CSF in Advanced Urothelial Carcinoma: A Multicenter, Randomized, Phase III Study From the Hellenic Cooperative Oncology Group
Authors: A. Bamias, G. Aravantinos, C. Deliveliotis, D. Bafaloukos, C. Kalofonos, N. Xiros, A. Zervas, D. Mitropoulos, E. Samantas, D. Pectasides, P. Papakostas, D. Gika, C. Kourousis, A. Koutras, C. Papadimitriou, C. Bamias, P. Kosmidis, M.A. Dimopoulos
Journal: Journal of Clinical Oncology (2003)

The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) represents the standard regimen for inoperable or metastatic urothelial cancer, but its toxicity is significant. We previously reported a 52% response rate (RR) using a docetaxel and cisplatin (DC) combination. The toxicity of this regimen compared favorably with that reported for MVAC. We thus designed a randomized phase III trial to compare DC with MVAC.Patients with inoperable or metastatic urothelial carcinoma; adequate bone marrow, renal, liver, and cardiac function; and Eastern Cooperative Oncology Group performance status < or = 2 were randomly assigned to receive MVAC at standard doses or docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) every 3 weeks. All patients received prophylactic granulocyte colony-stimulating factor (G-CSF) support.Two hundred twenty patients were randomly assigned (MVAC, 109 patients; DC, 111 patients). Treatment with MVAC resulted in superior RR (54.2% v 37.4%; P =.017), median time to progression (TTP; 9.4 v 6.1 months; P =.003) and median survival (14.2 v 9.3 months; P =.026). After adjusting for prognostic factors, difference in TTP remained significant (hazard ratio [HR], 1.61; P =.005), whereas survival difference was nonsignificant at the 5% level (HR, 1.31; P =.089). MVAC caused more frequent grade 3 or 4 neutropenia (35.4% v 19.2%; P =.006), thrombocytopenia (5.7% v 0.9%; P =.046), and neutropenic sepsis (11.6% v 3.8%; P =.001). Toxicity of MVAC was considerably lower than that previously reported for MVAC administered without G-CSF.MVAC is more effective than DC in advanced urothelial cancer. G-CSF-supported MVAC is well tolerated and could be used instead of classic MVAC as first-line treatment in advanced urothelial carcinoma.
Neutrophils recruited by chemoattractants in vivo induce microvascular plasma protein leakage through secretion of TNF
Authors: Michaela Finsterbusch, Mathieu-Benoit Voisin, Martina Beyrau, Timothy John Williams, Sussan Nourshargh
Journal: The Journal of Experimental Medicine (2014)

Microvascular plasma protein leakage is an essential component of the inflammatory response and serves an important function in local host defense and tissue repair. Mediators such as histamine and bradykinin act directly on venules to increase the permeability of endothelial cell (EC) junctions. Neutrophil chemoattractants also induce leakage, a response that is dependent on neutrophil adhesion to ECs, but the underlying mechanism has proved elusive. Through application of confocal intravital microscopy to the mouse cremaster muscle, we show that neutrophils responding to chemoattractants release TNF when in close proximity of EC junctions. In vitro, neutrophils adherent to ICAM-1 or ICAM-2 rapidly released TNF in response to LTB4, C5a, and KC. Further, in TNFR−/− mice, neutrophils accumulated normally in response to chemoattractants administered to the cremaster muscle or dorsal skin, but neutrophil-dependent plasma protein leakage was abolished. Similar results were obtained in chimeric mice deficient in leukocyte TNF. A locally injected TNF blocking antibody was also able to inhibit neutrophil-dependent plasma leakage, but had no effect on the response induced by bradykinin. The results suggest that TNF mediates neutrophil-dependent microvascular leakage. This mechanism may contribute to the effects of TNF inhibitors in inflammatory diseases and indicates possible applications in life-threatening acute edema.
La surveillance européenne des infections sexuellement transmissibles : une initiative opportune et adaptée
Authors: Kevin Fenton, Johan Giesecke, Françoise F Hamers
Journal: Eurosurveillance (2001)

Les infections sexuellement transmissibles (IST) dont l'infection a VIH, representent une menace importante pour la sante et le bien-etre des Europeens et necessitent une intervention concertee et soutenue. Au cours des dix dernieres annees, le nombre de cas declares de IST, dont les infections a Neisseria gonorrhoeae resistant aux antibiotiques, a considerablement augmente (1) et des epidemies de syphilis ont ete rapportees recemment dans plusieurs etats membres de l'Union Europeenne (UE) (2,3). Les groupes les plus touches semblent etre les jeunes, les hommes homosexuels et les personnes ayant un acces limite aux soins (y compris aux services de prevention et d'education sanitaire). Les facteurs determinants correspondent a l'augmentation des voyages et des migrations, aux comportements sexuels a haut risque et a une deterioration des reponses de sante publique dans la lutte contre les IST (par exemple, pour la declaration des partenaires). On observe en grande partie les memes tendances demographiques et comportementales dans tous les Etats de l'UE, ainsi qu'un souhait partage de developper et de mettre en œuvre des programmes efficaces de prevention et de lutte contre les IST.
Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism
Authors: Tim Vanuytsel, Sander van Wanrooy, Hanne Vanheel, Christophe Vanormelingen, Sofie Verschueren, Els Houben, Shadea Salim Rasoel, Joran Tόth, Lieselot Holvoet, Ricard Farré, Lukas Van Oudenhove, Guy Boeckxstaens, Kristin Verbeke, Jan Tack
Journal: Gut (2013)

<h3>Objective</h3> Intestinal permeability and psychological stress have been implicated in the pathophysiology of IBD and IBS. Studies in animals suggest that stress increases permeability via corticotropin-releasing hormone (CRH)-mediated mast cell activation. Our aim was to investigate the effect of stress on intestinal permeability in humans and its underlying mechanisms. <h3>Design</h3> Small intestinal permeability was quantified by a 2 h lactulose–mannitol urinary excretion test. In a first study, 23 healthy volunteers were subjected to four different conditions: <i>control</i>; indomethacin; public speech and anticipation of electroshocks. In a second study, five test conditions were investigated in 13 volunteers: <i>control</i>; after pretreatment with disodium cromoglycate (DSCG); administration of CRH; DSCG+CRH and DSCG+public speech. <h3>Results</h3> Indomethacin, as a positive comparator (0.071±0.040 vs 0.030±0.022; p&lt;0.0001), and public speech (0.059±0.040; p&lt;0.01), but not the shock protocol increased intestinal permeability. Similarly, salivary cortisol was only increased after public speech. Subgroup analysis demonstrated that the effect of public speech on permeability was only present in subjects with a significant elevation of cortisol. CRH increased the lactulose–mannitol ratio (0.042±0.021 vs 0.028±0.009; p=0.02), which was inhibited by the mast cell stabiliser DSCG. Finally, intestinal permeability was unaltered by public speech with DSCG pretreatment. <h3>Conclusions</h3> Acute psychological stress increases small intestinal permeability in humans. Peripheral CRH reproduces the effect of stress and DSCG blocks the effect of both stress and CRH, suggesting the involvement of mast cells. These findings provide new insight into the complex interplay between the central nervous system and GI function in man.
Determinants of endothelial function in patients with COPD
Authors: Christian F. Clarenbach, Oliver Senn, Noriane A. Sievi, Giovanni Camen, Arnoldus J.R. van Gestel, Valentina A. Rossi, Milo A. Puhan, Robert Thurnheer, Erich W. Russi, Malcolm Kohler
Journal: European Respiratory Journal (2013)

Chronic obstructive pulmonary disease (COPD) is associated with increased cardiovascular mortality. Endothelial dysfunction may underpin this association. This cross-sectional study aimed to determine the impact of airflow obstruction, systemic inflammation, oxidative stress, sympathetic activation, hypoxaemia and physical activity on endothelial function in COPD. In stable COPD patients, assessments of endothelial function by flow-mediated dilatation (FMD), cardiovascular risk (Pocock score), airflow obstruction (forced expiratory volume in 1 s (FEV1)), systemic inflammation (high-sensitivity C-reactive protein and interleukin-6), oxidative stress (malondialdehyde), sympathetic activation (baroreflex sensitivity), hypoxaemia (arterial oxygen tension), hypercapnia (arterial carbon dioxide tension (PaCO2)), physical activity (steps per day) and exercise capacity (6-min walking distance) were performed. Associations between FMD and potential determinants were assessed in univariate and multivariate analyses. 106 patients (Global Initiative for Chronic Obstructive Lung Disease stage I/II 35%, stage III 25% and stage IV 40%) were included. In multivariate analysis FEV1 was positively associated with FMD, independent of other significant FMD determinants from univariate analysis (sex, smoking, combined inhaled long-acting β-adrenergic and steroid medication, heart rate, baroreflex sensitivity and PaCO2) and adjusted for potential confounders (cardiovascular risk and age). In addition, the FMD and FEV1 association was modified by physical activity. The findings of this study demonstrate that the severity of airflow obstruction is a significant determinant of endothelial function in patients with COPD. A high level of physical activity seems to have a favourable effect on this association.
Correlation of increased PARP14 and CCL26 expression in biopsies from children with eosinophilic esophagitis
Authors: Purna Krishnamurthy, Joseph D. Sherrill, Kalyan Parashette, Shreevrat Goenka, Marc E. Rothenberg, Sandeep Gupta, Mark H. Kaplan
Journal: Journal of Allergy and Clinical Immunology (2013)
Breast cancer subtypes and outcome after local and regional relapse
Authors: E. Montagna, V. Bagnardi, N. Rotmensz, G. Viale, G. Renne, G. Cancello, A. Balduzzi, E. Scarano, P. Veronesi, A. Luini, S. Zurrida, S. Monti, M.G. Mastropasqua, L. Bottiglieri, A. Goldhirsch, M. Colleoni
Journal: Annals of Oncology (2011)
Chimeric antibodies to proteinase 3 of IgG1 and IgG3 subclasses induce different magnitudes of functional responses in neutrophils
Authors: R. Colman, A. Hussain, M. Goodall, S. P Young, T. Pankhurst, X. Lu, R. Jefferis, C. O S Savage, J. M Williams
Journal: Annals of the Rheumatic Diseases (2007)

Antineutrophil cytoplasmic antibodies (ANCA) are associated with small-vessel vasculitis and have been implicated in its pathogenesis. The subclass distribution of ANCA IgG deviates from normal patterns, and it has been suggested that the IgG3 subclass may have pathogenic potential over the IgG1 subclass and may be more likely to be associated with active disease and renal involvement.To deal with potential pathogenicity, chimeric antibodies were constructed of IgG1 and three subclasses with human IgG1 or three constant regions and a murine-derived variable region that binds an epitope within the ANCA antigen proteinase 3 (PR3) that is recognised by human autoantibodies.The antibodies were characterised for binding to PR3, including affinity and avidity, before being used as tools to explore their ability to activate human neutrophils for superoxide release, cytokine release, degranulation and ability to induce neutrophil adhesion under flow.Both subclass antibodies elicited similar neutrophil responses for superoxide release, degranulation and interleukin (IL) 8 production, although quantitative responses showed that the IgG1 subclass favoured degranulation and the IgG3 subclass favoured IL8 production. Both antibodies were able to convert neutrophils from selectin-dependent rolling adhesion to integrin-dependent stationary adhesion in a flow assay.These findings indicate that humanised antibodies directed against a single epitope of PR3 can recapitulate the effects of polyclonal human ANCA, which recognises multiple PR3 epitopes. Further, PR3-ANCA of both IgG1 and IgG3 subclasses can activate neutrophils, although the more potent IL8 response by IgG3 PR3-ANCA may encourage further neutrophil recruitment and amplify injury.
Combination Therapy with a Second-Generation Androgen Receptor Antagonist and a Metastasis Vaccine Improves Survival in a Spontaneous Prostate Cancer Model
Authors: Andressa Ardiani, Benedetto Farsaci, Connie J. Rogers, Andy Protter, Zhimin Guo, Thomas H. King, David Apelian, James W. Hodge
Journal: Clinical Cancer Research (2013)

Enzalutamide, a second-generation androgen antagonist, was approved by the U.S. Food and Drug Administration (FDA) for castration-resistant prostate cancer (CRPC) treatment. Immunotherapy has been shown to be a promising strategy for prostate cancer. This study was performed to provide data to support the combination of enzalutamide and immunotherapy for CRPC treatment.
Impaired Renal Function Further Increases Odds of 6-Year Coronary Artery Calcification Progression in Adults With Type 1 Diabetes
Authors: David M. Maahs, Diana Jalal, Michel Chonchol, Richard J. Johnson, Marian Rewers, Janet K. Snell-Bergeon
Journal: Diabetes Care (2013)

To determine whether baseline estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) independently predict coronary artery calcification (CAC) progression, and to determine how eGFR changes over 6 years in adults with type 1 diabetes compared with nondiabetic adults.The Coronary Artery Calcification in Type 1 Diabetes study participants (n = 1,066) with complete data for eGFR assessment at baseline and 6 years were included. Three Chronic Kidney Disease Epidemiology Collaboration equations (serum creatinine, cystatin C, and both) were used to estimate eGFR. The association of baseline ACR and eGFR with CAC progression was analyzed using multiple logistic regression.Increasing categorical baseline ACR (<10, 10-30, and >30 µg/mg) predicted CAC progression in participants with type 1 diabetes (odds ratio [OR], 2.15; 95% CI, 1.50-3.09; 7.19 [3.90-13.26]; and 18.09 [8.48-38.62]), respectively, compared with nondiabetic subjects. Baseline eGFR <60 mL/min/1.73 m(2) also predicted CAC progression (OR, 5-7, compared with nondiabetic participants). ORs for CAC progression were higher in women than in men when using the cystatin C-based Chronic Kidney Disease Epidemiology Collaboration equations. Participants with type 1 diabetes had greater eGFR decreases over 6 years than nondiabetic participants using cystatin C-based equations.Although increasing ACR or decreasing eGFR predicts CAC progression, coronary atherosclerosis progresses faster in people with type 1 diabetes even in the absence of diabetic kidney disease. These findings emphasize the interaction between kidney disease and cardiovascular disease in type 1 diabetes and highlight the public health importance of lowering cardiorenal risk in people with type 1 diabetes.
Evaluation of the Cutaneous Lupus Activity and Severity Score in the assessment of lupus erythematosus skin disease
Authors: K. Abdel-Aziz, M. Goodfield
Journal: British Journal of Dermatology (2007)

Journal Article Evaluation of the Cutaneous Lupus Activity and Severity Score in the assessment of lupus erythematosus skin disease Get access K. Abdel‐Aziz, K. Abdel‐Aziz Department of Dermatology, Leeds General Infirmary, Leeds LS1 3EX, U.K. Search for other works by this author on: Oxford Academic Google Scholar M. Goodfield M. Goodfield Department of Dermatology, Leeds General Infirmary, Leeds LS1 3EX, U.K. E‐mail: Mark.Goodfield@leedsth.nhs.uk Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 158, Issue 1, 1 January 2008, Pages 181–182, https://doi.org/10.1111/j.1365-2133.2007.08260.x Published: 01 January 2008