tbuckley/cabot-search huggingface dataset:
An audit of adherence to anti-tnf therapy in patients with inflammatory bowel disease
Authors: J. Duncan, M. Sastrillo, J. Baker, L. Younge, S. Anderson, J. Lindsay, J. Sanderson, P. Irving
Journal: Gut (2011)

<h3>Introduction</h3> Poor adherence is associated with worse outcomes and healthcare costs. Anti-TNF therapy is increasingly used in IBD management. There are 2 anti-TNF agents available to treat IBD in the UK: Adalimumab (ADA), self-administered at home and Infliximab (IFX), administered by a healthcare professional in hospital. Accordingly potential barriers to adherence vary between the two drugs though little is known about this. <h3>Aim</h3> to assess adherence to ADA and IFX in patients at two IBD tertiary referral centres; adherence to other IBD medication; and reasons for poor adherence. <h3>Methods</h3> We reviewed adherence to anti-TNF therapy over the preceding 12 months by recording postponement of, or failure to attend, scheduled IFX infusions along with the frequency of, and reasons for, missed infusions. In patients self-administering ADA we assessed adherence using the Medication Adherence Report Scale (MARS).1 Additionally we recorded reasons for missed or delayed injections. Missed/postponed doses for medical reasons (eg, infections) were not counted as failure to adhere. Adherence to (MARS), and reasons for non-adherence were also recorded for 5-ASA and immunomodulators. <h3>Results</h3> 106 patients were included (82 IFX, 24 ADA), 55 males. The median (range) age was 32 years (17–59). Median time on treatment was 17 months (1–110). There was no difference in the proportion of patients who failed to adhere to anti-TNF therapy completely (ADA 5/24 patients (21%): IFX 19/82 (23%), p=0.79). Over the preceding year, 5 IFX patients missed infusions on 8 occasions. 14 patients postponed a total of 32 infusions. Of those who failed to adhere to their scheduled infusions: 16 cited inconvenience and 1 forgot. The median MARS score in the ADA group was 25 (range 22–25). 3 people occasionally missed doses; 2 forgot and 1 cited inconvenience. 4 people delayed doses, most of whom forgot, although one cited the route of administration. 49 patients were on thiopurines, 8 methotrexate. 35% incompletely adhered to medication. The median MARS score was 25 (range 18–25). The most common reason for non-adherence was forgetting to take medication.8/18 patients on 5-ASA admitted to poor adherence. The median MARS score was 25 (range 15–25). Poor adherence was most commonly related to forgetting to take medication. <h3>Conclusion</h3> Adherence to anti-TNF therapy is generally good. While the challenges to adherence are different for the two drugs, overall adherence is similar for IFX and ADA.
Massive monoclonal expansion of CD4 T-cells specific for a<i>Mycobacterium tuberculosis</i>ESAT-6 peptide
Authors: Tobias Hodapp, Urban Sester, Ulrich Mack, Mahavir Singh, Thomas Meier, Elisabeth Wiech, Paul Fisch, Stephan Ehl, Martina Sester
Journal: European Respiratory Journal (2012)

T-cell responses towards tuberculin (purified protein derivative; PPD) or the Mycobacterium tuberculosis-specific antigens early secretory antigenic target (ESAT)-6 and culture filtrate protein-10 are indicative of prior contact with mycobacterial antigens. In this study, we investigated the exceptional case of a 75-yr-old patient who devoted more than one-third of his CD4 T-cells against PPD and ESAT-6. Antigen-specific T-cells were characterised using flow cytometric intracellular cytokine staining, ELISPOT assay, proliferation assays, and T-cell receptor spectratyping. T-cell frequencies were far above those found in age-matched controls (median 0.33%, range 0.05-6.32%) and remained at high levels for >2 yrs. The patient initially presented with haemoptysis, but active tuberculosis was ruled out by repeated analysis of sputum and bronchoalveolar lavage fluid. Skin testing was negative and haemoptyses did not have a M. tuberculosis-related aetiology. Phenotypical and functional properties of specific T-cells were consistent with a terminally differentiated effector-memory phenotype with capacity to produce interferon-γ, interleukin-2 and tumour necrosis factor-α. Epitope mapping showed that the CD4 T-cells were directed against a single peptide from ESAT-6 (amino acid 5-20) that was presented in context of HLA-DR. T-cell receptor Vβ-spectratyping and sequencing of specific CD4 T-cells revealed a prominent peak fraction of monoclonal origin. In conclusion, similar to monoclonal gammopathies of undetermined significance, this may represent the first T-cell counterpart with known specificity against M. tuberculosis.
Quantification and treatment patterns of real-world patients classified by the GOLD 2011 strategy
Authors: Mark Small, Sarah Broomfield, Victoria Higgins
Journal: European Respiratory Journal (2012)

Objectives 

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 Strategy classifies COPD patients into 4 categories (A: low risk, less symptoms; B: low risk, more symptoms; C: high risk, less symptoms; D: high risk, more symptoms) based on risk (FEV1 ≥ or <50% predicted and/or exacerbation history < or ≥2 per year) and symptoms (COPD Assessment test [CAT] score < or ≥10 or modified Medical Research Council [mMRC] dyspnoea scale < or ≥2). We examined the proportion of patients in each category when evaluated by CAT or mMRC, and corresponding pharmacological treatment (CAT classification).

Methods 

GOLD 2011 criteria were applied to a real-world international COPD population sampled from the Adelphi Respiratory Disease Specific Programme undertaken June to September 2011. Physicians and patients completed matched questionnaires.

Results 

2392 patients completed a questionnaire, of which 1508 with all 4 GOLD classification parameters were analyzed. The proportion of patients in categories A, B, C and D, respectively, when evaluated by CAT was 10, 49, 1 and 40%, and when evaluated by mMRC was 39, 20, 13 and 28%. By CAT evaluation in categories A, B, C, and D, patients were using a long-acting β2-agonist (LABA) alone (8, 6, 0 and 1%), long-acting muscarinic antagonist (LAMA) alone (37, 25, 8 and 5%), inhaled corticosteroid plus LABA (ICS/LABA) alone (22, 18, 8 and 8%), and ICS/LABA plus LAMA only (11, 20, 46, 43%).

Conclusion 

CAT assessment increased the number of patients in the more symptomatic categories (B and D), compared with mMRC. Contrary to the GOLD 2011 recommendations, by CAT assessment, a high proportion of low-risk patients (A and B) were using ICS/LABA.
Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation–based conditioning regimen to prevent disease progression in patients with high disability scores
Authors: Richard K. Burt, Bruce A. Cohen, Eric Russell, Kenneth Spero, Akash Joshi, Yu Oyama, William J. Karpus, Kehuan Luo, Borko Jovanovic, Ann Traynor, Karyn Karlin, Dusan Stefoski, William H. Burns
Journal: Blood (2003)
Antibody-Mediated Blockade of Integrin αvβ6 Inhibits Tumor Progression <i>In vivo</i> by a Transforming Growth Factor-β–Regulated Mechanism
Authors: Louise A. Koopman Van Aarsen, Diane R. Leone, Steffan Ho, Brian M. Dolinski, Patricia E. McCoon, Doreen J. LePage, Rebecca Kelly, Glenna Heaney, Paul Rayhorn, Carl Reid, Kenneth J. Simon, Gerald S. Horan, Nianjun Tao, Humphrey A. Gardner, Marilyn M. Skelly, Allen M. Gown, Gareth J. Thomas, Paul H. Weinreb, Stephen E. Fawell, Shelia M. Violette
Journal: Cancer Research (2008)

The alpha(v)beta(6) integrin is up-regulated on epithelial malignancies and has been implicated in various aspects of cancer progression. Immunohistochemical analysis of alpha(v)beta(6) expression in 10 human tumor types showed increased expression relative to normal tissues. Squamous carcinomas of the cervix, skin, esophagus, and head and neck exhibited the highest frequency of expression, with positive immunostaining in 92% (n = 46), 84% (n = 49), 68% (n = 56), and 64% (n = 100) of cases, respectively. We studied the role of alpha(v)beta(6) in Detroit 562 human pharyngeal carcinoma cells in vitro and in vivo. Prominent alpha(v)beta(6) expression was detected on tumor xenografts at the tumor-stroma interface resembling the expression on human head and neck carcinomas. Nonetheless, coculturing cells in vitro with matrix proteins did not up-regulate alpha(v)beta(6) expression. Detroit 562 cells showed alpha(v)beta(6)-dependent adhesion and activation of transforming growth factor-beta (TGF-beta) that was inhibited >90% with an alpha(v)beta(6) blocking antibody, 6.3G9. Although both recombinant soluble TGF-beta receptor type-II (rsTGF-beta RII-Fc) and 6.3G9 inhibited TGF-beta-mediated Smad2/3 phosphorylation in vitro, there was no effect on proliferation. Conversely, in vivo, 6.3G9 and rsTGF-beta RII-Fc inhibited xenograft tumor growth by 50% (n = 10, P < 0.05) and >90% (n = 10, P < 0.001), respectively, suggesting a role for the microenvironment in this response. However, stromal collagen and smooth muscle actin content in xenograft sections were unchanged with treatments. Although further studies are required to consolidate in vitro and in vivo results and define the mechanisms of tumor inhibition by alpha(v)beta(6) antibodies, our findings support a role for alpha(v)beta(6) in human cancer and underscore the therapeutic potential of function blocking alpha(v)beta(6) antibodies.
Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon
Authors: A Barcelo
Journal: Gut (2000)

<h3>BACKGROUND</h3> Mucins play an important protective role in the colonic mucosa. Luminal factors modulating colonic mucus release have been not fully identified. <h3>AIM</h3> To determine the effect of some dietary compounds on mucus discharge in rat colon. <h3>METHODS</h3> An isolated vascularly perfused rat colon model was used. Mucus secretion was induced by a variety of luminal factors administered as a bolus of 1 ml for 30 minutes in the colonic loop. Mucin release was evaluated using a sandwich enzyme linked immunosorbent assay supported by histological analysis. <h3>RESULTS</h3> The three dietary fibres tested in this study (pectin, gum arabic, and cellulose) did not provoke mucus secretion. Luminal administration of sodium alginate (an algal polysaccharide used as a food additive) or ulvan (a sulphated algal polymer) induced a dose dependent increase in mucin discharge over the concentration range 1–25 mg/l (p&lt;0.05 for 25 mg/l alginate and p&lt;0.05 for 10 and 25 mg/l ulvan). Glucuronic acid and galacturonic acid, which are major constituents of a variety of fibres, produced significant mucin secretion (p&lt;0.05). Hydrogen sulphide and mercaptoacetate, two sulphides produced in the colonic lumen by microbial fermentation of sulphated polysaccharides, did not modify mucin secretion. Among the short chain fatty acids, acetate (5–100 mM) induced a dose dependent release of mucus (p&lt;0.05 for 100 mM acetate). Interestingly, butyrate at a concentration of 5 mM produced colonic mucin secretion (p&lt;0.05), but increasing its concentration to 100 mM provoked a gradual decrease in mucus discharge. Propionate (5–100 mM) did not induce mucin release. Several dietary phenolic compounds (quercetin, epicatechin, resveratrol) did not provoke mucus discharge. <h3>CONCLUSIONS</h3> Two algal polysaccharides (alginate and ulvan), two uronic acids (glucuronic acid and galacturonic acid), and the short chain fatty acids acetate and butyrate induce mucin secretion in rat colon. Taken together, these data suggest that some food constituents and their fermentation products may regulate the secretory function of colonic goblet cells.
Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma
Authors: Pirro G Hysi, Ching-Yu Cheng, Henriët Springelkamp, Stuart Macgregor, Jessica N Cooke Bailey, Robert Wojciechowski, Veronique Vitart, Abhishek Nag, Alex W Hewitt, René Höhn, Cristina Venturini, Alireza Mirshahi, Wishal D Ramdas, Gudmar Thorleifsson, Eranga Vithana, Chiea-Chuen Khor, Arni B Stefansson, Jiemin Liao, Jonathan L Haines, Najaf Amin, Ya Xing Wang, Philipp S Wild, Ayse B Ozel, Jun Z Li, Brian W Fleck, Tanja Zeller, Sandra E Staffieri, Yik-Ying Teo, Gabriel Cuellar-Partida, Xiaoyan Luo, R Rand Allingham, Julia E Richards, Andrea Senft, Lennart C Karssen, Yingfeng Zheng, Céline Bellenguez, Liang Xu, Adriana I Iglesias, James F Wilson, Jae H Kang, Elisabeth M van Leeuwen, Vesteinn Jonsson, Unnur Thorsteinsdottir, Dominiek D G Despriet, Sarah Ennis, Sayoko E Moroi, Nicholas G Martin, Nomdo M Jansonius, Seyhan Yazar, E-Shyong Tai, Philippe Amouyel, James Kirwan, Leonieke M E van Koolwijk, Michael A Hauser, Fridbert Jonasson, Paul Leo, Stephanie J Loomis, Rhys Fogarty, Fernando Rivadeneira, Lisa Kearns, Karl J Lackner, Paulus T V M de Jong, Claire L Simpson, Craig E Pennell, Ben A Oostra, André G Uitterlinden, Seang-Mei Saw, Andrew J Lotery, Joan E Bailey-Wilson, Albert Hofman, Johannes R Vingerling, Cécilia Maubaret, Norbert Pfeiffer, Roger C W Wolfs, Hans G Lemij, Terri L Young, Louis R Pasquale, Cécile Delcourt, Timothy D Spector, Caroline C W Klaver, Kerrin S Small, Kathryn P Burdon, Kari Stefansson, Tien-Yin Wong, Ananth Viswanathan, David A Mackey, Jamie E Craig, Janey L Wiggs, Cornelia M van Duijn, Christopher J Hammond, Tin Aung
Journal: Nature Genetics (2014)
CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma.
Authors: Kam Fai Tse, Michael Jeffers, Vincent A Pollack, Denise A McCabe, Melanie L Shadish, Nikolai V Khramtsov, Craig S Hackett, Suresh G Shenoy, Bing Kuang, Ferenc L Boldog, John R MacDougall, Luca Rastelli, John Herrmann, Michael Gallo, Gadi Gazit-Bornstein, Peter D Senter, Damon L Meyer, Henri S Lichenstein, William J LaRochelle
Journal: Clinical Cancer Research (2006)

Abstract PURPOSE: Advanced melanoma is a highly drug-refractory neoplasm representing a significant unmet medical need. We sought to identify melanoma-associated cell surface molecules and to develop as well as preclinically test immunotherapeutic reagents designed to exploit such targets. EXPERIMENTAL DESIGN AND RESULTS: By transcript profiling, we identified glycoprotein NMB (GPNMB) as a gene that is expressed by most metastatic melanoma samples examined. GPNMB is predicted to be a transmembrane protein, thus making it a potential immunotherapeutic target in the treatment of this disease. A fully human monoclonal antibody, designated CR011, was generated to the extracellular domain of GPNMB and characterized for growth-inhibitory activity against melanoma. The CR011 monoclonal antibody showed surface staining of most melanoma cell lines by flow cytometry and reacted with a majority of metastatic melanoma specimens by immunohistochemistry. CR011 alone did not inhibit the growth of melanoma cells. However, when linked to the cytotoxic agent monomethylauristatin E (MMAE) to generate the CR011-vcMMAE antibody-drug conjugate, this reagent now potently and specifically inhibited the growth of GPNMB-positive melanoma cells in vitro. Ectopic overexpression and small interfering RNA transfection studies showed that GPNMB expression is both necessary and sufficient for sensitivity to low concentrations of CR011-vcMMAE. In a melanoma xenograft model, CR011-vcMMAE induced significant dose-proportional antitumor effects, including complete regressions, at doses as low as 1.25 mg/kg. CONCLUSION: These preclinical results support the continued evaluation of CR011-vcMMAE for the treatment of melanoma.
Evidence for P2-purinoceptors contribution in H2O2-induced contraction of rat aorta in the absence of endothelium
Authors: J Shen
Journal: Cardiovascular Research (2000)

Objective: H2O2 can contract many arteries, however the underlying mechanisms are not fully understood. This study aims to test whether H2O2-induced vasoconstriction could be functionally attributed to the activation of P2-purinoceptors in rat aorta and to explore its possible signaling mechanisms. Methods: Isometric tension recording of H2O2 and ATP-induced contractions of rat aortic rings were compared in the absence or presence of various pharmacological tools to identify their possible common signaling pathways. Results: Both H2O2 and ATP induced transient phasic contractions in a concentration-dependent manner (1–1000 μM). Removal of endothelium potentiated the contractile responses to H2O2 and to ATP. H2O2 (30 μM)-induced phasic contraction could be abolished by catalase (800 U/ml), but not affected by SOD (150 U/ml), DMSO (5 mM) and apyrase (5 U/ml), suggesting no involvement of O2−, hydroxyl free radicals and ATP release. Also, several receptor antagonists including phentolamine, atropine, methysergide and chlorpheniramine (each 3 μM) were without effect on H2O2 (30 μM)-induced phasic contraction, suggesting no involvement of typical neurotransmitter release. However, both H2O2 (30 μM) and ATP (1 mM)-induced phasic contractions not only presented homologous desensitization, but also showed heterogeneous desensitization. Furthermore, the phasic contractions in response to H2O2 (30 μM) or ATP (100 μM) could be inhibited or abolished in a concentration dependent manner by RB-2 and suramin (10–100 μM), two widely used P2-purinoceptor antagonists, with only partial inhibition by Evans blue (300 μM), a moderately selective P2x receptor blocker, or by α-β-methylene-ATP (100 μM), a selective P2x receptor desensitizer. On the other hand, both H2O2 (30 μM) and ATP (100 μM)-induced phasic contractions were also attenuated, to different degree, by inhibitors of several enzymes including PLC, PKC, PLA2 and cyclooxygenase. Lastly, removal of extracellular Ca2+ or pretreatment with procaine (10 mM) and dantrolene (30 μM), two putative intracellular Ca2+ release blockers, or with Ni2+ (100 μM) and tetrandrine (5 μM), two Ca2+ channel blockers, all significantly inhibited H2O2 and ATP-induced contractions. However, nifedipine (1 μM), a voltage-dependent L-type Ca2+ channel blocker, was without effect. Conclusions: Our results demonstrate that H2O2-induced phasic contraction of rat aorta involves, at least in part, the activation of P2-purinoceptors in the aortic smooth muscle cells
Prospective Early Response Imaging Biomarker for Neoadjuvant Breast Cancer Chemotherapy
Authors: Kuei C. Lee, Bradford A. Moffat, Anne F. Schott, Rachel Layman, Steven Ellingworth, Rebecca Juliar, Amjad P. Khan, Mark Helvie, Charles R. Meyer, Thomas L. Chenevert, Alnawaz Rehemtulla, Brian D. Ross
Journal: Clinical Cancer Research (2007)

The American Cancer Society estimates that in 2006, 212,920 women will be diagnosed with breast cancer and that 40,970 women will die from the disease. The development of more efficacious chemotherapies has improved outcomes, but the rapid assessment of clinical benefit from these agents remains challenging. In breast cancer patients receiving neoadjuvant chemotherapy, treatment response is traditionally assessed by physical examination and volumetric-based measurements, which are subjective and require macroscopic changes in tumor morphology. In this study, we evaluate the feasibility of using diffusion magnetic resonance imaging (MRI) as a reliable and quantitative measure for the early assessment of response in a breast cancer model.Mice implanted with human breast cancer (MX-1) were treated with cyclophosphamide and evaluated using diffusion MRI and growth kinetics. Histologic analyses using terminal nucleotidyl transferase-mediated nick end labeling and H&E were done on tumor samples for correlation with imaging results.Cyclophosphamide treatment resulted in a significant reduction in tumor volumes compared with controls. The mean apparent diffusion change for treated tumors at days 4 and 7 posttreatment was 44 +/- 5% and 94 +/- 7%, respectively, which was statistically greater (P < 0.05) than the control tumors at the same time intervals. The median time-to-progression for control and treated groups was 11 and 32 days, respectively (P < 0.05).Diffusion MRI was shown to detect early changes in the tumor microenvironment, which correlated with standard measures of tumor response as well as overall outcome. Moreover, these findings show the feasibility of using diffusion MRI for assessing treatment response of a breast tumor model in a neoadjuvant setting.
Prospective study of cosmetic reactions: 1977-1980
Authors: H.J. Eiermann, W. Larsen, H.I. Maibach, J.S. Taylor, H.I. Maibach, R.M. Adams, W.E. Clendenning, A.A. Fisher, W.J. Jordan, H. Kanof, W. Larsen, E.J. Rudner, W. Schorr, F. Storrs, J.S. Taylor, H.J. Eiermann, F.N. Marzulli, M. Greif, J.T. Atkinson, Z.W. Mally
Journal: Journal of the American Academy of Dermatology (1982)
Tumor-homing multifunctional nanoparticles for cancer theragnosis: Simultaneous diagnosis, drug delivery, and therapeutic monitoring
Authors: Kwangmeyung Kim, Jong Ho Kim, Hyungkyu Park, Yoo-Shin Kim, Kyeongsoon Park, Heayun Nam, Seulki Lee, Jae Hyung Park, Rang-Woon Park, In-San Kim
Journal: Journal of Controlled Release (2010)
Inhibitors of HMG-CoA Reductase Reduce Receptor-mediated Endocytosis in Human Kidney Proximal Tubular Cells
Authors: Anja Verhulst, Patrick C. D’Haese, Marc E. De Broe
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. The proximal tubular cells of the kidney are responsible for reabsorption of proteins from the tubular lumen. In a study using Opossum kidney (OK) cells, receptor-mediated protein endocytosis was reduced by statins, inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, which are widely used for therapeutic reduction of plasma cholesterol levels. To explore the possible clinical relevance of the observations in OK cells, protein endocytosis in human kidney tubular cells was investigated in the presence and absence of statins. The uptake of FITC-labeled albumin in these cultures of human kidney tubular cells was investigated by microscopy, flow cytometry and spectrofluorometry. Protein uptake occurred selectively into proximal tubular cells while it was absent in distal tubular/collecting duct cells. Three statins (simvastatin, pravastatin, and rosuvastatin) significantly inhibited the uptake of protein in a concentration-dependent way. This inhibitory effect of statins could be prevented by the co-addition of mevalonate, the product of HMG-CoA reductase. This effect was not the result of a statin-induced cytotoxicity since cell-viability was unaffected. Finally, it was demonstrated that statins strongly inhibited cholesterol synthesis in the human kidney tubular cells. These data suggest that statins have the potential to inhibit albumin uptake by the human proximal nephron as a result of inhibition of HMG-CoA reductase in the proximal tubule cells. Taken into account the data of the accompanying manuscript this inhibitory effect most probably results from a reduced prenylation of some proteins critically involved in endocytosis. It is suggested that these data help to explain the occurrence of proteinuria in some patients treated with high statin doses. E-mail: marc.debroe@ua.ac.be
Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma
Authors: A. Keith Stewart, Susanna Jacobus, Rafael Fonseca, Matthias Weiss, Natalie S. Callander, Asher A. Chanan-Khan, S. Vincent Rajkumar
Journal: Blood (2015)