tbuckley/cabot-search huggingface dataset:
Systemic Interleukin-2 and Adoptive Transfer of Lymphokine-Activated Killer Cells Improves Antibody-Dependent Cellular Cytotoxicity in Patients with Relapsed B-Cell Lymphoma Treated with Rituximab
Authors: Jesús G. Berdeja, Allan Hess, David M. Lucas, Paul O'Donnell, Richard F. Ambinder, Louis F. Diehl, Denise Carter-Brookins, Susan Newton, Ian W. Flinn
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Murine models have shown that antibody-dependent cellular cytotoxicity (ADCC) can be improved with addition of lymphokine-activated killer (LAK) cells to monoclonal antibodies. A pilot trial of rituximab and LAK cells in patients with rituximab-refractory CD20+ lymphoma was conducted to evaluate this approach. Experimental Design: Ten patients received 3 million units/m2 of interleukin-2 (IL-2) i.v. qd on days 1 to 5 and leukapheresed on days 8, 9, and 10. The leukapheresis product was cultured with IL-2 for 48 h to produce LAK cells. Patients then received 375 mg/m2 i.v. rituximab and LAK cells on days 10, 11, and 12. The patients also received 3 million units/m2 of IL-2 i.v. for 5 days starting day 10. For safety purposes, the first three patients did not receive any LAK cell infusions. Results: The LAK cell infusions improved the ADCC activity of peripheral blood lymphocytes compared with pretreatment activity and prevented the decline in ADCC seen after infusion of rituximab alone. Therapy was well tolerated and the most clinically significant toxicities were fever and fatigue. Two patients achieved a partial remission and five had stable disease. Conclusions: The results from these studies suggest that the addition of LAK cells to rituximab augments ADCC in patients with rituximab-refractory lymphoma.
Effectiveness of triclosan-coated PDS Plus versus uncoated PDS II sutures for prevention of surgical site infection after abdominal wall closure: the randomised controlled PROUD trial
Authors: Markus K Diener, Phillip Knebel, Meinhard Kieser, Philipp Schüler, Tobias S Schiergens, Vladimir Atanassov, Jens Neudecker, Erwin Stein, Henryk Thielemann, Reiner Kunz, Moritz von Frankenberg, Utz Schernikau, Jörg Bunse, Boris Jansen-Winkeln, Lars I Partecke, Gerald Prechtl, Julius Pochhammer, Ralf Bouchard, René Hodina, K Tobias E Beckurts, Lothar Leißner, Hans-Peter Lemmens, Friedrich Kallinowski, Oliver Thomusch, Daniel Seehofer, Thomas Simon, Alexander Hyhlik-Dürr, Christoph M Seiler, Thilo Hackert, Christoph Reissfelder, René Hennig, Colette Doerr-Harim, Christina Klose, Alexis Ulrich, Markus W Büchler
Journal: The Lancet (2014)
From data gathering to systems medicine
Authors: Manuel Mayr
Journal: Cardiovascular Research (2013)

While molecular interactions have been a research focus for many years, the advent of updated molecular profiling methods has shifted the attention towards a more integrative approach. The ‘-omics’ technologies—genomics, transcriptomics, proteomics, and metabolomics—allow us to gather a vast amount of information at the level of the genome, transcriptome, proteome, and metabolome. However, these updated technologies have also brought about the challenge to understand the complex interplay of molecular changes related to cardiovascular disease. This will be the formidable task of systems biology.1,2 In this thematic Mini-Spotlight issue, four reviews summarize strategies how to advance this field.

Classic genomics aims to link variations in the DNA sequence directly to distinct phenotypes. As pointed out by Ware et al. ,3 the subsequent identification of the causative gene remains a substantial challenge. Currently, a wealth of susceptibility loci have been identified, i.e. the latest association analysis took the number of susceptibility loci for coronary artery disease to 46.4 With the exception of loci related to lipid metabolism, for which an involvement of hepatocytes is a reasonable assumption,5 it is largely unclear what cell types are affected. Moreover, most mutations …
Comparison of Statistical Analysis Plans in Randomize-All Phase III Trials with a Predictive Biomarker
Authors: Shigeyuki Matsui, Yuki Choai, Takahiro Nonaka
Journal: Clinical Cancer Research (2014)

When there are no compelling biologic or early trial data for a candidate predictive biomarker with regard to its ability to predict the effect of an anticancer treatment at the initiation of definitive phase III trials, it is generally reasonable to include all patients as eligible for randomization but to plan for a prospective subgroup analysis based on the biomarker. We assessed such statistical analysis plans, fixed-sequence, fallback, and treatment-by-biomarker interaction approaches, in terms of the probability of asserting treatment efficacy for either the overall patient population or a biomarker-positive subpopulation of patients. If there was some evidence that the treatment would work better in the biomarker-positive subgroup than the biomarker-negative subgroup, then the fixed-sequence approaches would be favored, whereas if evidence was weak that there would be much difference in responsiveness between the two subgroups, then the fallback approach would be favored. If there was substantial uncertainty in the difference in treatment effects between the two subgroups, the treatment-by-biomarker interaction approach could be a reasonable choice as this approach generally provided a high probability of asserting treatment efficacy for the right patient population under homogeneous treatment effects and a qualitative interaction over biomarker-based subgroups. Clin Cancer Res; 20(11); 2820-30. ©2014 AACR.
P121 Differential responses of M1 and M2 monocyte-derived macrophage phenotypes in COPD
Authors: A. J. N. Ward, K. K. Chana, C. M. Thomas, P. S. Fenwick, L. E. Donnelly
Journal: Thorax (2011)

<h3>Introduction</h3> Inflammation in chronic obstructive pulmonary disease (COPD) is associated with increased numbers of highly activated macrophages with a reduced phagocytic capacity. Macrophages may exist as M1 “classically activated” or M2 “alternatively activated” with different phagocytic and inflammatory mediator profiles, suggesting in COPD a more persistent, M1 macrophage predominates. It is unknown whether circulating monocytes in COPD patients predetermine whether M1 macrophages will be preferentially activated, thus driving an inflammatory phenotype. <h3>Objectives</h3> This study investigated differences between monocyte-derived macrophages (MDM) from non-smokers, smokers and COPD patients driven towards M1and M2 phenotypes. <h3>Methods</h3> Monocytes were isolated from whole blood and cultured with GM-CSF (2 ng/ml) or M-CSF (100 ng/ml) for 12d to generate M1 and M2 MDM respectively. Cells were stimulated with LPS (0.01–100 ng/ml) for 24 h and TNFα, CXCL8 and IL-10 measured by ELISA. Phagocytosis was measured fluorimetrically following exposure to fluorescent beads, <i>H influenzae</i> or <i>S pneumoniae</i> for 4 h. <h3>Results</h3> There were no differences in baseline release of any of the cytokines measured between subject groups. Cells released cytokines in response to LPS in a concentration-dependent manner. M1MDM derived from non-smokers and COPD patients released greater concentrations of LPS-stimulated (10 ng/ml) TNFα compared to M2 MDM. (Non-smokers: 7.4±2.3 vs 1.5±0.2 ng/ml, n=4; p&lt;0.01; COPD: 7.0±1.8 vs 2.1±0.9 ng/ml, n=4) and significantly less IL-10 (Non-smokers: 0.4±0.2 vs 3.0±0.6 ng/ml, n=4; p&lt;0.05; COPD: 0.3±0.04 vs 1.5±0.5 ng/ml, n=3) than M2 MDM. These differences were not apparent in cells from smokers. Both M1 and M2 MDM released LPS-stimulated CXCL8 similarly with no difference between subject groups. Phagocytosis of polystyrene beads was similar by both MDM phenotypes in all subject groups. However, there was a trend for M2 MDM to phagocytose more bacteria compared with M1 MDM which reached significance in healthy subjects (p&lt;0.05). <h3>Conclusions</h3> M1 and M2 MDM from non-smokers and COPD subjects showed distinct differences with respect to LPS-stimulated cytokine release and phagocytosis, however these differences were not apparent in cells from smokers without COPD. This suggests that smokers without COPD have altered circulating monocytes that do not differentiate into the pro-inflammatory M1 macrophage and may be protective against the development of COPD.
THE INFLUENCE OF ANTIBODIES ON IMMUNOLOGIC RESPONSES
Authors: David S. Pearlman
Journal: The Journal of Experimental Medicine (1967)

The influence of antibody on antibody formation to particulate antigen was examined in the rabbit with special reference to the importance of immunoglobulin type, the amount and relative proportion of antigen and antibody involved, and the specificity of this influence. 19S as well as 7S antibody was shown to be an effective inhibitor of antibody formation, although there was some evidence that 7S antibody was the more efficient of the two in doing so. The inhibitory effect of antibody was found to be specific for homologous antigenic determinants. Both 19S and 7S antibody were also able to enhance antibody formation. In contrast to the suppressive phenomenon, however, enhancement appeared to be nonspecific since antibody reactive with homologous (sheep red blood cell) determinants could enhance the response not only to homologous determinants but to heterologous (dinitrobenzene) determinants conjugated to the red blood cells as well. Smaller amounts of antibody were needed to enhance than to suppress antibody formation, and suppression and enhancement depended to some extent on the amount of antigen as well as to the amount of antibody used. The enhancing and suppressing influence of antibody on antibody formation appeared to be exerted concomitantly, for the response to some antigenic determinants was sometimes suppressed at the same time that the response to others was enhanced. It is suggested that enhancement or suppression of immunologic responses by antibody represents a different balance of at least two competing factors operating together: specific neutralization of appropriate determinants thus decreasing the total effective concentration of these determinants available to stimulate the formation of antibodies, and a nonspecific increase in the availability of antigen to immunologically competent cells.
Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects.
Authors: O G Kolterman, J Insel, M Saekow, J M Olefsky
Journal: Journal of Clinical Investigation (1980)

To assess the mechanisms of the insulin resistance in human obesity, we have determined, using a modification of the euglycemic glucose clamp technique, the shape of the in vivo insulin-glucose disposal dose-response curves in 7 control and 13 obese human subjects. Each subject had at least three euglycemic studies performed at insulin infusion rates of 15, 40, 120, 240, or 1,200 mU/M2/min. The glucose disposal rate was decreased in all obese subjects compared with controls (101 +/- 16 vs. 186 +/- 16 mg/M2/min) during the 40 mU/M2/min insulin infusion. The mean dose-response curve for the obese subjects was displaced to the right, i.e., the half-maximally effective insulin concentration was 270 +/- 27 microU/ml for the obese compared with 130 +/- 10 microU/ml for controls. In nine of the obese subjects, the dose-response curves were shifted to the right, and maximal glucose disposal rates (at a maximally effective insulin concentration) were markedly decreased, indicating both a receptor and a postreceptor defect. On the other hand, four obese patients had right-shifted dose-response curves but reached normal maximal glucose disposal rates, consistent with decreased insulin receptors as the only abnormality. When the individual data were analyzed, it was found that the lease hyperinsulinemic, least insulin-resistant patients displayed only the receptor defect, whereas those with the greatest hyperinsulinemia exhibited the largest post-receptor defect, suggesting a continuous spectrum of defects as one advances from mild to severe insulin resistance. When insulin's ability to suppress hepatic glucose output was assessed, hyperinsulinemia produced total suppresssion in all subjects. The dose-response curve for the obese subjects was shifted to the right, indicating a defect in insulin receptors. Insulin binding to isolated adipocytes obtained from the obese subjects was decreased, and a highly significant inverse linear relationship was demonstrated between insulin binding and the serum insulin concentration required for halfmaximal stimulation of glucose disposal. In conclusion: (a) decreased cellular insulin receptors contribute to the insulin resistance associated with human obesity in all subjects; (b) in the least hyperinsulinemic, insulin-resistant patients, decreased insulin receptors are the sole defect, whereas in the more hyperinsulinemic, insulin-resistant patients, the insulin resistance is the result of a combination of receptor and postreceptor abnormalities; (c) all obese patients were insensitive to insulin's suppressive effects on hepatic glucose output; this was entirely the result of decreased insulin receptors; no postreceptor defect in this insulin effect was demonstrated.
Antibodies to GP2, the major zymogen granule membrane glycoprotein, in inflammatory bowel diseases
Authors: Katrijn Op De Beéck, Séverine Vermeire, Paul Rutgeerts, Xavier Bossuyt
Journal: Gut (2010)

It was with interest that we read the paper by Roggenbuck et al 1 in a recent issue of Gut , where GP2, the major zymogen granule membrane glycoprotein, is demonstrated to be the autoantigen of pancreatic antibodies in Crohn's disease. The authors concluded that quantification of this novel Crohn's disease-specific marker could significantly improve the serological diagnosis of inflammatory bowel disease. A commercial assay for the detection of anti-GP2 antibodies has recently become available (Generic Assays, Dahlewitz/Berlin). In the present paper, we evaluated this assay on a large well-characterised study population.

The patient cohort has been previously described2 and consisted of 164 patients with Crohn's disease, 118 patients with ulcerative colitis, and 75 control patients with other gastrointestinal diseases (non-inflammatory bowel disease diarrhoeal illnesses). One hundred blood donors were included as well. The diagnosis of ulcerative coliltis or Crohn's disease was based on accepted clinical …
Impact of Comorbidity on Survival Among Men With Localized Prostate Cancer
Authors: Peter C. Albertsen, Dirk F. Moore, Weichung Shih, Yong Lin, Hui Li, Grace L. Lu-Yao
Journal: Journal of Clinical Oncology (2011)

To provide patients and clinicians more accurate estimates of comorbidity-specific survival stratified by patient age, tumor stage, and tumor grade.We conducted a 10-year competing risk analysis of 19,639 men 66 years of age and older identified by the Surveillance, Epidemiology, and End Results (SEER) program linked to Medicare program files. All men were diagnosed with localized prostate cancer and received no surgery or radiation within 180 days of diagnosis. The analysis was stratified by tumor grade and stage and by age and comorbidity at diagnosis classified using the Charlson comorbidity index. Underlying causes of death were obtained from SEER.During the first 10 years after diagnosis, men with moderately and poorly differentiated prostate cancer were more likely to die from causes other than their disease. Depending on patient age, Gleason score, and number of comorbidities present at diagnosis, 5-year overall mortality rates for men with stage T1c disease ranged from 11.7% (95% CI, 10.2% to 13.1%) to 65.7% (95% CI, 55.9% to 70.1%), and prostate cancer-specific mortality rates ranged from 1.1% (95% CI, 0.0% to 2.7%) to 16.3% (95% CI, 13.8% to 19.4%). Ten-year overall mortality rates ranged from 28.8% (95% CI, 25.3% to 32.6%) to 94.3% (95% CI, 87.4% to 100%), and prostate cancer-specific mortality rates ranged from 2.0% (95% CI, 0.0% to 5.3%) to 27.5% (95% CI, 21.5% to 36.5%).Patients and clinicians should consider using comorbidity-specific data to estimate the threat posed by newly diagnosed localized prostate cancer and the threat posed by competing medical hazards.
The Evolving Treatment of Breast Cancer
Authors: Willcox Kirkland Ruffin
Journal: JAMA (1989)

<h3>To the Editor.—</h3> Surgical and medical treatment of the patient with breast cancer has changed dramatically in the past two decades. The Halsted radical mastectomy has been replaced by the modified radical mastectomy, and, more recently, evidence has appeared supporting segmental mastectomy as an acceptable alternative when combined with axillary dissection and postoperative radiation therapy. The National Surgical Adjuvant Breast Project has performed numerous studies attempting to resolve the dilemma surrounding the various treatments. One such study, protocol B-04, compared radical mastectomy and total mastectomy with and without radiation therapy. The results showed no significant difference in overall survival when comparing the three treatment arms.<sup>1</sup>Of equal importance, the data indicated that surgical removal of the axillary lymph nodes was useful for staging but did not benefit survival, supporting the theory that breast cancer is a systemic disease and that involved axillary nodes serve only as a marker of
RETRACTED: Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months predates and predicts atopic dermatitis at 1 year
Authors: Maeve Kelleher, Audrey Dunn-Galvin, Jonathan O'B Hourihane, Deirdre Murray, Linda E Campbell, W H Irwin McLean, Alan D Irvine
Journal: Journal of Allergy and Clinical Immunology (2015)
Results of a Randomized Study of Preradiation Chemotherapy Versus Radiotherapy Alone for Nonmetastatic Medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children’s Cancer Study Group PNET-3 Study
Authors: Roger E. Taylor, Clifford C. Bailey, Kath Robinson, Claire L. Weston, David Ellison, James Ironside, Helen Lucraft, Richard Gilbertson, Diana M. Tait, David A. Walker, Barry L. Pizer, John Imeson, Linda S. Lashford
Journal: Journal of Clinical Oncology (2003)

Purpose: To determine whether preradiotherapy (RT) chemotherapy would improve outcome for Chang stage M0–1 medulloblastoma when compared with RT alone. Chemotherapy comprised vincristine 1.5 mg/m 2 weekly for 10 weeks and four cycles of etoposide 100 mg/m 2 daily for 3 days, and carboplatin 500 mg/m 2 daily for 2 days alternating with cyclophosphamide 1.5 g/m 2 . Patients and Methods: Patients aged 3 to 16 years inclusive were randomly assigned to receive 35 Gy craniospinal RT with a 20 Gy posterior fossa boost, or chemotherapy followed by RT. Results: Of 217 patients randomly assigned to treatment, 179 were eligible for analysis (chemotherapy + RT, 90 patients; RT alone, 89 patients). Median age was 7.67 years, and median follow-up was 5.40 years. Overall survival (OS) at 3 and 5 years was 79.5% and 70.7%, respectively. Event-free survival (EFS) at 3 and 5 years was 71.6% and 67.0%, respectively. EFS was significantly better for chemotherapy and RT (P = .0366), with EFS of 78.5% at 3 years and 74.2% at 5 years compared with 64.8% at 3 years and 59.8% at 5 years for RT alone. There was no statistically significant difference in 3-year and 5-year OS between the two arms (P = .0928). Multivariate analysis identified use of chemotherapy (P = .0248) and time to complete RT (P = .0100) as having significant effect on EFS. Conclusion: This is the first large multicenter randomized study to demonstrate improved EFS for chemotherapy compared with RT alone. It is anticipated that this regimen could reduce ototoxicity and nephrotoxicity compared with cisplatin-containing schedules. The importance of avoiding interruptions to RT has been confirmed.
Novel Targeting of Phospho-cMET Overcomes Drug Resistance and Induces Antitumor Activity in Multiple Myeloma
Authors: Michele Moschetta, Antonio Basile, Arianna Ferrucci, Maria Antonia Frassanito, Luigia Rao, Roberto Ria, Antonio Giovanni Solimando, Nicola Giuliani, Angelina Boccarelli, Fabio Fumarola, Mauro Coluccia, Bernardo Rossini, Simona Ruggieri, Beatrice Nico, Eugenio Maiorano, Domenico Ribatti, Aldo M. Roccaro, Angelo Vacca
Journal: Clinical Cancer Research (2013)

The aim of the study was to verify the hypothesis that the cMet oncogene is implicated in chemio- and novel drug resistance in multiple myeloma.We have evaluated the expression levels of cMET/phospho-cMET (p-cMET) and the activity of the novel selective p-cMET inhibitor (SU11274) in multiple myeloma cells, either sensitive (RPMI-8226 and MM.1S) or resistant (R5 and MM.1R) to anti-multiple myeloma drugs, in primary plasma cells and in multiple myeloma xenograft models.We found that resistant R5 and MM.1R cells presented with higher cMET phosphorylation, thus leading to constitutive activation of cMET-dependent signaling pathways. R5 cells exhibited a higher susceptibility to the SU11274 inhibitory effects on viability, proliferation, chemotaxis, adhesion, and to its apoptogenic effects. SU11274 was able to revert drug resistance in R5 cells. R5 but not RPMI-8226 cells displayed cMET-dependent activation of mitogen-activated protein kinase pathway. The cMET and p-cMET expression was higher on plasma cells from patients with multiple myeloma at relapse or on drug resistance than on those from patients at diagnosis, complete/partial remission, or from patients with monoclonal gammopathy of unknown significance. Viability, chemotaxis, adhesion to fibronectin or paired bone marrow stromal cells of plasma cells from relapsed or resistant patients was markedly inhibited by SU11274. Importantly, SU11274 showed higher therapeutic activity in R5- than in RPMI-8226-induced plasmocytomas. In R5 tumors, it caused apoptosis and necrosis and reverted bortezomib resistance.Our findings suggest that the cMET pathway is constitutively activated in relapsed and resistant multiple myeloma where it may also be responsible for induction of drug resistance, thus providing the preclinical rationale for targeting cMET in patients with relapsed/refractory multiple myeloma.
Lymphatic function in the yellow nail syndrome
Authors: R.H. BULL, D.A. FENTON, P.S. MORTIMER
Journal: British Journal of Dermatology (1996)

Peripheral oedema is commonly seen in the yellow nail syndrome (YNS). Contrast lymphangiography has shown abnormal collecting lymphatics in some patients with YNS. In this study, lymphatic function in the upper and lower limbs of 17 patients with YNS, in normal controls, and in patients with established classical lymphoedema, has been assessed using quantitative lymphoscintigraphy. Nine subjects with YNS had swelling of the legs and two had features typical of lymphoedema. The lymphatic drainage was significantly reduced in the legs of patients with YNS but not to the level seen in lymphoedema. Lymphatic function was also reduced in the arms in patients with YNS. Venous insufficiency did not contribute to the leg oedema. These results suggest that the underlying cause of YNS is not primarily a lymphatic abnormality. The lymphatic impairment associated with YNS appears to be secondary, and predominantly functional in nature, rather than due to structural changes.
An outbreak of norovirus gastroenteritis at a swimming club - Vermont, 2004.
Authors: L. Z. Blevins, D. Itani, A. Burns, C. Lohff, S. Schoenfeld, W. Knight, N. Thayer, J. Oetjen, N. Pugsley, C. Otto, M. Beach, M. A. Widdowson, J. Bresee, R. Glass, S. Monroe, L. Browne, S. Adams, M. Amundson, L. J. Podewils
Journal: MMWR Morbidity and Mortality Weekly Report (2004)