tbuckley/cabot-search huggingface dataset:
IN VITRO STIMULATION OF ANTIBODY FORMATION BY PERITONEAL CELLS
Authors: G. J. V. Nossal, A. E. Bussard, H. Lewis, J. C. Mazie
Journal: The Journal of Experimental Medicine (1970)

An improved method for the short-term culture of mouse peritoneal cells in a medium containing carboxymethylcellulose (CMC), sheep erythrocytes (SRBC), and guinea pig complement is described. It involves preparation of microcultures, of thickness 12–15 µ and volume 3.6 µl, under paraffin oil. With such cultures, peritoneal cells from normal, unimmunized young male CBA mice give about 3000 hemolytic plaques per million cells cultured, this figure being attained within 24 hr. The plaque detection method is about four times as sensitive as the Jerne technique. A method is described whereby such plaque-forming cells (PFC) can be transferred, by micromanipulation, to fresh monolayer cultures containing SRBC, CMC, and complement. In this fashion, the secretory capacity and susceptibility to inhibitors of peritoneal PFC can be tested in detail. Using this technique, evidence is presented that the hemolytic substance responsible for plaque formation is actually secreted by the cell at the center of the plaque, and is not a complement component but probably an antibody. Studies on the time of plaque appearance after cell transfer, and the subsequent growth rate of the zone of hemolysis, have been performed. They speak against the idea that the PFC is either a reservoir of cytophilic antibody or a "background" PFC. Rather they suggest that active antibody secretion is induced in the cell at some defined time point in culture. Detailed kinetics of the rate of appearance of plaques in peritoneal cell cultures revealed an exponential phase lasting from about 3 to about 13 hr with a doubling time of 2 hr. The reasons for this are not known. A greatly heightened reactivity was shown in peritoneal cells of mice that had been pregnant several times. Cultures of such cells showed more rapid plaque appearance and a peak activity about 20 times higher than with cells from young male mice. Cultures in which 1 cell in 10 formed a plaque were not infrequent. A series of experiments on germ-free mice showed reactivity similar to that of conventional mice from the same strain and source. The significance of the findings for cellular immunology are discussed.
Calcitonin Stimulates Lysosomal Enzyme Release and Uptake in LLC-PK1 Cells
Authors: MASAKO GOTO, KAZUTOSHI MIZUNASHI
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Renal tubular targeted hormones increase urinary excretion of a lysosomal enzyme, N -acetyl-β-D-glucosaminidase (NAG). To elucidate the mechanism of this event, the calcitonin effect on NAG handling by LLC-PK 1 cells was examined. Calcitonin (1 nM to 1 μM), phorbol myristate (10 nM to 1 μM), and ionomycin (1 to 10 μM) promoted NAG release without any increase in lactate dehydrogenase release or any reduction of mitochondrial dehydrogenase activity. Treatment with 100 nM calphostin C or 50 μM KN-93 partially reversed the calcitonin effect on NAG release. Calcitonin promoted secretion of fluorescence ceramide, a reporter of protein transport from Golgi apparatus to cell surface. Calcitonin-stimulated NAG release was partially inhibited by 10 μg/ml brefeldin A, a blocker of protein transport through the Golgi apparatus. Calcitonin accelerated cellular uptake of exogenous NAG, which was inhibited by low temperature, 0.1 mM monodansyl cadaverine (receptor-mediated endocytosis inhibitor), and 10 mM mannose-6-phosphate. Furthermore, calcitonin promoted progression of intracellular membranes stained by a fluorescence membrane marker, styryl pyridinium dye, from cell periphery to perinuclear regions (commonly referred to as recycling vesicles) and increased dye release from preloaded cells. Fluorescence release from the cells preloaded with FITC-labeled NAG or albumin was also stimulated by calcitonin. These calcitonin effects on endocytotic and re-exocytotic pathways were inhibited by 100 nM cytochalasin D, 100 nM nocodazole, 0.1 to 1 μM bafilomycin A1, or 0.1 mM monodansyl cadaverine. Increased urinary NAG excretion has been considered to reflect renal tubular damage. However, it was demonstrated here that stimulation of secretory and recycling pathways may be an alternative mechanism for calcitonin-induced enzymuria, which will become a new indicator of renal tubular response to this hormone.
Women with gestational diabetes should be targeted to reduce cardiovascular risk
Authors: V Toescu
Journal: BMJ (2002)

EDITOR —Sattar and Greer discuss the probability that complications in pregnancy may predispose women to vascular and metabolic disease in later life.1 The link between pregnancy complications and coronary heart disease remains unexplained. We believe that during pregnancy the hormonal and other stresses provoke cardiovascular and metabolic abnormalities in susceptible individuals, which may recur and become permanent as the patient ages. Many of these are coronary risk factors; disturbances in glucose metabolism, which underlie the development of gestational diabetes, are a good example.



Triglyceride concentrations and …
WNK1 Affects Surface Expression of the ROMK Potassium Channel Independent of WNK4
Authors: Georgina Cope, Meena Murthy, Amir P. Golbang, Abbas Hamad, Che-Hsiung Liu, Alan W. Cuthbert, Kevin M. O’Shaughnessy
Journal: Journal of the American Society of Nephrology (2006)

The WNK (with no lysine kinase) kinases are a novel class of serine/threonine kinases that lack a characteristic lysine residue for ATP docking. Both WNK1 and WNK4 are expressed in the mammalian kidney, and mutations in either can cause the rare familial syndrome of hypertension and hyperkalemia (Gordon syndrome, or pseudohypoaldosteronism type 2). The molecular basis for the action of WNK4 is through alteration in the membrane expression of the NaCl co-transporter (NCCT) and the renal outer-medullary K channel KCNJ1 (ROMK). The actions of WNK1 are less well defined, and evidence to date suggests that it can affect NCCT expression but only in the presence of WNK4. The results of co-expressing WNK1 with ROMK in Xenopus oocytes are reported for the first time. These studies show that WNK1 is able to suppress total current directly through ROMK by causing a marked reduction in its surface expression. The effect is mimicked by a kinase-dead mutant of WNK1 (368D>A), suggesting that it is not dependent on its catalytic activity. Study of the time course of ROMK expression further suggests that WNK1 accelerates trafficking of ROMK from the membrane, and this effect seems to be dynamin dependent. Using fragments of full-length WNK1, it also is shown that the effect depends on residues in the middle section of the protein (502 to 1100 WNK1) that contains the acidic motif. Together, these findings emphasize that the molecular mechanisms that underpin WNK1 regulation of ROMK expression are distinct from those that affect NCCT expression.
Expression of a Functional CCR2 Receptor Enhances Tumor Localization and Tumor Eradication by Retargeted Human T cells Expressing a Mesothelin-Specific Chimeric Antibody Receptor
Authors: Edmund K. Moon, Carmine Carpenito, Jing Sun, Liang-Chuan S. Wang, Veena Kapoor, Jarrod Predina, Daniel J. Powell, James L. Riley, Carl H. June, Steven M. Albelda
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Adoptive T-cell immunotherapy with tumor infiltrating lymphocytes or genetically-modified T cells has yielded dramatic results in some cancers. However, T cells need to traffic properly into tumors to adequately exert therapeutic effects. Experimental Design: The chemokine CCL2 was highly secreted by malignant pleural mesotheliomas (MPM; a planned tumor target), but the corresponding chemokine receptor (CCR2) was minimally expressed on activated human T cells transduced with a chimeric antibody receptor (CAR) directed to the MPM tumor antigen mesothelin (mesoCAR T cells). The chemokine receptor CCR2b was thus transduced into mesoCAR T cells using a lentiviral vector, and the modified T cells were used to treat established mesothelin-expressing tumors. Results: CCR2b transduction led to CCL2-induced calcium flux and increased transmigration, as well as augmentation of in vitro T-cell killing ability. A single intravenous injection of 20 million mesoCAR + CCR2b T cells into immunodeficient mice bearing large, established tumors (without any adjunct therapy) resulted in a 12.5-fold increase in T-cell tumor infiltration by day 5 compared with mesoCAR T cells. This was associated with significantly increased antitumor activity. Conclusions: CAR T cells bearing a functional chemokine receptor can overcome the inadequate tumor localization that limits conventional CAR targeting strategies and can significantly improve antitumor efficacy in vivo. Clin Cancer Res; 17(14); 4719–30. ©2011 AACR.
Chemotherapeutic drugs sensitize human renal cell carcinoma cells to ABT-737 by a mechanism involving the Noxa-dependent inactivation of Mcl-1 or A1
Authors: Henry Zall, Arnim Weber, Robert Besch, Niko Zantl, Georg Häcker
Journal: Molecular Cancer (2010)

Abstract Background Human renal cell carcinoma (RCC) is very resistant to chemotherapy. ABT-737 is a novel inhibitor of anti-apoptotic proteins of the Bcl-2 family that has shown promise in various preclinical tumour models. Results We here report a strong over-additive pro-apoptotic effect of ABT-737 and etoposide, vinblastine or paclitaxel but not 5-fluorouracil in cell lines from human RCC. ABT-737 showed very little activity as a single agent but killed RCC cells potently when anti-apoptotic Mcl-1 or, unexpectedly, A1 was targeted by RNAi. This potent augmentation required endogenous Noxa protein since RNAi directed against Noxa but not against Bim or Puma reduced apoptosis induction by the combination of ABT-737 and etoposide or vinblastine. At the level of mitochondria, etoposide-treatment had a similar sensitizing activity and allowed for ABT-737-induced release of cytochrome c . Conclusions Chemotherapeutic drugs can overcome protection afforded by Mcl-1 and A1 through endogenous Noxa protein in RCC cells, and the combination of such drugs with ABT-737 may be a promising strategy in RCC. Strikingly, A1 emerged in RCC cell lines as a protein of similar importance as the well-established Mcl-1 in protection against apoptosis in these cells.
Volumetric Analysis of In-Stent Intimal Hyperplasia in Diabetic Patients Treated With or Without Abciximab
Authors: Áurea J. Chaves, Amanda G.M.R. Sousa, Luiz A. Mattos, Alexandre Abizaid, Rodolfo Staico, Fausto Feres, Marinella Centemero, Luiz F. Tanajura, Andrea Abizaid, Ibraim Pinto, Galo Maldonado, Ana Seixas, Marco A. Costa, Ângela Paes, Gary S. Mintz, J. Eduardo Sousa
Journal: Circulation (2004)

Background— In diabetic patients in the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial, abciximab reduced target vessel revascularization by ≈50% compared with placebo. Whether this is a result of a lower restenosis rate caused by inhibition of intimal hyperplasia remains to be defined. Methods and Results— The purpose of this study was to determine whether abciximab at the time of stent implantation would reduce in-stent intimal hyperplasia measured by intravascular ultrasound at 6-month follow-up in type 2 diabetics. Ninety-six diabetic patients (96 lesions) who underwent elective stent implantation for a de novo lesion in a native coronary artery were randomly assigned to receive abciximab or no abciximab. In-stent intimal hyperplasia volume, expressed as percentage of stent volume, did not differ between groups: 41.3±21.0% for those treated with abciximab versus 40.5±18.3% for those treated without abciximab ( P =0.9). There were also no significant differences in angiographic minimal luminal diameter at follow-up (1.74±0.69 versus 1.66±0.63 mm; P =0.5), late loss (1.03±0.63 versus 1.07±0.58 mm; P =0.7), restenosis rate (17.8% versus 22.9%; P =0.5), or cumulative incidence of major adverse cardiac events at 12 months (19.1% versus 20.4%; P =0.9). Conclusions— Six-month intravascular ultrasound volumetric analysis showed that abciximab, at the time of coronary stent implantation, was not associated with a reduction of in-stent intimal hyperplasia in diabetic patients.
Dosing and efficacy in specific immunotherapy
Authors: P. Demoly, M. A. Calderon
Journal: Allergy (2011)

Allergen-specific immunotherapy is used to treat allergic rhinoconjuctivitis and asthma worldwide. The clinical efficacy of the most common routes, subcutaneous (SCIT) and sublingual (SLIT) immunotherapy, is documented for respiratory allergy by double-blind, placebo-controlled, randomised clinical trials (DB PC RCT). However, dose-effect relationships are not available for all extracts. The 1998 WHO Consensus Report on Allergen Immunotherapy found SCIT ineffective at low doses, with high doses more likely to result in an unacceptably high level of systemic reactions. Recent large well-designed DB PC RCTs using SLIT grass pollen tablets have undergone phase II-III studies in adults with allergic rhinitis, yielding proper dose-response studies. These were analysed by the European Academy of Allergy and Clinical Immunology Immunotherapy Interest Group task force on dose effect. In general, low doses (5-7 μg of allergen Phl p 5 per day) are ineffective. Daily doses of 15-25 μg of the major allergen protein are required for significant clinical improvement measured by symptom scores. A higher dose (33-40 μg of Phl p 5 per day) was not more effective than 15-25 μg. Optimization of the allergen/adjuvant ratio may allow for lower allergen doses, increase the safety/efficacy profile and allow for shorter updosing. However, our analysis of the available studies concluded that every product requires its own dose-response relationship study.
INTEGRATIVE GENOMIC CHARACTERIZATION OF LOWER GRADE GLIOMAS
Authors: D. J. Brat
Journal: Neuro-Oncology (2014)

BACKGROUND: Lower grade gliomas (LGG) are infiltrative brain tumors that include astrocytomas, oligodendrogliomas and oligoastrocytomas, grades II and III. LGGs almost always progress, typically to glioblastoma (GBM, grade IV), and are uniformly fatal. The Cancer Genome Atlas (TCGA) is conducting a comprehensive molecular analysis of LGG, incorporating genetic and genomic alterations, DNA methylation profiles, and RNA and proteomic signatures. The rich, integrated clinical data of TCGA provides an outstanding platform to uncover biomarkers of therapy response and outcome. METHODS: We analyzed 289 lower grade gliomas for exome sequence to uncover somatic mutations; DNA copy number alterations; RNA sequencing for expression and gene fusion; DNA methlyation; microRNA expression; and protein level and phosphorylation. Supervised and unsupervised clustering was performed to segregate LGGs into robust molecular categories. RESULTS: Among 289 LGGs, exome sequencing identified 19 significantly mutated genes, including IDH1, TP53, ATRX, CIC, FUBP1, NOTCH1, PIK3CA, NF1, PIK3R1, ARID1A, PTEN, SMARCA4 and EGFR. Frequent arm-level deletions were 1p, 19q, 13q, 9p, 10q, 10p, 4q and 4p; arm-level gains included 7q, 7p, 19p and 11q. There were 15 significant genomic amplifications, among which were 7p11.2 (EGFR), 12q14.1 (CDK4), 1q32.1 (MDM4), 8q24.21 (MYC), 12p13.32 (CCND2) and 4q12 (PDGFR). Among 28 deletions were 9p21.3 (CDKN2A, CDKN2B), 19q13.42 (TFPT, ZNF331), 2q37.3, 10q26.2 (FGFR2, DUX4) and 14q24.3 (TSHR, GPHN).Global analysis of DNA methylation identified 5 stable clusters, with one showing substantial hypomethylation. Gene expression profiling identified 4 stable clusters. On integrative analysis, IDH1/2 wt LGGs had features of “pre-GBM”: they formed distinct hypomethylation and gene expression clusters; had molecular alterations typical of GBM, such as EGFR amplifications, PTEN mutations, CDKN2A loss and RTK gene fusions; were mostly grade III astrocytomas; and had short survivals. IDH1/2 mutant LGGs were hypermethylated. One subgroup was enriched for 1p/19q co-deletion, CIC and FUBP mutations, and oligodendrogliomas. Another subset was enriched for TP53 and ATRX mutations and astrocytomas. These groups clustered separately on gene expression analysis. A fourth gene expression cluster had elements of these two IDH1/2 mutant subgroups and the longest survival. A cluster-of-cluster analysis of mRNA, copy number, miRNA and methylation analyses reinforced the clear separation of three molecular classes of LGG based on the status of IDH1/2 and 1p/19q. CONCLUSIONS: These data illustrate a potential stratification of LGGs that emphasizes molecular characteristics. IDH wt LGG have molecular alterations and clinical behavior similar to GBMs, whereas IDH mutant LGGs segregate based on 1p/19q status. SECONDARY CATEGORY: Tumor Biology.
Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol
Authors: Björn Dahlöf, Richard B Devereux, Sverre E Kjeldsen, Stevo Julius, Gareth Beevers, Ulf de Faire, Frej Fyhrquist, Hans Ibsen, Krister Kristiansson, Ole Lederballe-Pedersen, Lars H Lindholm, Markku S Nieminen, Per Omvik, Suzanne Oparil, Hans Wedel
Journal: The Lancet (2002)
Psychosocial Treatments for Child and Adolescent Disorders: Empirically Based Strategies for Clinical Practice, Second Editionedited by Euthymia D. Hibbs, Ph.D., and Peter S. Jensen, M.D. Washington, D.C., American Psychological Association, 2005, 839 pp, $69.95.
Authors: Lawrence Hartmann
Journal: American Journal of Psychiatry (2006)
Fertility and gonadal function in female survivors after treatment of early unfavorable Hodgkin lymphoma (HL) within the German Hodgkin Study Group HD14 trial
Authors: K. Behringer, I. Thielen, H. Mueller, H. Goergen, A.D. Eibl, J. Rosenbrock, T. Halbsguth, D.A. Eichenauer, M. Fuchs, K.S. Reiners, J.H. Renno, K. van der Ven, M. Kuehr, M. von Wolff, V. Diehl, A. Engert, P. Borchmann
Journal: Annals of Oncology (2012)
Oral Treatment with Live <i>Lactobacillus reuteri</i> Inhibits the Allergic Airway Response in Mice
Authors: Paul Forsythe, Mark D. Inman, John Bienenstock
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Clinical trials have demonstrated that probiotics may be effective in the treatment and prevention of atopic disease in children but there have been few reports of therapeutic effects of oral probiotics outside the gastrointestinal tract.We investigated the effect of two probiotic organisms on the response to antigen challenge in a mouse model of allergic airway inflammation.We used an ovalbumin-sensitized asthma model in BALB/c and Toll-like receptor 9-deficient mice. Animals were treated with probiotic organisms via gavaging needle before antigen challenge. After antigen challenge, airway responsiveness to methacholine, influx of inflammatory cells to the lung, and cytokine levels in bronchoalveolar lavage fluid were assessed.Oral treatment with live Lactobacillus reuteri but not Lactobacillus salivarius significantly attenuated the influx of eosinophils to the airway lumen and parenchyma and reduced the levels of tumor necrosis factor, monocyte chemoattractant protein-1, IL-5, and IL-13 in bronchoalveolar lavage fluid of antigen-challenged animals, but there was no change in eotaxin or IL-10. L. reuteri but not L. salivarius also decreased allergen-induced airway hyperresponsiveness. These responses were dependent on Toll-like receptor 9 and were associated with increased activity of indoleamine 2,3-dioxygenase. Killed organisms did not mimic the ability of the live L. reuteri to attenuate inflammation or airway hyperresponsiveness.Oral treatment with live L. reuteri can attenuate major characteristics of an asthmatic response in a mouse model of allergic airway inflammation. These results suggest that oral treatment with specific live probiotic strains may have therapeutic potential in the treatment of allergic airway disease.
Combined effects of overweight and smoking in late adolescence on subsequent mortality: nationwide cohort study
Authors: M. Neovius, J. Sundstrom, F. Rasmussen
Journal: BMJ (2009)

<b>Objective</b> To investigate the combined effects on adult mortality of overweight and smoking in late adolescence. <b>Design</b> Record linkage study with Cox proportional hazard ratios adjusted for muscle strength, socioeconomic position, and age. <b>Setting</b> Swedish military service conscription register, cause of death register, and census data. <b>Participants</b> 45 920 Swedish men (mean age 18.7, SD 0.5) followed for 38 years. <b>Main outcome measures</b> Body mass index (underweight (BMI &lt;18.5), normal weight (18.5-24.9), overweight (25-29.9), and obesity (≥30)), muscle strength, and self reported smoking (non-smoker, light smoker (1-10 cigarettes/day), heavy smoker (&gt;10/day)) at mandatory military conscription tests in 1969-70. All cause mortality. <b>Results</b> Over 1.7 million person years, 2897 men died. Compared with normal weight men (incidence rate 17/10 000 person years, 95% confidence interval 16 to 18), risk of mortality was increased in overweight (hazard ratio 1.33, 1.15 to 1.53; incidence rate 23, 20 to 26) and obese men (hazard ratio 2.14, 1.61 to 2.85; incidence rate 38, 27 to 48), with similar relative estimates in separate analyses of smokers and non-smokers. No increased risk was detected in underweight men (hazard ratio 0.97, 0.86 to 1.08; incidence rate 18, 16 to 19), though extreme underweight (BMI &lt;17) was associated with increased mortality (hazard ratio 1.33, 1.07 to 1.64; incidence rate 24, 19 to 29). The relative excess risk due to interaction between BMI and smoking status was not significant in any stratum. Furthermore, all estimates of interaction were of small magnitude, except for the combination of obesity and heavy smoking (relative excess risk 1.5, −0.7 to 3.7). Compared with non-smokers (incidence rate 14, 13 to 15), risk was increased in both light (hazard ratio 1.54, 1.41 to 1.70; incidence rate 15, 14 to 16) and heavy smokers (hazard ratio 2.11, 1.92 to 2.31; incidence rate 26, 24 to 27). <b>Conclusions</b> Regardless of smoking status, overweight and obesity in late adolescence increases the risk of adult mortality. Obesity and overweight were as hazardous as heavy and light smoking, respectively, but there was no interaction between BMI and smoking status. The global obesity epidemic and smoking among adolescents remain important targets for intensified public health initiatives.
CHANGES IN LEFT VENTRICULAR DIASTOLIC FUNCTION AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Smita I. Negi, Prakash Balan, Robert Lee, Ali Denktas, Aashish Anand, Pranav Loyalka, Biswajit Kar, Anthony Estrera, Igor Gregoric, Richard Smalling
Journal: Journal of the American College of Cardiology (2014)
Antidouble-stranded DNA isotypes in lupus erythematosus patients with prevalent cutaneous presentation
Authors: A. Parodi, M. Drosera, L. Barbieri, G. Babbini, A. Rebora
Journal: British Journal of Dermatology (2002)

Antidouble-stranded DNA antibodies (anti-dsDNA Ab), in particular of the IgG isotype, are usually considered a marker of systemic lupus erythematosus and often correlate with the disease activity.To determine IgG, IgA and IgM anti-dsDNA Ab in a group of 330 patients with lupus erythematosus and prevalent cutaneous lesions.The titre of anti-dsDNA Ab was determined by enzyme-linked immunosorbent assay, and disease activity was assessed by means of the systemic lupus activity measure.One hundred and six patients had anti-dsDNA Ab. Thirty-nine patients had antibodies of all three isotypes of immunoglobulins, 17 had IgG + IgM, five IgG + IgA, and two IgA + IgM. Forty-three patients had a single isotype of anti-dsDNA Ab. Patients with systemic disease and higher disease activity had antibodies of all three isotypes of immunoglobulins or of IgG isotype. Remarkably, anti-dsDNA Ab of the IgA isotype, alone or associated with IgM, marked dermatological patients with low disease activity, but often with disquieting clinical and/or laboratory alterations.These results indicate a correlation between disease activity and both frequency and isotype of anti-dsDNA Ab.