tbuckley/cabot-search huggingface dataset:
Membrane Expression of Proteinase 3 Is Genetically Determined
Authors: Adrian Schreiber, Andreas Busjahn, Friedrich C. Luft, Ralph Kettritz
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Isolated human neutrophils exhibit a bimodal membrane proteinase 3 (PR3) expression. PR3 is the main target antigen in Wegener granulomatosis (WG). Cells with low expression can be easily distinguished from cell subsets with high expression. In a recent study, a large neutrophil subset expressing membrane PR3 (mPR3+) was a risk factor for systemic ANCA-associated vasculitis. PR3 membrane expression patterns are quite stable in a given individual, raising the possibility of genetic variance. The aims of this study were: (1) to investigate the association of mPR3 expression and the risk of WG in an independent German cohort; (2) to test the hypothesis that mPR3 expression on neutrophils is genetically influenced; and (3) to investigate whether or not mPR3 expression is a function of intracellular PR3 content. mPR3 expression was assessed by FACS analysis in isolated human neutrophils. Neutrophil mPR3 expression was studied in 35 patients with WG, 15 patients with other inflammatory diseases, 125 healthy volunteers, and 27 (15 monozygotic and 12 dizygotic) pairs of twins. The intracellular PR3 content was assessed by intracellular flow cytometry and by Western blotting after separating mPR3 low and high expressing cells by FACSort. FACS analysis in a subset of 16 healthy subjects showed a highly conserved PR3 phenotype in two independent investigations >12 mo apart (r = 0.937). Patients with WG demonstrated a significantly higher percentage of mPR3+ neutrophils than healthy controls and patients with other inflammatory diseases. The mPR3+ percentage was highly correlated in MZ twins (r = 0.99) compared with DZ twins (r = 0.06). The intracellular PR3 content was not different in persons with low or high mPR3 expression, nor was the PR3 content different in cells with low or high mPR3 expression within a given individual. These data indicate that WG patients have a higher percentage of mPR3-expressing neutrophils. Furthermore, mPR3 expression is influenced by genetic variance. Finally, mPR3 expression is independent of intracellular PR3 content. E-mail [email protected]
Effect of terbutaline on bronchoconstriction induced by nebulised pentamidine.
Authors: T R Leigh, J Wiggins, B G Gazzard, J V Collins
Journal: Thorax (1991)

The severity, duration, and reversibility of pentamidine induced bronchial narrowing was studied with and without pretreatment with nebulised terbutaline 10 mg in an open study of 40 patients seropositive for the human immunodeficiency virus (HIV). All subjects received pentamidine 300 mg in 5 ml water via an Acorn System 22 jet nebuliser. The forced expiratory volume in one second (FEV1) fell in all 20 patients given pentamidine alone, the mean maximum fall being 20.6%. In the 20 patients given pentamidine preceded by nebulised terbutaline the mean maximum fall in FEV1 was 4%; three subjects had a fall in FEV1 of more than 10%.
Aurora A and B Overexpression and Centrosome Amplification in Early Estrogen-Induced Tumor Foci in the Syrian Hamster Kidney: Implications for Chromosomal Instability, Aneuploidy, and Neoplasia
Authors: Adrianne E. Hontz, Sara Antonia Li, Wilma L. Lingle, Vivian Negron, Amy Bruzek, Jeffrey L. Salisbury, Jonathan J. Li
Journal: Cancer Research (2007)

Abstract Estrogen-induced Syrian hamster tumors in the kidney represent a useful model to gain insight into the role of estrogens in oncogenic processes. We provided evidence that early tumor foci in the kidney arise from interstitial ectopic uterine-like germinal stem cells, and that early tumor foci and well-established tumors are highly aneuploid (92–94%). The molecular mechanisms whereby estrogens mediate this process are unclear. Here, we report that estrogen treatment induced significant increases in Aurora A protein expression (8.7-fold), activity (2.6-fold), mRNA (6.0-fold), and Aurora B protein expression (4.6-fold) in tumors, compared with age-matched cholesterol-treated kidneys. Immunohistochemistry revealed that this increase in Aurora A and B protein expression was essentially confined to cells within early and large tumor foci at 3.5 and 6 months of estrogen treatment, respectively. Upon estrogen withdrawal or coadministration of tamoxifen for 10 days, a 78% to 79% and 81% to 64% reduction in Aurora A and B expression, respectively, were observed in primary tumors compared with tumors continuously exposed to estrogens. These data indicate that overexpressed Aurora A and B in these tumors are under estrogen control via estrogen receptor α. Aurora A coenriched with the centrosome fraction isolated from tumors in the kidney. Centrosome amplification (number and area/cell) was detected in early tumor foci and large tumors but not in adjacent uninvolved or age-matched control kidneys. Taken together, these data indicate that persistent overexpression of Aurora A and B is under estrogen control, and is coincident with centrosome amplification, chromosomal instability, and aneuploidy, and represent an important mechanism driving tumorigenesis. [Cancer Res 2007;67(7):2957–63]
Inhibition of mTOR Activity Restores Tamoxifen Response in Breast Cancer Cells with Aberrant Akt Activity
Authors: Linda A. deGraffenried, William E. Friedrichs, Douglas H. Russell, Elissa J. Donzis, Amanda K. Middleton, Jessica M. Silva, Richard A. Roth, Manuel Hidalgo
Journal: Clinical Cancer Research (2004)

Abstract The Akt kinase is a serine/threonine protein kinase that has been implicated in mediating a variety of biological responses. Studies show that high Akt activity in breast carcinoma is associated with a poor pathophenotype, as well as hormone and chemotherapy resistance. Additionally, high Akt activity is associated with other features of poor prognosis. Thus, a chemotherapeutic agent directed specifically toward tumors with high Akt activity could prove extremely potent in treating those breast tumors with the most aggressive phenotypes. Several studies have demonstrated that rapamycin, which inhibits mammalian target of rapamycin (mTOR), a downstream target of Akt, sensitizes certain resistant cancer cells to chemotherapeutic agents. This study evaluated the efficacy of mTOR inhibition in the treatment of tamoxifen-resistant breast carcinoma characterized by high Akt activity. We found that MCF-7 breast cancer cell lines expressing a constitutively active Akt are able to proliferate under reduced estrogen conditions and are resistant to the growth inhibitory effects of tamoxifen, both in vitro as well as in vivo in xenograft models. Cotreatment with the mTOR inhibitor rapamycin in vitro, or the ester of rapamycin, CCI-779 (Wyeth) in vivo, inhibited mTOR activity and restored sensitivity to tamoxifen, suggesting that Akt-induced tamoxifen resistance is mediated in part by signaling through the mTOR pathway. Although the mechanism underlying the synergism remains to be understood, the results were associated with rapamycin’s ability to block transcriptional activity mediated by estrogen receptor α, as assessed by reporter gene assays with estrogen-responsive element luciferase. These data corroborate prior findings indicating that Akt activation induces resistance to tamoxifen in breast cancer cells. Importantly, these data indicate a novel mechanism for tamoxifen resistance and suggest that blockage of the phosphatidylinositol 3′-kinase/Akt signaling pathway by mTOR inhibition effectively restores the susceptibility of these cells to tamoxifen. These data may have implication for future clinical studies of mTOR inhibition in breast carcinoma.
CORRELATIVE OBSERVATIONS ON CEREBRAL METABOLISM AND CARDIAC OUTPUT IN MYXEDEMA 1
Authors: P. Scheinberg, E. A. Stead, E. S. Brannon, J. V. Warren
Journal: Journal of Clinical Investigation (1950)

Patients with myxedema present an unusual op- portunity for studying the effect of lowered metabolism on organ blood flow and for observing the effect of changes in peripheral circulation on cardiac output.Studies of cerebral metabolism in myxedema are of interest to the physician be- cause changes in cerebral metabolism may be of importance in understanding the alterations in mental status which occur with this disease (1-3).The cerebral blood flow was measured by the ni- trous oxide method of Kety and Schmidt (4) in eight patients with myxedema.The cardiac out- put was measured by the technique of right atrial catheterization in seven other patients with myxedema. METHODThe diagnosis of myxedema was a clinical one, de- pending upon the history and physical findings, and supported by laboratory data.The basal metabolic rates were abnormally low and the serum cholesterol levels ab- normally high in all of the patients.The right atrial pressure was increased in one patient (P.B., Table I).No attempt was made to evaluate the mental status of the patients in whom the cardiac output was measured.Com- plete mental status examinations, with particular at- tention to level of awareness, were performed on all the subjects in the cerebral blood flow group.These were arbitrarily graded from 1+, indicating personality changes, memory defects, and inability to concentrate, to 3+, which indicated disorientation and confusion.One of the patients (M.M., Table II) was frankly psychotic, with delusions and hallucinations.Neither she nor E. M. remembered their previous studies when they returned for re-examination.Electroencephalograms were done on five of the patients on whom cerebral blood flow was measured.Cardiac output was measured by the method of right heart catheterization utilizing the direct Fick principle (5, 6).The samples of mixed venous blood were taken from the right atrium, and the femoral arterial pressure
Interleukin 1 induces gastric epithelial cell matrix metalloproteinase secretion and activation during Helicobacter pylori infection
Authors: M Gooz
Journal: Gut (2003)

<b>Background and aims:</b> Matrix metalloproteinases (MMPs) are endopeptidases with roles in extracellular matrix remodelling, cell proliferation, and inflammatory processes. We showed previously that <i>Helicobacter pylori</i> infection of human gastric adenocarcinoma (AGS) cells increased epithelial secretion of epithelial MMP-1 and MMP-3 and bacterial secretion of MMP-3-like activity. In the present study, we sought to characterise the role of interleukin (IL)-1β in <i>H pylori</i> induced secretion of epithelial MMPs. <b>Methods and results:</b> AGS cells were treated with <i>H pylori</i> and/or IL-1β. Comparable IL-8 secretory responses (∼1700 ng/ml) measured by ELISA were induced by 2.0 ng/ml IL-1β and by <i>H pylori</i> at a multiplicity of infection (MOI) of 50. The same IL-1β and <i>H pylori</i> concentrations induced comparable increases in AGS cell caseinolytic activity at 60 kDa. MMP-3 monoclonal antibody immunoblots of AGS cell conditioned media detected immunoreactive bands at 71 kDa and 56 kDa. <i>H pylori</i> (MOI=50–100) induced dose dependent increases in both bands whereas IL-1β (0.2–2 ng/ml) induced dose dependent increases only in the 71 kDa band, which was identified as a MMP-3/TIMP-3 (tissue inhibitor of metalloproteinases 3) heterodimer. AGS/<i>H pylori</i> conditioned media expressed 24 times more MMP-3 activity than AGS/IL-1β conditioned media. There was a strong interaction between IL-1β and <i>H pylori</i> on MMP-3 secretion. <b>Conclusions:</b> We conclude that IL-1β induces gastric epithelial cell MMP-3 secretion, contributing to epithelial tissue destruction during <i>H pylori</i> infection. However, other bacterial/host factors are needed to mediate the full gastric epithelial cell MMP-3 secretory response induced by <i>H pylori</i> infection.
Bone tissue formation with human mesenchymal stem cells and biphasic calcium phosphate ceramics: The local implication of osteoclasts and macrophages
Authors: Anne-Laure Gamblin, Meadhbh A. Brennan, Audrey Renaud, Hideo Yagita, Frédéric Lézot, Dominique Heymann, Valérie Trichet, Pierre Layrolle
Journal: Biomaterials (2014)

Human mesenchymal stem cells (hMSC) have immunomodulative properties and, associated with calcium phosphate (CaP) ceramics, induce bone tissue repair. However, the mechanisms of osteoinduction by hMSC with CaP are not clearly established, in particular the role of osteoclasts and macrophages. Biphasic calcium phosphate (BCP) particles were implanted with or without hMSC in the paratibial muscles of nude mice. hMSC increased osteoblastic gene expression at 1 week, the presence of macrophages at 2 and 4 weeks, osteoclastogenesis at 4 and 8 weeks, and osteogenesis at 4 and 8 weeks. hMSC disappeared from the implantation site after 2 weeks, indicating that hMSC were inducers rather than effectors of bone formation. Induced blockage of osteoclastogenesis by anti-Rankl treatment significantly impaired bone formation, revealing the pivotal role of osteoclasts in bone formation. In summary, hMSC positively influence the body foreign reaction by attracting circulating haematopoietic stem cells and inducing their differentiation into macrophages M1 and osteoclasts, thus favouring bone formation.
Treatment of Complicated Grief in Elderly Persons
Authors: M. Katherine Shear, Yuanjia Wang, Natalia Skritskaya, Naihua Duan, Christine Mauro, Angela Ghesquiere
Journal: JAMA Psychiatry (2014)

Complicated grief (CG) is a debilitating condition, most prevalent in elderly persons. However, to our knowledge, no full-scale randomized clinical trial has studied CG in this population.To determine whether complicated grief treatment (CGT) produces greater improvement in CG and depressive symptoms than grief-focused interpersonal psychotherapy (IPT).Randomized clinical trial enrolling 151 individuals 50 years or older (mean [SD] age, 66.1 [8.9] years) scoring at least 30 on the Inventory of Complicated Grief (ICG). Participants were recruited from the New York metropolitan area from August 20, 2008, through January 7, 2013, and randomized to receive CGT or IPT. The main outcome was assessed at 20 weeks after baseline, with interim measures collected at 8, 12, and 16 weeks after baseline.Sixteen sessions of CGT (n = 74) or IPT (n = 77) delivered approximately weekly.Rate of treatment response, defined as a rating from an independent evaluator of much or very much improved on the Improvement subscale of the Clinical Global Impression Scale.Both treatments produced improvement in CG symptoms. Response rate for CGT (52 individuals [70.5%]) was more than twice that for IPT (24 [32.0%]) (relative risk, 2.20 [95% CI, 1.51-3.22]; P < .001), with the number needed to treat at 2.56. Secondary analyses of CG severity and CG symptom and impairment questionnaire measures confirmed that CGT conferred a significantly greater change in illness severity (22 individuals [35.2%] in the CGT group vs 41 [64.1%] in the IPT group were still at least moderately ill [P = .001]), rate of CG symptom reduction (1.05 ICG points per week for CGT vs 0.75 points per week for IPT [t633 = 3.85; P < .001]), and the rate of improvement in CG impairment (0.63 work and Social Adjustment Scale points per week with CGT and 0.39 points per week with IPT [t503 = 2.87; P = .004]). Results were not moderated by participant age.Complicated grief treatment produced clinically and statistically significantly greater response rates for CG symptoms than a proven efficacious treatment for depression (IPT). Results strongly support the need for physicians and other health care providers to distinguish CG from depression. Given the growing elderly population, the high prevalence of bereavement in aging individuals, and the marked physical and psychological impact of CG, clinicians need to know how to treat CG in older adults.clinicaltrials.gov Identifier: NCT01244295.
Olive green or chestnut brown?
Authors: Rolf G. Kuehni
Journal: Behavioral and Brain Sciences (2003)

Abstract Reflectance and spectral power functions are poor predictors of color experiences. Only in completely relativized conditions (single observer, non-metameric set of stimuli, and single set of viewing conditions) is the relationship close. Variation in reflectance of Munsell chips experienced by color-normal observers as having a unique green hue encompasses approximately sixty percent of the complete range of hues falling under the category “green”; and in recent determinations of unique hues, ranges of yellow and green as well as green and blue unique hues overlap.
Comparative Preclinical and Clinical Pharmacokinetics of a Cremophor-Free, Nanoparticle Albumin-Bound Paclitaxel (ABI-007) and Paclitaxel Formulated in Cremophor (Taxol)
Authors: Alex Sparreboom, Charity D. Scripture, Vuong Trieu, Paul J. Williams, Tapas De, Andrew Yang, Bridget Beals, William D. Figg, Michael Hawkins, Neil Desai
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To compare the preclinical and clinical pharmacokinetic properties of paclitaxel formulated as a Cremophor-free, albumin-bound nanoparticle (ABI-007) and formulated in Cremophor-ethanol (Taxol). Experimental Design: ABI-007 and Taxol were given i.v. to Harlan Sprague-Dawley male rats to determine pharmacokinetic and drug disposition. Paclitaxel pharmacokinetic properties also were assessed in 27 patients with advanced solid tumors who were randomly assigned to treatment with ABI-007 (260 mg/m2, 30 minutes; n = 14) or Taxol (175 mg/m2, 3 hours; n = 13), with cycles repeated every 3 weeks. Results: The volume of distribution at steady state and clearance for paclitaxel formulated as Cremophor-free nanoparticle ABI-007 were significantly greater than those for paclitaxel formulated with Cremophor (Taxol) in rats. Fecal excretion was the main elimination pathway with both formulations. Consistent with the preclinical data, paclitaxel clearance and volume of distribution were significantly higher for ABI-007 than for Taxol in humans [21.13 versus 14.76 L/h/m2 (P = 0.048) and 663.8 versus 433.4 L/m2 (P = 0.040), respectively]. Conclusions: Paclitaxel formulated as ABI-007 differs from paclitaxel formulated as Taxol, with a higher plasma clearance and a larger volume of distribution. This finding is consistent with the absence of paclitaxel-sequestering Cremophor micelles after administration of ABI-007. This unique property of ABI-007 could be important for its therapeutic effectiveness.
Variation in referral practice and differential cancer outcome: a strong reason to reflect on whether current guidelines are fit for purpose or implemented effectively in primary care
Authors: Keith Bodger, Mustafa Shawihdi,
Journal: Gut (2013)

We thank the authors for their interest in our research1 which has attracted both professional and public media interest.2–4 Certainly, we accept that epidemiological studies can be at risk of ‘ecological fallacy’ and cannot adjust for all possible confounders. We make no claim that association proves causality. However, in offering a generic note of caution, Ford et al provide no specific hypothesis or insight to explain why the associations illustrated in our particular study could be explained by unacknowledged bias or an artefact of data aggregation. Taking the logic from their example, the counter hypothesis for our findings would be that people who are destined for a poor cancer outcome were selectively choosing to register at a general practice with a low gastroscopy rate—this seems unlikely.

We took great care to explore potential bias in our approach to data aggregation by undertaking extensive sensitivity analyses.5 Each case of oesophagogastric cancer was assigned a range of alternative …
Attenuated cardiac contractile responsiveness to insulin-like growth factor I in ventricular myocytes from biobreeding spontaneous diabetic rats
Authors: J Ren
Journal: Cardiovascular Research (2000)

Objective: Insulin-like growth factor I (IGF-1) stimulates cardiac growth and contraction, but resistance to its action has been reported in diabetes. This study was to determine if IGF-1-induced cardiac contractile action is altered in rats genetically predisposed to diabetes. Method: Ventricular myocytes were isolated from spontaneously biobreeding diabetes-prone (BB/DP) rats and their diabetes-resistant littermates (BB/DR). Mechanical properties were evaluated in cardiomyocytes using a video-based edge-detection system. Myocytes were electrically stimulated at 0.5 Hz. Contractile properties analyzed included peak shortening (PS), time-to-PS (TPS) and time-to-90% relengthening (TR90). Intracellular Ca2+ transients were measured as changes in fura-2 fluorescence intensity (ΔFFI). Results: Myocytes from BB/DP rats displayed increased PS, prolonged TPS and TR90, as well as reduced resting FFI compared to the BB/DR group. IGF-1 (10−10–10−6 M) caused a dose-dependent increase in PS in myocytes from BB/DR but not BB/DP rats. The increase of PS was blunted by IGF-1 antagonist H-1356, phosphatidylinositol-3 (PI-3) kinase inhibitor wortmannin, but not tyrosine kinase inhibitor genistein. None of these agents affected responses to IGF-1 in BB/DP myocytes. Interestingly, IGF-1 elicited a comparable dose-dependent increase in Ca2+ transients in myocytes from both BB/DR and BB/DP rats. Conclusion: These results suggest that the attenuation of IGF-1-induced cardiac contractile response in chemically-induced diabetes also exists in diabetes of genetic origin, possibly due to mechanisms involving PI-3 kinase and intracellular Ca2+ sensitivity.
Transforming Growth Factor-β Suppresses the Ability of Ski to Inhibit Tumor Metastasis by Inducing Its Degradation
Authors: Erwan Le Scolan, Qingwei Zhu, Long Wang, Abhik Bandyopadhyay, Delphine Javelaud, Alain Mauviel, LuZhe Sun, Kunxin Luo
Journal: Cancer Research (2008)

Abstract c-Ski is an important corepressor of transforming growth factor-β (TGF-β) signaling through its ability to bind to and repress the activity of the Smad proteins. It was initially identified as an oncogene that promotes anchorage-independent growth of chicken and quail embryo fibroblasts when overexpressed. Although increased Ski expression is detected in many human cancer cells, the roles of Ski in mammalian carcinogenesis have yet to be defined. Here, we report that reducing Ski expression in breast and lung cancer cells does not affect tumor growth but enhances tumor metastasis in vivo. Thus, in these cells, Ski plays an antitumorigenic role. We also showed that TGF-β, a cytokine that is often highly expressed in metastatic tumors, induces Ski degradation through the ubiquitin-dependent proteasome in malignant human cancer cells. On TGF-β treatment, the E3 ubiquitin ligase Arkadia mediates degradation of Ski in a Smad-dependent manner. Although Arkadia interacts with Ski in the absence of TGF-β, binding of phosphorylated Smad2 or Smad3 to Ski is required to induce efficient degradation of Ski by Arkadia. Our results suggest that the ability of TGF-β to induce degradation of Ski could be an additional mechanism contributing to its protumorigenic activity. [Cancer Res 2008;68(9):3277–85]