tbuckley/cabot-search huggingface dataset:
Decreased Accessibility and Lack of Activation of ErbB2 in JIMT-1, a Herceptin-Resistant, MUC4-Expressing Breast Cancer Cell Line
Authors: Peter Nagy, Elza Friedländer, Minna Tanner, Anita I. Kapanen, Kermit L. Carraway, Jorma Isola, Thomas M. Jovin
Journal: Cancer Research (2005)

Overexpression of erbB2 in breast tumors is associated with poor prognosis and is a target of receptor-oriented cancer therapy. Trastuzumab (Herceptin), a monoclonal antibody against a membrane-proximal epitope in the extracellular region of erbB2, shows a therapeutic effect against a fraction of erbB2-amplified breast tumors. Unfortunately, resistance to Herceptin is common, and its cause is as yet unclear. Here we investigated the properties of erbB2 in a Herceptin-resistant cell line, JIMT-1, established from a breast cancer patient showing erbB2 gene amplification and primary resistance to Herceptin. The expression profile of erbB proteins, Herceptin-induced erbB2 internalization, and down-regulation in JIMT-1 were similar to those in Herceptin-sensitive lines. However, the mean number of Herceptin Mab binding sites in JIMT-1 was 1/5 that of the expressed erbB2 molecules, although 5% to 10% of the cells showed a approximately 10-fold higher Herceptin binding than the main population. Herceptin Fab and Mab 2C4, an antibody binding to an epitope in the ectodomain further removed from the membrane, bound more efficiently to JIMT-1 cells than Herceptin Mab, implying that erbB2 was partly masked. The expression of MUC4, a membrane-associated mucin that according to reports contributes to the masking of membrane proteins, was higher in JIMT-1 than in Herceptin-sensitive lines, and its level was inversely correlated with the Herceptin binding capacity of single cells. Knockdown of MUC4 expression by RNA interference increased the binding of Herceptin. Western blotting showed a low level of proteolytic processing, shedding, and tyrosine phosphorylation of erbB2 in JIMT-1. The latter finding may explain its Herceptin-resistant phenotype characterizing both the low and high Herceptin binding subpopulations. We conclude that masking of erbB2 in JIMT-1 leads to diminished Herceptin binding and isolation of erbB2 from its normal interaction and activation partners.
Rare diseases bullet 11: Churg-Strauss syndrome
Authors: M. Conron
Journal: Thorax (2000)

In 1951 the pathologists Churg and Strauss identified 13 patients who presented with a clinical syndrome characterised by asthma, hypereosinophilia, and evidence of vasculitis affecting a number of organs.1 The three main histological features found on pathological examination of these cases were extravascular granulomas, tissue eosinophilia, and necrotising vasculitis (fig 1). Most of these patients had been previously diagnosed with “periarteritis nodosa”. After reviewing a number of cases of periarteritis nodosa without asthma and finding no evidence of an eosinophilic granulomatous process, Churg and Strauss suggested that their 13 cases represented a separate disease process and coined the term “allergic granulomatosis and angiitis”. Later “Churg-Strauss syndrome” (CSS) became the accepted title of this distinctive form of systemic vasculitis. More recent pathological case series involving patients with CSS have highlighted the fact that not all patients have the three main histological features originally described by Churg and Strauss.2 3 Given the absence of a histological definition, it was proposed by Lanham et al that the following clinical criteria were required for the diagnosis of CSS: asthma, peripheral blood eosinophilia >1.5 × 109/l (or >10% of total white cell count), and evidence of a systemic vasculitis involving two or more extrapulmonary organs.2 More recently the American College of Rheumatology has developed diagnostic criteria for CSS when there is biopsy proven vasculitis.4 In this review we provide a clinical overview of CSS, review the evidence on which treatment protocols are based, and discuss the current understanding of the pathogenesis of the disease. In addition, we highlight recent controversies in the classification of systemic vasculitis and possible alternative management strategies.



Figure 1 
Open lung biopsy specimen from a patient with Churg-Strauss syndrome demonstrating the three main histological criteria originally described by Churg and Strauss. (A) Extravascular granulomas (arrowheads) are seen …
The cognitive economy: The probabilistic turn in psychology and human cognition
Authors: Petko Kusev, Paul van Schaik
Journal: Behavioral and Brain Sciences (2013)

According to the foundations of economic theory, agents have stable and coherent "global" preferences that guide their choices among alternatives. However, people are constrained by information-processing and memory limitations and hence have a propensity to avoid cognitive load. We propose that this in turn will encourage them to respond to "local" preferences and goals influenced by context and memory representations.
Association Between Prescription Co-Payment Amount and Compliance With Adjuvant Hormonal Therapy in Women With Early-Stage Breast Cancer
Authors: Alfred I. Neugut, Milayna Subar, Elizabeth Ty Wilde, Scott Stratton, Corey H. Brouse, Grace Clarke Hillyer, Victor R. Grann, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2011)

Purpose Noncompliance with adjuvant hormonal therapy among women with breast cancer is common. Little is known about the impact of financial factors, such as co-payments, on noncompliance. Patients and Methods We conducted a retrospective cohort study by using the pharmacy and medical claims database at Medco Health Solutions. Women older than age 50 years who were taking aromatase inhibitors (AIs) for resected breast cancer with two or more mail-order prescriptions, from January 1, 2007, to December 31, 2008, were identified. Patients who were eligible for Medicare were analyzed separately. Nonpersistence was defined as a prescription supply gap of more than 45 days without subsequent refill. Nonadherence was defined as a medication possession ratio less than 80% of eligible days. Results Of 8,110 women younger than age 65 years, 1,721 (21.1%) were nonpersistent and 863 (10.6%) were nonadherent. Among 14,050 women age 65 years or older, 3,476 (24.7%) were nonpersistent and 1,248 (8.9%) were nonadherent. In a multivariate analysis, nonpersistence (ever/never) in both age groups was associated with older age, having a non-oncologist write the prescription, and having a higher number of other prescriptions. Compared with a co-payment of less than $30, a co-payment of $30 to $89.99 for a 90-day prescription was associated with less persistence in women age 65 years or older (odds ratio [OR], 0.69; 95% CI, 0.62 to 0.75) but not among women younger than age 65, although a co-payment of more than $90 was associated with less persistence both in women younger than age 65 (OR, 0.82; 95% CI, 0.72 to 0.94) and those age 65 years or older (OR, 0.72; 95% CI, 0.65 to 0.80). Similar results were seen with nonadherence. Conclusion We found that higher prescription co-payments were associated with both nonpersistence and nonadherence to AIs. This relationship was stronger in older women. Because noncompliance is associated with worse outcomes, future policy efforts should be directed toward interventions that would help patients with financial difficulties obtain life-saving medications.
AZD8055 Is a Potent, Selective, and Orally Bioavailable ATP-Competitive Mammalian Target of Rapamycin Kinase Inhibitor with <i>In vitro</i> and <i>In vivo</i> Antitumor Activity
Authors: Christine M. Chresta, Barry R. Davies, Ian Hickson, Tom Harding, Sabina Cosulich, Susan E. Critchlow, John P. Vincent, Rebecca Ellston, Darren Jones, Patrizia Sini, Dominic James, Zoe Howard, Phillippa Dudley, Gareth Hughes, Lisa Smith, Sharon Maguire, Marc Hummersone, Karine Malagu, Keith Menear, Richard Jenkins, Matt Jacobsen, Graeme C.M. Smith, Sylvie Guichard, Martin Pass
Journal: Cancer Research (2009)

The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, cell survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, with an IC50 of 0.8 nmol/L. AZD8055 showed excellent selectivity (approximately 1,000-fold) against all class I phosphatidylinositol 3-kinase (PI3K) isoforms and other members of the PI3K-like kinase family. Furthermore, there was no significant activity against a panel of 260 kinases at concentrations up to 10 micromol/L. AZD8055 inhibits the phosphorylation of mTORC1 substrates p70S6K and 4E-BP1 as well as phosphorylation of the mTORC2 substrate AKT and downstream proteins. The rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1 were fully inhibited by AZD8055, resulting in significant inhibition of cap-dependent translation. In vitro, AZD8055 potently inhibits proliferation and induces autophagy in H838 and A549 cells. In vivo, AZD8055 induces a dose-dependent pharmacodynamic effect on phosphorylated S6 and phosphorylated AKT at plasma concentrations leading to tumor growth inhibition. Notably, AZD8055 results in significant growth inhibition and/or regression in xenografts, representing a broad range of human tumor types. AZD8055 is currently in phase I clinical trials.
Differing platelet aggregating effects by two tumor cell lines: Absence of role for platelet‐derived ADP
Authors: Eva Bastida, Antonio Ordinas, G. A. Jamieson
Journal: American Journal of Hematology (1981)

Abstract Two different mechanisms of aggregation of heparinized human platelet‐rich plasma have been identified with two tumor cell lines: In neither case are these mechanisms dependent on platelet‐derived ADP. U87MG cells from a glioblastoma line of human origin caused a single irreversible wave of aggregation simultaneously with the onset of platelet secretion, and this was inhibited by heparin and hirudin but not by apyrase or phospholipase D. In contrast, Hut 20 cells from an undifferentiated tumor cell line of murine origin gave an initial reversible wave followed by a second irreversible wave, which then led to secretion. The first wave of platelet aggregation was unaffected by heparin or hirudin but was inhibited by apyrase, and the second wave was inhibited by phospholipase D. Citrate caused irreversible inhibition with either cell line, and aggregation did not occur with gel filtered platelets. These results suggest that platelet aggregation by the Hut 20 line is initially dependent on ADP released from the tumor cells, whereas aggregation induced by the U87MG line is dependent on a procoagulant activity of the tumor cell surface.
PREPARATION OF A STABLE HUMAN PLASMA PROTEIN SOLUTION 1
Authors: Dwight J. Mulford, Edward H. Mealey, Lewis D. Welton
Journal: Journal of Clinical Investigation (1955)

Studies on the effect of heat on the virus of se- rum hepatitis have shown that a mixture of nor- mal serum albumin and proved icterogenic plasma failed to produce serum hepatitis when inoculated into volunteers after it had been heated at 600C. for 10 hours (1).Studies by Murray and Diefen- bach (2) on the effect of heating infected plasma pools showed that after four hours heating at
End of life care services are in limbo after phasing out of Liverpool Care Pathway, MPs hear
Authors: A. O'Dowd
Journal: BMJ (2015)

<h3>Background</h3> There are valid tools to measure disease activity and damage in JSLE, but to date there is no gold standard. <h3>Objectives</h3> To test the correlation between two activity indices, the M-SLEDAI-2K and ECLAM, and their respective correlation to the Pediatric SLICC/ACR Damage Index (Ped-SDI) during standard care of JSLE patients. <h3>Methods</h3> M-SLEDAI-2K is a variant of the original SLEDAI-2K where a-DNA and complement testing is suppressed for feasibility of standard approach (Uribe et al., 2004). It has not been previously tested in JSLE. The tools were retrospectively scored during follow up and summarized by adjusted means and area under the curve (AUC). The Pediatric SLICC/ACR Damage Index (Ped-SDI) was scored during the last visit and only after the first year of follow up. Pearson correlation between the M-SLEDAI-2K and ECLAM and Spearman correlation between the M-SLEDAI-2K and ECLAM, respectively to Ped-SDI were calculated. ROC analysis tested discriminating properties of both activity indices in relation to Ped-SDI damage scores. <h3>Results</h3> Thirty seven patients with 11.2 years median age at diagnosis and 2.7 years median follow up were scored during 781 visits. The M-SLEDAI-2K and ECLAM adjusted means were highly correlated (r Pearson =0.78 and p&lt;0.0001; Figure 1). Similarly, a strong correlation was found for both at disease presentation and throughout disease course (r Spearman &gt;0.7 and p&lt;0.001). Correlation between the M-SLEDAI-2K and ECLAM respectively to Ped-SDI was moderate. Their respective ROC AUC were 0.74 and 0.73, and cutoff points of 3.62 and 1.28, discriminating Ped-SDI. <h3>Conclusions</h3> The strong correlation between the M-SLEDAI-2K and ECLAM on retrospective approach indicated that both tools may be equally useful for JSLE activity measure in clinical practice. <h3>References</h3> Uribe AG, Vilá LM, McGwin G Jr, Sanchez ML, Reveille JD, Alarcόn GS. The Systemic Lupus Activity Measure-revised, the Mexican Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and a modified SLEDAI-2K are adequate instruments to measure disease activity in systemic lupus erythematosus. J Rheumatol 2004; 31: 1934-40. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4135
Association of LDL Cholesterol, Non–HDL Cholesterol, and Apolipoprotein B Levels With Risk of Cardiovascular Events Among Patients Treated With Statins
Authors: S Matthijs Boekholdt, Benoit J Arsenault, Samia Mora, Terje R Pedersen, John C LaRosa, Paul J Nestel, R John Simes, Paul Durrington, Graham A Hitman, K M A Welch, David A DeMicco, Aeilko H Zwinderman, Michael B Clearfield, John R Downs, Andrew M Tonkin, Helen M Colhoun, Antonio M Gotto, Paul M Ridker, John J P Kastelein
Journal: JAMA (2012)

The associations of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB) levels with the risk of cardiovascular events among patients treated with statin therapy have not been reliably documented.To evaluate the relative strength of the associations of LDL-C, non-HDL-C, and apoB with cardiovascular risk among patients treated with statin therapy.Meta-analysis of individual patient data from randomized controlled statin trials in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up.Relevant trials were identified by a literature search updated through December 31, 2011. Investigators were contacted and individual patient data were requested and obtained for 62,154 patients enrolled in 8 trials published between 1994 and 2008.Hazard ratios (HRs) and corresponding 95% CIs for risk of major cardiovascular events adjusted for established risk factors by 1-SD increase in LDL-C, non-HDL-C, and apoB.Among 38,153 patients allocated to statin therapy, 158 fatal myocardial infarctions, 1678 nonfatal myocardial infarctions, 615 fatal events from other coronary artery disease, 2806 hospitalizations for unstable angina, and 1029 fatal or nonfatal strokes occurred during follow-up. The adjusted HRs for major cardiovascular events per 1-SD increase were 1.13 (95% CI, 1.10-1.17) for LDL-C, 1.16 (95% CI, 1.12-1.19) for non-HDL-C, and 1.14 (95% CI, 1.11-1.18) for apoB. These HRs were significantly higher for non-HDL-C than LDL-C (P = .002) and apoB (P = .02). There was no significant difference between apoB and LDL-C (P = .21).Among statin-treated patients, on-treatment levels of LDL-C, non-HDL-C, and apoB were each associated with risk of future major cardiovascular events, but the strength of this association was greater for non-HDL-C than for LDL-C and apoB.
Glucocorticoids Inhibit Cell Death in Ovarian Cancer and Up-regulate Caspase Inhibitor cIAP2
Authors: Ingo B. Runnebaum, Ansgar Brüning
Journal: Clinical Cancer Research (2005)

Almost all patients with epithelial ovarian cancer receive chemotherapy and, concurrently, the synthetic steroid hormone dexamethasone to alleviate the side effects. This study aims to test the impact of steroid hormones on the apoptosis of epithelial ovarian cancer cells and to identify its mediators.Tumor cell lines from 19 patients with advanced epithelial ovarian cancer were analyzed for glucocorticoid receptor, estrogen receptor, progesterone receptor, and androgen receptor expression. Cells were incubated with corresponding steroid hormones at serum-equivalent doses in hormone-depleted medium. Apoptosis was induced by application of tumor necrosis factor-related apoptosis-inducing ligand or staurosporine and determined by poly(ADP-ribose)polymerase cleavage and cell survival. Microarray with 8K cDNA chips including apoptosis-relevant genes was used to study genes regulated by glucocorticoids.In cell culture, tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in OV-MZ-30 and OV-MZ-31 cells was reduced after treatment with dexamethasone or cortisol, but not with estradiol, progesterone, or androstenedione. Microarray analysis revealed a 7-fold up-regulation of the caspase inhibitor cIAP2 by dexamethasone in OV-MZ-30 and OV-MZ-31 cells. cIAP2 up-regulation by glucocorticoids was confirmed by RT-PCR and Western blot analysis in OV-MZ-30, OV-MZ-31, OV-CAR3, and SK-OV-3 cells. Down-regulation of cIAP2 expression by small interfering RNA sensitized SK-OV-3 cells to apoptosis inducer staurosporine. Under clinical conditions, treatment with dexamethasone was associated with significant up-regulation of cIAP2 in the ascites cells.Activation of the glucocorticoid receptor in epithelial ovarian cancer cells caused an anti-apoptotic effect associated with the enhanced cellular expression level of cIAP2. Dexamethasone pretreatment of epithelial ovarian cancer patients receiving apoptosis-inducing chemotherapy raises questions about a negative effect on antitumor efficacy.
Comparison of Subcutaneous Versus Intravenous Administration of Rituximab As Maintenance Treatment for Follicular Lymphoma: Results From a Two-Stage, Phase IB Study
Authors: Antonio Salar, Irit Avivi, Beate Bittner, Reda Bouabdallah, Mike Brewster, Olivier Catalani, George Follows, Andrew Haynes, Florence Hourcade-Potelleret, Andrea Janikova, Jean-François Larouche, Christine McIntyre, Michael Pedersen, Juliana Pereira, Pakeeza Sayyed, Ofer Shpilberg, Gayane Tumyan
Journal: Journal of Clinical Oncology (2014)

Purpose This two-stage phase IB study investigated the pharmacokinetics and safety of subcutaneous (SC) versus intravenous (IV) administration of rituximab as maintenance therapy in follicular lymphoma. Patients and Methods In stage 1 (dose finding), 124 patients who responded to rituximab induction were randomly assigned to SC rituximab (375 mg/m 2 , 625 mg/m 2 , or an additional group at 800 mg/m 2 ) or IV rituximab (375 mg/m 2 ). The objective was to determine an SC dose that would yield a rituximab serum trough concentration (C trough ) in the same range as that of IV rituximab. In stage 2, 154 additional patients were randomly assigned (1:1) to SC rituximab (1,400 mg) or IV rituximab (375 mg/m 2 ) given at 2- or 3-month intervals. The objective was to demonstrate noninferior rituximab C trough of SC rituximab relative to IV rituximab 375 mg/m 2 . Results Stage 1 data predicted that a fixed dose of 1,400 mg SC rituximab would result in a serum C trough in the range of that of IV rituximab. Noninferiority (ie, meeting the prespecified 90% CI lower limit of 0.8) was then confirmed in stage 2, with geometric mean C trough SC :C trough IV ratios for the 2- and 3-month regimens of 1.24 (90% CI, 1.02 to 1.51) and 1.12 (90% CI, 0.86 to 1.45), respectively. Overall safety profiles were similar between formulations (in stage 2, 79% of patients experienced one or more adverse events in each group). Local administration-related reactions (mainly mild to moderate) occurred more frequently after SC administration. Conclusion The fixed dose of 1,400 mg SC rituximab predicted by using stage 1 results was confirmed to have noninferior C trough levels relative to IV rituximab 375 mg/m 2 dosing during maintenance, with a comparable safety profile. Additional investigation will be required to determine whether the SC route of administration for rituximab provides equivalent efficacy compared with that of IV administration.
THE EFFECT OF ANTIGENIC COMPETITION ON VARIOUS MANIFESTATIONS OF HUMORAL ANTIBODY FORMATION AND CELLULAR IMMUNITY
Authors: David Eidinger, Salahuddin A. Khan, Kenneth G. Millar
Journal: The Journal of Experimental Medicine (1968)

The effect of antigenic competition on various parameters of humoral antibody formation and cellular immunity was studied in mice. Several pairs of antigens were employed in the investigation of the competitive aspects of induction of humoral antibody formation. Induction of a primary immune response to hemocyanin in Swiss white female mice moderately suppressed the induction of both 19S and 7S antibody formation to goose or rat erythrocytes. Suppression of 7S antibody formation was maximal when a time interval of 1-3 days separated the sequence of injections, although suppression was noted for intervals of up to 14 days. The induction of a primary immune response to rat RBC, the second of the two antigens in sequence, also suppressed The induction of both 19S and 7S antibody formation to goose RBC when appropriate intervals of 1-3 days were employed between injections. The induction of a secondary immune response to rat RBC totally suppressed the primary induction of both 19S and 7S antibody formation to goose RBC administered in the appropriate time sequence. Subsequently, it was shown that the secondary immune response to the suppressed antigen (goose RBC) elicited 30 days after induction of a primary immune response (5 days after secondary immunization with rat RBC) was characterized by deficient 19S and 7S antibody production. These levels were suppressed even in comparison with a normal primary immune response to this antigen. The results were interpreted in part on the basis of a deficiency of formation of primed cells associated with immunological memory. Alternatively, evidence was obtained for the development of a split type of immunological tolerance in 6 of 10 animals studied, since a total suppression of 7S antibody production was obtained in association with deficient 19S antibody synthesis (titers < 1/10). The induction of a primary immune response to several antigens in A/J female mice suppressed the processes of cellular immunity as manifested by prolonged survival of skin grafts from C57 BL/6J female donors. These results were interpreted as evidence for the existence and utilization of processing cells by the initial immune stimulus yielding a deficiency of cells available for processing the second antigen administered in sequence.