tbuckley/cabot-search huggingface dataset:
IMPLICATIONS OF THE RESULTS OF COMMUNITY INTERVENTION TRIALS
Authors: Glorian Sorensen, Karen Emmons, Mary Kay Hunt, Douglas Johnston
Journal: Annual Review of Public Health (1998)

▪ Abstract This paper examines the results of population-level interventions conducted in three settings: entire communities, worksites, and schools. Four major conclusions are discussed: (a) Directions for the next generation of community-based interventions include targeting multiple levels of influence; addressing social inequalities in disease risk; involving communities in program planning and implementation; incorporating approaches for “tailoring” interventions; and utilizing rigorous process evaluation. (b) In addition to randomized controlled trials, it is time to use the full range of research phases available, from hypothesis generation and methods development to dissemination research. (c) The public health research agenda may have contributed to observed secular trends by placing behavioral risk factors on the social and media agendas. (d) The magnitude of the results of community intervention trials must be judged according to their potential public health or population-level effects. Small changes at the individual level may result in large benefits at the population level.
Magnetic Resonance T <sub>1</sub> Relaxation Time of Venous Thrombus Is Determined by Iron Processing and Predicts Susceptibility to Lysis
Authors: Prakash Saha, Marcelo E. Andia, Bijan Modarai, Ulrike Blume, Julia Humphries, Ashish S. Patel, Alkystis Phinikaridou, Colin E. Evans, Katherine Mattock, Steven P. Grover, Anwar Ahmad, Oliver T. Lyons, Rizwan Q. Attia, Thomas Renné, Sobath Premaratne, Andrea J. Wiethoff, René M. Botnar, Tobias Schaeffter, Matthew Waltham, Alberto Smith
Journal: Circulation (2013)

The magnetic resonance longitudinal relaxation time (T1) changes with thrombus age in humans. In this study, we investigate the possible mechanisms that give rise to the T1 signal in venous thrombi and whether changes in T1 relaxation time are informative of the susceptibility to lysis.Venous thrombosis was induced in the vena cava of BALB/C mice, and temporal changes in T1 relaxation time correlated with thrombus composition. The mean T1 relaxation time of thrombus was shortest at 7 days following thrombus induction and returned to that of blood as the thrombus resolved. T1 relaxation time was related to thrombus methemoglobin formation and further processing. Studies in inducible nitric oxide synthase (iNOS(-/-))-deficient mice revealed that inducible nitric oxide synthase mediates oxidation of erythrocyte lysis-derived iron to paramagnetic Fe3+, which causes thrombus T1 relaxation time shortening. Studies using chemokine receptor-2-deficient mice (Ccr2(-/-)) revealed that the return of the T1 signal to that of blood is regulated by removal of Fe3+ by macrophages that accumulate in the thrombus during its resolution. Quantification of T1 relaxation time was a good predictor of successful thrombolysis with a cutoff point of <747 ms having a sensitivity and specificity to predict successful lysis of 83% and 94%, respectively.The source of the T1 signal in the thrombus results from the oxidation of iron (released from the lysis of trapped erythrocytes in the thrombus) to its paramagnetic Fe3+ form. Quantification of T1 relaxation time appears to be a good predictor of the success of thrombolysis.
Dynamics of Major Histocompatibility Complex Class II Compartments during B Cell Receptor–mediated Cell Activation
Authors: Danielle Lankar, Hélène Vincent-Schneider, Volker Briken, Takeaki Yokozeki, Graça Raposo, Christian Bonnerot
Journal: The Journal of Experimental Medicine (2002)

Antigen recognition by clonotypic B cell receptor (BcR) is the first step of B lymphocytes differentiation into plasmocytes. This B cell function is dependent on efficient major histocompatibility complex (MHC) class II–restricted presentation of BcR-bound antigens. In this work, we analyzed the subcellular mechanisms underlying antigen presentation after BcR engagement on B cells. In quiescent B cells, we found that MHC class II molecules mostly accumulated at the cell surface and in an intracellular pool of tubulovesicular structures, whereas H2-M molecules were mostly detected in distinct lysosomal compartments devoid of MHC class II. BcR stimulation induced the transient intracellular accumulation of MHC class II molecules in newly formed multivesicular bodies (MVBs), to which H2-M was recruited. The reversible downregulation of cathepsin S activity led to the transient accumulation of invariant chain–MHC class II complexes in MVBs. A few hours after BcR engagement, cathepsin S activity increased, the p10 invariant chain disappeared, and MHC class II–peptide complexes arrived at the plasma membrane. Thus, BcR engagement induced the transient formation of antigen-processing compartments, enabling antigen-specific B cells to become effective antigen-presenting cells.
A prospective randomised controlled trial comparing the efficacy of somatostatin with injection sclerotherapy in the control of bleeding oesophageal varices
Authors: R. Shields, S.A. Jenkins, J.N. Baxter, A.N. Kingsnorth, S. Ellenbogen, C.A. Makin, I. Gilmore, A.I. Morris, D. Ashby, C.R. West
Journal: Journal of Hepatology (1992)
Inflammation, Immunity, and HMG-CoA Reductase Inhibitors
Authors: Uwe Schönbeck, Peter Libby
Journal: Circulation (2004)

According to traditional thinking, atherosclerosis results from passive lipid deposition in the vascular wall. Thus, therapies predominantly targeted lipid metabolism. The contemporary view of atherosclerosis, however, has broadened to include an active and complex role for inflammation, orchestrated in part by mediators of the immune system. This recognition prompted the question of whether antiinflammatory interventions might provide a novel avenue for the treatment of atherosclerosis. Uncertainties about the type of antiinflammatory regimen and appropriate patient selection currently hamper clinical investigation. Yet cardiovascular scientists have begun to address these questions at the bench, in experimental models, and indirectly in humans. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A HMG-CoA reductase (statins) have emerged as promising tools with dual functions. Originally designed to target elevated lipids, the “traditional” cause of atherosclerosis, statins might also confer cardiovascular benefit by directly or indirectly modulating the inflammatory component of this prevalent disease. Yet controversy persists regarding the (clinical) relevance of these potential non–LDL-lowering “pleiotropic” functions of statins. This overview addresses the controversy by reviewing in vitro and in vivo evidence regarding statins as antiinflammatory agents.
EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors
Authors: Dalia Ercan, Hwan Geun Choi, Cai-Hong Yun, Marzia Capelletti, Ting Xie, Michael J. Eck, Nathanael S. Gray, Pasi A. Jänne
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Mutant selective irreversible pyrimidine-based EGFR kinase inhibitors, including WZ4002, CO-1686, and AZD9291, are effective in preclinical models and in lung cancer patients harboring the EGFR T790M gefitinib/erlotinib resistance mutation. However, little is known about how cancers develop acquired resistance to this class of EGFR inhibitors. We sought to identify and study EGFR mutations that confer resistance to this class of agents. Experimental Design: We performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen in EGFR-mutant (sensitizing alone or with concurrent EGFR T790M) Ba/F3 cells and selected drug-resistant clones. We evaluated the sensitivity of EGFR inhibitors in models harboring drug-resistant EGFR mutations. Results: We identified 3 major drug resistance mutations. EGFR L718Q, L844V, and C797S cause resistance to both WZ4002 and CO-1686 while, in contrast, only EGFR C797S leads to AZD9291 resistance. Cells containing an EGFR-sensitizing mutation, Del 19 or L858R, in conjunction with L718Q, L844V, or C797S retain sensitivity to quinazoline-based EGFR inhibitors, gefitinib and afatinib. The C797S mutation, in the presence of Del 19 or L858R and T790M, causes resistance to all current EGFR inhibitors, but L858R/T790M/C797S remains partially sensitive to cetuximab which leads to disruption of EGFR dimerization. Conclusions: Our findings provide insights into resistance mechanisms to irreversible pyrimidine-based EGFR inhibitors and identify specific genomic contexts in which sensitivity is retained to existing clinical EGFR inhibitors. These findings will guide the development of new strategies to inhibit EGFR. Clin Cancer Res; 21(17); 3913–23. ©2015 AACR. See related commentary by Ayeni et al., p. 3818
Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group
Authors: K. J. Cohen, I. F. Pollack, T. Zhou, A. Buxton, E. J. Holmes, P. C. Burger, D. J. Brat, M. K. Rosenblum, R. L. Hamilton, R. S. Lavey, R. L. Heideman
Journal: Neuro-Oncology (2011)

To determine whether temozolomide is an active agent in the treatment of children with high-grade astrocytomas and whether survival is influenced by the expression of the O6-methylguanine-methyltransferase gene (MGMT) in these patients. In the Children's Oncology Group study ACNS0126, 107 patients with a diagnosis of anaplastic astrocytoma (AA), glioblastoma multiforme (GBM), or gliosarcoma were enrolled. All patients underwent concomitant chemoradiotherapy with temozolomide, followed by adjuvant chemotherapy with temozolomide. The outcomes were compared with those of children treated in Children's Cancer Group (CCG) study CCG-945. Formalin-fixed, paraffin-embedded tumor tissue was available in 71 cases for immunohistochemical analysis of MGMT expression. Ninety patients were deemed eligible, 31 with AA, 55 with GBM, and 4 with other eligible diagnoses. The 3-year event-free survival (EFS) and overall survival (OS) rates were 11 ± 3% and 22 ± 5%, respectively. There was no evidence that temozolomide given during radiation therapy and as adjuvant therapy resulted in improved EFS compared with that found in CCG-945 (p = 0.98). The 3-year EFS rate for AA was 13 ± 6% in ACNS0126 compared with 22 ± 5.5% in CCG-945 (p = 0.95). The 3-year EFS rate for GBM was 7 ± 4% in ACNS0126 compared with 15 ± 5% in CCG-945 (p = 0.77). The 2-year EFS rate was 17 ± 5% among patients without MGMT overexpression and 5 ± 4% among those with MGMT overexpression (p = 0.045). Temozolomide failed to improve outcome in children with high-grade astrocytomas. MGMT overexpression was adversely associated with survival.
Hydroxychloroquine versus phlebotomy in the treatment of porphyria cutanea tarda
Authors: T. CAINELLI, C. PADOVA, L. MARCHESI, G. GORI, P. ROVAGNATI, S.A. PODENZANI, E. BESSONE, L. CANTONI
Journal: British Journal of Dermatology (1983)

Hydroxychloroquine and phlebotomy were compared in the treatment of porphyria cutanea tarda (PCT). Thirty patients received hydroxychloroquine (200 mg twice weekly) for 1 year and thirty‐one underwent twice‐monthly phlebotomies of 400 ml whole blood each, also for 1 year. Clinical signs of disease improved equally in both groups. At the end of the year, urinary porphyrin excretion had significantly improved in twenty‐two out of thirty hydroxychloroquine‐ treated subjects, but in only eight out of the thirty‐one patients who received phlebotomy. Liver histology showed significant regression of steatosis and siderosis in both groups compared with the pretrial biopsy, but the activity of liver disease, as judged by the extent of necrosis, inflammation and fibrosis, worsened in twelve hydroxychloroquine and in seven phlebotomy‐treated patients. It is concluded that hydroxychloroquine is more effective than phlebotomy in decreasing porphyrin production. However, further work is needed to assess whether long‐term hydroxychloroquine treatment favours the progression of the chronic liver disease associated with PCT.
Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer
Authors: Charles M. Rudin, Christine L. Hann, Edward B. Garon, Moacyr Ribeiro de Oliveira, Philip D. Bonomi, D. Ross Camidge, Quincy Chu, Giuseppe Giaccone, Divis Khaira, Suresh S. Ramalingam, Malcolm R. Ranson, Caroline Dive, Evelyn M. McKeegan, Brenda J. Chyla, Barry L. Dowell, Arunava Chakravartty, Cathy E. Nolan, Niki Rudersdorf, Todd A. Busman, Mack H. Mabry, Andrew P. Krivoshik, Rod A. Humerickhouse, Geoffrey I. Shapiro, Leena Gandhi
Journal: Clinical Cancer Research (2012)

Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-x(L). The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy.Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates.The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III-IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro-gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit.Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies.
Peptide Vaccination after T-Cell Transfer Causes Massive Clonal Expansion, Tumor Eradication, and Manageable Cytokine Storm
Authors: Long V. Ly, Marjolein Sluijter, Mieke Versluis, Gre P.M. Luyten, Sjoerd H. van der Burg, Cornelis J.M. Melief, Martine J. Jager, Thorbald van Hall
Journal: Cancer Research (2010)

Adoptive T-cell transfer (ACT) is successfully applied as a cancer treatment that is based on the activation and effector functions of tumor-specific T cells. Here, we present results from a mouse model in which ACT is combined with a long peptide-based vaccine comprising gp100 T-cell epitopes. Transferred CD8(+) T cells expanded up to 1,000-fold after peptide vaccination, leading to a 3-fold increase in white blood cell count and a very high frequency in the generation of antigen-specific memory T cells, the generation of which tended to correlate with effective antitumor responses. An enormous pool of effector T cells spread widely to different tissues, including the skin and the immune-privileged eye, where they mediate tumor eradication. Importantly, these striking T-cell dynamics occurred in immunocompetent mice without prior hematologic conditioning. Continued activation of the specific T-cell pool by vaccination led to strong T-cell-mediated cytokine storm and lethality due to multi-organ failure. However, this immunopathology could be prevented by controlling the rapid biodistribution of the peptide or by using a weakly agonistic peptide. Together, these results identify a peptide vaccination strategy that can potently accentuate effective ACT in non-lymphodepleted hosts.
Counterpoint: Visceral Adiposity Is Not Causally Related to Insulin Resistance
Authors: John M. Miles, Michael D. Jensen
Journal: Diabetes Care (2005)

It has been known for over half a century that accumulation of fat in the upper body is associated with metabolic complications of obesity. The mechanism responsible for this association is widely believed to be insulin resistance, which is frequently present in individuals with upper-body obesity (1) and is associated with increased cardiovascular risk (2). The upper-body obesity phenotype is accompanied by increased free fatty acid (FFA) flux and concentration, whereas individuals with predominantly lower-body obesity tend to have normal FFA kinetics (3). Increased FFA concentrations, in turn, are thought to be a major mediator of insulin resistance (4) and have been shown to cause endothelial dysfunction (5), impair pancreatic β-cell function (6), and acutely raise blood pressure (7). Increased delivery of FFA to skeletal muscle can result in insulin resistance in that tissue, either directly or via accumulation of increased intramyocellular triglyceride stores (8). Similarly, increased delivery of FFA to the liver may be responsible for hepatic insulin resistance (9), accumulation of intrahepatocellular triglyceride (10), and increased synthesis and secretion of VLDL (11). Hormone-sensitive lipase in adipocytes is exquisitely sensitive to the antilipolytic effect of insulin in lean healthy individuals (12). However, impaired insulin suppression of adipose tissue lipolysis is a feature of, and may even be the primary cause of, insulin resistance (13). To our knowledge, insulin resistance has not been reported in individuals with normal sensitivity to the antilipolytic effects of insulin.

The degree of upper-body obesity can be estimated by measurement of waist circumference, which is predictive of cardiovascular risk (14). However, nonobese individuals exhibit considerable variability in insulin sensitivity (15) that is not necessarily explained by differences in waist circumference (16). It is possible that differences in the distribution of upper-body fat could explain variability in insulin sensitivity at a given BMI and a given …
Platelet-Derived Growth Factor Production by B16 Melanoma Cells Leads to Increased Pericyte Abundance in Tumors and an Associated Increase in Tumor Growth Rate
Authors: Masao Furuhashi, Tobias Sjöblom, Alexandra Abramsson, Jens Ellingsen, Patrick Micke, Hong Li, Erika Bergsten-Folestad, Ulf Eriksson, Rainer Heuchel, Christer Betsholtz, Carl-Henrik Heldin, Arne Östman
Journal: Cancer Research (2004)

Abstract Platelet-derived growth factor (PDGF) receptor signaling participates in different processes in solid tumors, including autocrine stimulation of tumor cell growth, recruitment of tumor stroma fibroblasts, and stimulation of tumor angiogenesis. In the present study, the B16 mouse melanoma tumor model was used to investigate the functional consequences of paracrine PDGF stimulation of host-derived cells. Production of PDGF-BB or PDGF-DD by tumor cells was associated with an increased tumor growth rate. Characterization of tumors revealed an increase in pericyte abundance in tumors derived from B16 cells producing PDGF-BB or PDGF-DD. The increased tumor growth rate associated with PDGF-DD production was not seen in mice expressing an attenuated PDGF β-receptor and was thus dependent on host PDGF β-receptor signaling. The increased pericyte abundance was not associated with an increased tumor vessel density. However, tumor cell apoptosis, but not proliferation, was reduced in tumors displaying PDGF-induced increased pericyte coverage. Our findings thus demonstrate that paracrine PDGF production stimulates pericyte recruitment to tumor vessels and suggest that pericyte abundance influences tumor cell apoptosis and tumor growth.
S50 Evaluation of secretory leucoprotease inhibitor (SLPI) as an anti-inflammatory therapy for donor lung inflammation
Authors: H. R. Walden, D. M. Karamanou, C. R. Fox, A. J. Rostron, J. A. Kirby, A. J. Simpson, J. H. Dark, A. J. Fisher
Journal: Thorax (2010)

<h3>Introduction</h3> Donor lung inflammation, reflected by high concentrations of interleukin-8 in bronchoalveolar lavage (BAL) and an imbalance between pro-inflammatory IL-6 and anti inflammatory IL-10 in tissue, correlates with poor graft function and reduced survival after human lung transplantation. Secretory leucoprotease inhibitor (SLPI) is an anti-protease abundant in the lung. SLPI inhibits neutrophil elastase and down regulates inflammatory cytokine transcription via the NFκB pathway. We investigated the effect of SLPI on inflammatory mediators, in a rat model of brain death induced lung injury. <h3>Methods</h3> Brain death (BD) was induced in anesthetised ventilated male Wistar rats (n=16) by rapid inflation of an intracranial balloon, the balloon was not inflated in non-BD sham animals. Rats received intra-tracheal human recombinant SLPI (400 ng/g) (n=8) or saline (control n=8, sham n=9) at 1 h. The experiment was terminated at 5 h. Serum samples were taken at 0, 1, 3 and 5 h, and BAL from one lung was taken for cytokine analysis. The second lung was used for wet/dry ratio and Q-PCR analysis. <h3>Results</h3> CXCL1, TNF-α, IFN-γ and IL-6 were significantly higher in BAL and serum of control than sham rats, demonstrating that BD induced lung inflammation in this model. There was no change in lung wet-dry ratio between SLPI treated and control groups. Surprisingly, CXCL1 levels were higher in the BAL of SLPI treated rats than controls (p=0.05), however no significant difference was detected for any other cytokine. There was a non-significant trend towards a higher number of CD45+ leucocytes in BAL in SLPI treated rats compared to controls. CXCL1 mRNA was also increased 1.5-fold in the SLPI treated group compared to controls (p&lt;0.05). <h3>Conclusions</h3> In this study, SLPI does not appear to have an anti-inflammatory effect in the rat lung, and may exacerbate inflammation as seen by an increased concentration of the chemokine CXCL1. This surprising effect may be due to the short time course of this experiment where the initial effect of SLPI may be pro-inflammatory. Given the small window of opportunity available to treat donor lungs we believe that SLPI is an inappropriate intervention for use in lung transplantation.
An Ideal Prognostic Test for Estrogen Receptor–Positive Breast Cancer?
Authors: Soonmyung Paik, Gong Tang, Debora Fumagalli
Journal: Journal of Clinical Oncology (2008)

The decision to administer chemotherapy to patients diagnosed with early-stage breast cancer ideally should be based on assessment of baseline risk and expected degree of benefit from chemotherapy. Because chemotherapy will not be needed if baseline risk is excellent, most of the time decision is purely based on prognostic factors. Currently two independently validated prognostic tests are widely used for breast cancer. The Adjuvant! algorithm is based on clinical and patho