tbuckley/cabot-search huggingface dataset:
Treatment of Pancreatic Cancer Cells with Dicumarol Induces Cytotoxicity and Oxidative Stress
Authors: Anne Lewis, Matthew Ough, Ling Li, Marilyn M. Hinkhouse, Justine M. Ritchie, Douglas R. Spitz, Joseph J. Cullen
Journal: Clinical Cancer Research (2004)

Abstract Purpose: NAD(P)H:quinone oxidoreductase (NQO1) catalyzes the two-electron reduction of quinones to hydroquinones. This reaction is believed to prevent the one-electron reduction of quinones that would result in redox cycling with generation of superoxide (O2.-). We have recently demonstrated that inhibition of NQO1 with dicumarol increases intracellular O2.- production and inhibits the in vitro malignant phenotype of pancreatic cancer cells (J. Cullen et al., Cancer Res., 63: 5513–5520, 2003). We hypothesized that inhibition of NQO1 would increase cell killing, induce oxidative stress, and inhibit in vivo tumor growth. Experimental Design and Results: In the human pancreatic cancer cell line MIA PaCa-2, dicumarol decreased cell viability, as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and decreased clonogenic survival. Dicumarol increased the percentage of apoptotic cells in a time-dependent and dose-dependent manner as measured by 3,3′-diaminobenzidine staining and flow cytometry, which was associated with cytochrome c release and poly(ADP-ribose) polymerase cleavage. Dicumarol also induced oxidative stress as evidenced by increased total glutathione and oxidized glutathione, as well as sensitizing to cell killing mediated by menadione. In established orthotopic pancreatic tumors in nude mice, intratumoral injections of dicumarol slowed tumor growth and extended survival. Conclusions: Inhibition of NQO1 with dicumarol induces cell killing and oxidative stress in pancreatic cancer cells and speculate that dicumarol may prove to be useful in pancreatic cancer therapeutics.
The Path to High Drug Resistance for Staph Infections
Authors: J. Caspermeyer
Journal: Molecular Biology and Evolution (2015)

Antibiotic-resistant pathogens pose a severe public health threat with difficult to treat infections often requiring multiple drug combinations. Now, in the advanced online edition of Molecular Biology and Evolution, authors Mari de Evgrafov et al. (2015) examined how several strains of Staphlococcus aureus evolved resistance to five different antibiotic drugs and three different combinations (including the increasingly threat of methicillin-resistant S. aureus, or MRSA). In all, 24 different bacterial lineages (15 single drug and 9 combinations) were followed during their adaptation experiments. Alarmingly, the study showed that high-level exposure to single antibiotics specifically selects for resistant strains, increasing the ability to adapt and survive with each exposure. The resistance after five exposures was 100 to 1,000 times greater than normal. In contrast, drug combinations were found to be effective at limiting resistance evolution. DNA sequencing revealed that the resistance patterns are reflected by mutational differences in the evolved S. aureus strains. “In this study, we show that collateral effects of drug resistance evolution can be exploited in the selection of drug combinations to limit the evolution of antibiotic resistance in S. aureus.” said corresponding author Morten Sommer. They conclude that resistance toward drug combinations is largely mediated by the same mutations that confer resistance toward the drugs individually. Additionally, they find that collateral effects of resistance evolution play a key role in modulating resistance evolution for drug combinations. These results could aid in the selection of novel treatments of S. aureus with limited resistance potential.
Mechanoenergetic inefficiency in the septic left ventricle is due to enhanced oxygen requirements for excitation?contraction coupling
Authors: E AGHAJANI
Journal: Cardiovascular Research (2004)

Myocardial oxygen consumption (MVO2) in the septic myocardium is increased despite reduced left ventricular mechanical work. We investigated the mechanism behind this energetic inefficiency in the septic myocardium.To clarify whether energy consumption in basal metabolism or excitation-contraction (EC) coupling is elevated in the septic myocardium, we separated MVO2 used for these two processes. We assessed hemodynamics, left ventricular pressure-volume area, left ventricular MVO2, myocardial substrate metabolism and the inflammatory response in eight control pigs and in eight septic pigs receiving E. coli endotoxin. Using cardiopulmonary bypass (CPB), unloaded MVO2 was assessed before and after arrest of electromechanical activity using KCl infusions.Unloaded MVO2 was significantly higher in the septic group compared to the control group (65.7 +/- 12.9 vs. 43.3 +/- 15.1 J.min(-1).100 g LV(-1), p < 0.005), but basal MVO2 after 5 min KCl arrest was equal in the two groups. No difference in mechanical energy consumption or substrate metabolism was observed between groups.Basal MVO2 in the septic myocardium is not elevated, but an increased MVO2 for EC coupling is responsible for the energetic inefficiency.
Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers
Authors: Vincenzo Bronte, Tihana Kasic, Giorgia Gri, Keti Gallana, Giovanna Borsellino, Ilaria Marigo, Luca Battistini, Massimo Iafrate, Tommaso Prayer-Galetti, Francesco Pagano, Antonella Viola
Journal: The Journal of Experimental Medicine (2005)

Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix–supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy.
Volumetric and scintigraphic changes following endoscopic lung volume reduction
Authors: Carmen Pizarro, Hojjat Ahmadzadehfar, Markus Essler, Rolf Fimmers, Georg Nickenig, Dirk Skowasch
Journal: European Respiratory Journal (2014)

Bronchoscopic treatment of emphysema represents an emerging therapeutic modality for advanced emphysematous lung destruction in chronic obstructive pulmonary disease (COPD). Within the proposed techniques for endoscopic lung volume reduction (ELVR), a significant amount of experience exists for the placement of endobronchial valves (EBV) (Zephyr® valves; Pulmonx, Inc., Redwood City, CA, USA) targeting atelectasis of the treated, emphysematous lobe [1, 2]. However, post-procedural clinical improvement has also been documented in patients lacking lobar exclusion 3. While volumetric and density adaptations following ELVR have repeatedly been a focus [3, 4], the interaction of volume and perfusional/ventilatory changes remains unclear. In this observational study, we defined the extent of interdependency of ELVR-mediated volumetric and scintigraphic adaptations. EBV treatment reduces target lobe volume, ventilation and perfusion with consistent redistributive pattern <http://ow.ly/C95Ue>
Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data
Authors: J A P Da Silva
Journal: Annals of the Rheumatic Diseases (2005)

Adverse effects of glucocorticoids have been abundantly reported. Published reports on low dose glucocorticoid treatment show that few of the commonly held beliefs about their incidence, prevalence, and impact are supported by clear scientific evidence. Safety data from recent randomised controlled clinical trials of low dose glucocorticoid treatment in RA suggest that adverse effects associated with this drug are modest, and often not statistically different from those of placebo.
Comparison of Studies on Mobile Phone Use and Risk of Tumors
Authors: Florence Samkange-Zeeb, Joachim Schüz, Brigitte Schlehofer, Gabrielle Berg-Beckhoff, Maria Blettner
Journal: Journal of Clinical Oncology (2010)

published results of ameta-analysis of studies on mobile phone use and risk of tumors. Intheir analysis, the authors included 23 case-control studies, covering abroad spectrum of tumor entities including uveal melanoma, testicu-lar cancer, parotid gland tumors, and brain tumors.However, the authors give no rationale for pooling these hetero-geneous, biologically rather diverse cancer sites, for which the local-ized exposure from the use of mobile phones is completely different.The key difference between this particular meta-analysis com-pared with earlier ones is the use of a quality score. The use of qualityscoreshasbeenreportedtobea“formofsubjectivitymasqueradingasobjectivity”andithasbeensaidto“subjectivelymergeobjectiveinfor-mationwitharbitraryjudgmentsinamannerthatcanobscureimpor-tant sources of heterogeneity among study results.”
Improved Cardiac Risk Assessment With Noninvasive Measures of Coronary Flow Reserve
Authors: Venkatesh L. Murthy, Masanao Naya, Courtney R. Foster, Jon Hainer, Mariya Gaber, Gilda Di Carli, Ron Blankstein, Sharmila Dorbala, Arkadiusz Sitek, Michael J. Pencina, Marcelo F. Di Carli
Journal: Circulation (2011)

Background— Impaired vasodilator function is an early manifestation of coronary artery disease and may precede angiographic stenosis. It is unknown whether noninvasive assessment of coronary vasodilator function in patients with suspected or known coronary artery disease carries incremental prognostic significance. Methods and Results— A total of 2783 consecutive patients referred for rest/stress positron emission tomography were followed up for a median of 1.4 years (interquartile range, 0.7–3.2 years). The extent and severity of perfusion abnormalities were quantified by visual evaluation of myocardial perfusion images. Rest and stress myocardial blood flows were calculated with factor analysis and a 2-compartment kinetic model and were used to compute coronary flow reserve (coronary flow reserve equals stress divided by rest myocardial blood flow). The primary end point was cardiac death. Overall 3-year cardiac mortality was 8.0%. The lowest tertile of coronary flow reserve (&lt;1.5) was associated with a 5.6-fold increase in the risk of cardiac death (95% confidence interval, 2.5–12.4; P &lt;0.0001) compared with the highest tertile. Incorporation of coronary flow reserve into cardiac death risk assessment models resulted in an increase in the c index from 0.82 (95% confidence interval, 0.78–0.86) to 0.84 (95% confidence interval, 0.80–0.87; P =0.02) and in a net reclassification improvement of 0.098 (95% confidence interval, 0.025–0.180). Addition of coronary flow reserve resulted in correct reclassification of 34.8% of intermediate-risk patients (net reclassification improvement=0.487; 95% confidence interval, 0.262–0.731). Corresponding improvements in risk assessment for mortality from any cause were also demonstrated. Conclusion— Noninvasive quantitative assessment of coronary vasodilator function with positron emission tomography is a powerful, independent predictor of cardiac mortality in patients with known or suspected coronary artery disease and provides meaningful incremental risk stratification over clinical and gated myocardial perfusion imaging variables.
Chronic venous ulcer
Authors: N. Angle, J. J Bergan
Journal: BMJ (1997)

<h3>Objective</h3> To explore the potential impact of demand management strategies on patient decision-making in medically non-urgent and urgent scenarios during out-of-hours for children between the ages of 0 and 4 years. <h3>Design and methods</h3> We conducted a cross-sectional survey with paper-based case scenarios. A survey was sent to all 797 parents of children aged between 0 and 4 years from four Dutch general practitioner (GP) practices. Four demand management strategies (copayment, online advice, overview medical cost and GP appointment next morning) were incorporated in two medically non-urgent and two urgent case scenarios. Combining the case scenarios with the demand management strategies resulted in 16 cases (four scenarios each with four demand management strategies). Each parent randomly received a questionnaire with three different case scenarios with three different demand strategies and a baseline case scenario without a demand management strategy. <h3>Results</h3> The response rate was 47.4%. The strategy online advice led to more medically appropriate decision-making for both non-urgent case scenarios (OR 0.26; 95% CI 0.11 to 0.58) and urgent case scenarios (OR 0.16; 95% CI 0.08 to 0.32). Overview of medical cost (OR 0.59; 95% CI 0.38 to 0.92) and a GP appointment planned the next morning (OR 0.57; 95% CI 0.34 to 0.97) had some influence on patient decisions for urgent cases, but not for non-urgent cases. Copayment had no influence on patient decisions. <h3>Conclusion</h3> Online advice has the highest potential to reduce medically unnecessary use. Furthermore it enhanced safety of parents9 decisions on seeking help for their young children during out-of-hours primary care. Valid online information on health symptoms for patients should be promoted.
Nonproteasomal Targets of the Proteasome Inhibitors Bortezomib and Carfilzomib: a Link to Clinical Adverse Events
Authors: Shirin Arastu-Kapur, Janet L. Anderl, Marianne Kraus, Francesco Parlati, Kevin D. Shenk, Susan J. Lee, Tony Muchamuel, Mark K. Bennett, Christoph Driessen, Andrew J. Ball, Christopher J. Kirk
Journal: Clinical Cancer Research (2011)

Bortezomib (Velcade), a dipeptide boronate 20S proteasome inhibitor and an approved treatment option for multiple myeloma, is associated with a treatment-emergent, painful peripheral neuropathy (PN) in more than 30% of patients. Carfilzomib, a tetrapeptide epoxyketone proteasome inhibitor, currently in clinical investigation in myeloma, is associated with low rates of PN. We sought to determine whether PN represents a target-mediated adverse drug reaction (ADR).Neurodegenerative effects of proteasome inhibitors were assessed in an in vitro model utilizing a differentiated neuronal cell line. Secondary targets of both inhibitors were identified by a multifaceted approach involving candidate screening, profiling with an activity-based probe, and database mining. Secondary target activity was measured in rats and patients receiving both inhibitors.Despite equivalent levels of proteasome inhibition, only bortezomib reduced neurite length, suggesting a nonproteasomal mechanism. In cell lysates, bortezomib, but not carfilzomib, significantly inhibited the serine proteases cathepsin G (CatG), cathepsin A, chymase, dipeptidyl peptidase II, and HtrA2/Omi at potencies near or equivalent to that for the proteasome. Inhibition of CatG was detected in splenocytes of rats receiving bortezomib and in peripheral blood mononuclear cells derived from bortezomib-treated patients. Levels of HtrA2/Omi, which is known to be involved in neuronal survival, were upregulated in neuronal cells exposed to both proteasome inhibitors but was inhibited only by bortezomib exposure.These data show that bortezomib-induced neurodegeneration in vitro occurs via a proteasome-independent mechanism and that bortezomib inhibits several nonproteasomal targets in vitro and in vivo, which may play a role in its clinical ADR profile.
Genomic analysis and selective small molecule inhibition identifies BCL-XL as a critical survival factor in a subset of colorectal cancer
Authors: Haichao Zhang, John Xue, Paul Hessler, Stephen K. Tahir, Jun Chen, Sha Jin, Andrew J. Souers, Joel D. Leverson, Lloyd T. Lam
Journal: Molecular Cancer (2015)

Defects in programmed cell death, or apoptosis, are a hallmark of cancer. The anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins, including BCL-2, BCL-X(L), and MCL-1 have been characterized as key survival factors in multiple cancer types. Because cancer types with BCL2 and MCL1 amplification are more prone to inhibition of their respectively encoded proteins, we hypothesized that cancers with a significant frequency of BCL2L1 amplification would have greater dependency on BCL-X(L) for survival.To identify tumor subtypes that have significant frequency of BCL2L1 amplification, we performed data mining using The Cancer Genome Atlas (TCGA) database. We then assessed the dependency on BCL-X(L) in a panel of cell lines using a selective and potent BCL-X(L) inhibitor, A-1155463, and BCL2L1 siRNA. Mechanistic studies on the role of BCL-X(L) were further undertaken via a variety of genetic manipulations.We identified colorectal cancer as having the highest frequency of BCL2L1 amplification across all tumor types examined. Colorectal cancer cell lines with BCL2L1 copy number >3 were more sensitive to A-1155463. Consistently, cell lines with high expression of BCL-XL and NOXA, a pro-apoptotic protein that antagonizes MCL-1 activity were sensitive to A-1155463. Silencing the expression of BCL-X(L) via siRNA killed the cell lines that were sensitive to A-1155463 while having little effect on lines that were resistant. Furthermore, silencing the expression of MCL-1 in resistant cell lines conferred sensitivity to A-1155463, whereas silencing NOXA abrogated sensitivity.This work demonstrates the utility of characterizing frequent genomic alterations to identify cancer survival genes. In addition, these studies demonstrate the utility of the highly potent and selective compound A-1155463 for investigating the role of BCL-X(L) in mediating the survival of specific tumor types, and indicate that BCL-X(L) inhibition could be an effective treatment for colorectal tumors with high BCL-X(L) and NOXA expression.
Tumor-Derived Tissue FactorBearing Microparticles Are Associated With Venous Thromboembolic Events in Malignancy
Authors: Jeffrey I. Zwicker, Howard A. Liebman, Donna Neuberg, Romaric Lacroix, Kenneth A. Bauer, Barbara C. Furie, Bruce Furie
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Despite the strong association between malignant disease and thromboembolic disorders, the molecular and cellular basis of this relationship remains uncertain. We evaluated the hypothesis that tumor-derived tissue factorbearing microparticles in plasma contribute to cancer-associated thrombosis. Experimental Design: We developed impedance-based flow cytometry to detect, quantitate, and size microparticles in platelet-poor plasma. We evaluated the number of tissue factorbearing microparticles in a cohort of cancer patients of different histologies (N = 96) and conducted a case-control study of 30 cancer patients diagnosed with an acute venous thromboembolic event (VTE) compared with 60 cancer patients of similar age, stage, sex, and diagnosis without known VTE, as well as 22 patients with an idiopathic VTE. Results: Tissue factorbearing microparticles were detected in patients with advanced malignancy, including two thirds of patients with pancreatic carcinoma. Elevated levels of tissue factorbearing microparticles were associated VTE in cancer patients (adjusted odds ratio, 3.72; 95 confidence interval, 1.18-11.76; P = 0.01). In cancer patients without VTE, a retrospective analysis revealed a 1-year cumulative incidence of VTE of 34.8 in patients with tissue factorbearing microparticles versus 0 in those without detectable tissue factorbearing microparticles (Gray test P = 0.002).The median number of tissue factorbearing microparticles in the cancer VTE cohort (7.1 104 microparticles/L) was significantly greater than both the idiopathic VTE and cancerno VTE groups (P = 0.002 and P = 0.03, respectively). Pancreatectomy in three patients eliminated or nearly eliminated these microparticles which coexpressed the epithelial tumor antigen, MUC-1. Conclusion: We conclude that tumor-derived tissue factorbearing microparticles are associated with VTE in cancer patients and may be central to the pathogenesis of cancer-associated thrombosis. (Clin Cancer Res 2009;15(22):683040)
Gut-grabbing T cells trigger GVHD
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

![Graphic][1] 

CD8+ T cell-induced intestinal pathology during GVHD (top) is absent in mice lacking the integrin CD103 (bottom).Effector CD8

+ T cells that cling to the intestine trigger graft-versus-host disease (GVHD), according to El-Asady and colleagues on [page 1647][2]. By
Hints of Future Progress for HER-2 Breast Cancer
Authors: R. Twombly
Journal: JNCI Journal of the National Cancer Institute (2011)

treat, but now we have options that in some cases are very effective, with the prospect of even better therapies to come.” But no one is ready yet to declare unmitigated success. For one thing, the two combination studies featured at the meeting, Neo-ALTTO and Neosphere, tested neoadjuvant clinical benefi t by using pathological complete response (pCR), or the absence of invasive cancer in the breast tissue and regional lymph nodes. Even though giving chemotherapy before or after surgery results in the same long-term outcome, researchers, especially those in the U.S., say pCR has never been fi rmly statistically correlated with improved disease-free and overall survival. Therefore, results cannot be considered practice changing in that the studies were not designed to be defi nitive tests of survival, said Jo Anne Zujewski, M.D., head of breast cancer therapeutics at the National Cancer Institute.
Loss of Fc receptor activity after culture of human monocytes on surface-bound immune complexes. Mediation by cyclic nucleotides.
Authors: C G Ragsdale, W P Arend
Journal: The Journal of Experimental Medicine (1980)

Human monocytes cultured on surface-bound immune complexes exhibited a loss of ability to form rosettes with IgG-sensitized sheep erythrocytes (EA). This loss was not a result of inhibition of Fc receptors by solubilized complexes nor of release of soluble factors by the cells. Loss of EA rosetting was not prevented by culture of monocytes at 4 degrees C, or by treatment with colchicine, cytochalasin B, or local anethetic agents. These results suggested that the loss was not secondary to capping or interiorization of Fc receptors. The results of other studies indicated that the Fc receptors were not damaged by lysosomal enzymes or oxygen radicals. Maintenance of EA rosetting ability of monocytes cultured on surface-bound immune complexes was seen after a 3-h preincubation of the cells in 100 mM 2-deoxy-D-glucose (2dG). A similar preincubation in ATP or in 8-bromoadenosine 3':5'-cyclic monophosphoric acid plus the phosphodiesterase inhibitor methyl isobutyl xanthine led to a partial loss of EA rosetting of cells on plain fibrin and to a partial reversal of the effects of 2dG seen with cells on complexes. We conclude that EA rosetting of monocytes cultured on surface-bound immune complexes is reduced by cyclic nucleotide-mediated effects on Fc receptor number or function.
FoxM1 Promotes β-Catenin Nuclear Localization and Controls Wnt Target-Gene Expression and Glioma Tumorigenesis
Authors: Nu Zhang, Ping Wei, Aihua Gong, Wen-Tai Chiu, Hsueh-Te Lee, Howard Colman, He Huang, Jianfei Xue, Mingguang Liu, Yong Wang, Raymond Sawaya, Keping Xie, W.K. Alfred Yung, René H. Medema, Xi He, Suyun Huang
Journal: Cancer Cell (2011)