tbuckley/cabot-search huggingface dataset:
Inhibition of Glutathione Synthesis Overcomes Bcl-2-Mediated Topoisomerase Inhibitor Resistance and Induces Nonapoptotic Cell Death via Mitochondrial-Independent Pathway
Authors: Akira Yoshida, Haruyuki Takemura, Hitoshi Inoue, Toshiyuki Miyashita, Takanori Ueda
Journal: Cancer Research (2006)

Abstract Bcl-2 protein plays a critical role in inhibiting anticancer drug–induced apoptosis. We found that Bcl-2 overexpression is associated with a nearly 3-fold increase in cellular glutathione levels and with increased resistance to cell death after treatment with etoposide or SN-38, a derivative of camptothecin, in leukemia 697 cells with wild-type p53. Treatment of Bcl-2-overexpressing 697 cells (697-Bcl-2) with buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, reduced cellular glutathione levels and completely abolished Bcl-2-mediated drug resistance. Morphologic studies revealed that nonapoptotic cell death was induced in 697-Bcl-2 cells after treatment with BSO plus etoposide or SN-38. Activation of caspase-3/7 and cytochrome c release could not be detected in 697-Bcl-2 cells after these drug treatments. Notably, we showed that proteasome-mediated down-regulation of Puma and Noxa proteins occurs in 697-Bcl-2 cells after treatment with BSO plus topoisomerase inhibitor, although there is an increase in the protein levels of p53 in these 697-Bcl-2 cells. In contrast, parental 697 cells underwent typical apoptosis with up-regulation of Puma and Noxa proteins, followed by cytochrome c release and caspase-3/7 activation after treatment with topoisomerase inhibitor in the presence or absence of BSO. Our data suggest that BSO may possess a unique activity to overcome Bcl-2-mediated drug resistance by stimulating the signals that can bypass mitochondrial process in Bcl-2-overexpressing cells. (Cancer Res 2006; 66(11): 5772-80)
Association of tumour necrosis factor promoter haplotype with chronic pancreatitis
Authors: M-C Chang, Y-T Chang, Y-W Tien, P-C Liang, S-C Wei, J-M Wong
Journal: Gut (2006)

Genetic risk factors are attributed an important role in the pathogenesis of chronic pancreatitis.1 The genetic basis of chronic pancreatitis is complex. The cationic trypsinogen gene,2 serine protease inhibitor Kazal type 1 (SPINK1),3 and cystic fibrosis transmembrane conductance regulator4 genes have been most extensively studied in chronic pancreatitis. However, the frequency of hereditary pancreatitis, which may be related to the trypsinogen gene and SPINK1 in Orientals, is regarded as relatively low and hardly explains the genetic susceptibility of chronic pancreatitis in Chinese.5 Chronic pancreatitis is a progressive chronic inflammatory disease characterised by irreversible destruction of exocrine pancreatic tissue and extensive fibrosis. Tumour necrosis factor (TNF)-α, a prototype proinflammatory cytokine, has been implicated as an important pathogenic mediator in a variety of inflammatory …
Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade
Authors: J S Smolen, C Han, D M F M van der Heijde, P Emery, J M Bathon, E Keystone, R N Maini, J R Kalden, D Aletaha, D Baker, J Han, M Bala, E W St Clair
Journal: Annals of the Rheumatic Diseases (2008)

To examine the association of radiographic progression and disease activity states in patients with rheumatoid arthritis (RA) treated with methotrexate with or without infliximab.Patients (n = 1049) with active RA for 3 years or less and no previous methotrexate treatment were randomly assigned (4 : 5 : 5) to receive methotrexate plus placebo or methotrexate plus infliximab 3 or 6 mg/kg at weeks 0, 2 and 6, and every 8 weeks thereafter to week 46. Disease activity was classified by the simplified disease activity index as remission (< or =3.3), low (>3.3 to < or =11), moderate (>11 to < or =26), high (>26). Radiographic progression was measured as a change from baseline to week 54 in total Sharp score.At weeks 14 and 54, more patients receiving methotrexate plus infliximab than methotrexate plus placebo were in remission (10.7% versus 2.8% week 14; 21.3% versus 12.3% week 54; p<0.001 for both). Methotrexate plus placebo halted radiographic progression only if patients achieved remission within 3 months, whereas methotrexate plus infliximab also halted or minimised progression in patients with low or moderate activity, respectively. Patients with persistently high disease activity levels had much less progression of joint damage if treated with methotrexate plus infliximab versus methotrexate monotherapy. Even with infliximab plus methotrexate there was a direct relationship between disease activity and radiographic changes, although the slope was deflected when compared with methotrexate monotherapy.With methotrexate, joint damage progresses even at low and moderate disease activity levels, whereas methotrexate plus infliximab inhibits radiographic progression across all disease activity states.
Inhibition of endogenous thioredoxin in the heart increases oxidative stress and cardiac hypertrophy
Authors: Mitsutaka Yamamoto, Guiping Yang, Chull Hong, Jing Liu, Eric Holle, Xianzhong Yu, Thomas Wagner, Stephen F. Vatner, Junichi Sadoshima
Journal: Journal of Clinical Investigation (2003)

Thioredoxin 1 (Trx1) has redox-sensitive cysteine residues and acts as an antioxidant in cells. However, the extent of Trx1 contribution to overall antioxidant mechanisms is unknown in any organs. We generated transgenic mice with cardiac-specific overexpression of a dominant negative (DN) mutant (C32S/C35S) of Trx1 (Tg-DN-Trx1 mice), in which the activity of endogenous Trx was diminished. Markers of oxidative stress were significantly increased in hearts from Tg-DN-Trx1 mice compared with those from nontransgenic (NTg) mice. Tg-DN-Trx1 mice exhibited cardiac hypertrophy with maintained cardiac function at baseline. Intraperitoneal injection of N-2-mercaptopropionyl glycine, an antioxidant, normalized cardiac hypertrophy in Tg-DN-Trx1 mice. Thoracic aortic banding caused greater increases in myocardial oxidative stress and enhanced hypertrophy in Tg-DN-Trx1 compared with NTg mice. In contrast, transgenic mice with cardiac-specific overexpression of wild-type Trx1 did not show cardiac hypertrophy at baseline but exhibited reduced levels of hypertrophy and oxidative stress in response to pressure overload. These results demonstrate that endogenous Trx1 is an essential component of the cellular antioxidant mechanisms and plays a critical role in regulating oxidative stress in the heart in vivo. Furthermore, inhibition of endogenous Trx1 in the heart primarily stimulates hypertrophy, both under basal conditions and in response to pressure overload through redox-sensitive mechanisms.
Does Paclitaxel (Taxol) Given after 111In-Labeled Monoclonal Antibodies Increase Tumor-Cumulated Activity in Epithelial Cancers?
Authors: Laird Miers, Kathleen Lamborn, Aina Yuan, Carol Richman, Arutselvan Natarajan, Sally DeNardo, Gerald DeNardo
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Paclitaxel synergized radiolabeled monoclonal antibodies, enhancing therapeutic effect in studies in mice with human xenografts. Paclitaxel was also observed to increase tumor uptake in imaging studies of 111In-DOTA-Gly3Phe-m170 in patients with breast and prostate cancers. Further evaluations of tissue-cumulated activities, therapeutic indices, and pharmacokinetics were done using data for patients with breast and prostate cancer and for mice with human breast cancer xenografts. Experimental Design: In radioimmunotherapy trials, 12 patients with breast or prostate cancer were given two imaging doses (5 mCi each) of 111In-DOTA-Gly3Phe-m170 1 week apart. Five of these patients were given a single dose of paclitaxel i.v. (75 mg/m2) 2 days after the second dose of 111In. In a subsequent study, athymic mice with human breast cancer xenografts were given 111In-DOTA-Gly3Phe-ChL6 alone, or in combination with daily paclitaxel i.p. (300 μg) one or more times. Pharmacokinetics were studied for at least 6 days in patients and 5 days in mice. Cumulated activities were determined for tumors and normal tissues. Results: Tumor-cumulated activity for every patient in the paclitaxel-treated group increased for the second dose of 111In-DOTA-Gly3Phe-m170. The median ratio of cumulated activities in tumors for imaging dose 2 to those for dose 1 was 1.0 (0.8-1.3) in patients that were not given paclitaxel and 1.3 (1.2-1.4) in patients given paclitaxel. Normal tissue-cumulated activities were not different for the two doses. Mice given paclitaxel 1 day after 111In-DOTA-Gly3Phe-ChL6 also showed an increase in tumor-cumulated activity, 22.9 (± 1.3) versus 19.4 (± 3.3) μCi h/g/μCi (P = 0.05). Cumulated activities of normal tissues were similar for all groups of mice. Conclusions: Paclitaxel given 1 to 2 days after 111In-DOTA-Gly3Phe-monoclonal antibody increased the tumor-cumulated activity in patients and in mice with epithelial cancers and did not alter cumulated activities in normal tissues.
Antioxidants protect from atherosclerosis by a heme oxygenase-1 pathway that is independent of free radical scavenging
Authors: Ben J. Wu, Krishna Kathir, Paul K. Witting, Konstanze Beck, Katherine Choy, Cheng Li, Kevin D. Croft, Trevor A. Mori, David Tanous, Mark R. Adams, Antony K. Lau, Roland Stocker
Journal: The Journal of Experimental Medicine (2006)

Oxidative stress is implicated in atherogenesis, yet most clinical trials with antioxidants, particularly vitamin E, have failed to protect against atherosclerotic diseases. A striking exception is probucol, which retards atherosclerosis in carotid arteries and restenosis of coronary arteries after angioplasty. Because probucol has in vitro cellular-protective effects independent of inhibiting lipid oxidation, we investigated the mode of action of probucol in vivo. We used three models of vascular disease: apolipoprotein E-deficient mice, a model of atherosclerosis; rabbit aortic balloon injury, a model of restenosis; and carotid injury in obese Zucker rats, a model of type 2 diabetes. Unexpectedly, we observed that the phenol moieties of probucol were insufficient, whereas its sulphur atoms were required for protection. Probucol and its sulphur-containing metabolite, but not a sulphur-free phenolic analogue, protected via cell-specific effects on inhibiting macrophage accumulation, stimulating reendothelialization, and inhibiting vascular smooth muscle cell proliferation. These processes were mediated via induction of heme oxygenase-1 (HO-1), an activity not shared by vitamin E. Our findings identify HO-1 as the molecular target of probucol. They indicate 2-electron rather than radical (1-electron) oxidants as important contributors to atherogenesis, and point to novel lead compounds for therapeutic intervention against atherosclerotic diseases.
Efficacy Correlates with Plasma Levels in Opus-1, a Proof-of-Concept Study of Oral Kallikrein Inhibitor BCX4161 As a Prophylaxis Against Attacks of Hereditary Angioedema (HAE)
Authors: Emel Aygören-Pürsün, Markus Magerl, Jochen Graff, Inmaculada Martinez-Saguer, Wolfhart Kreuz, Hilary Longhurst, Iman Nasr, Murat Bas, Ulrich Straßen, Jian Zong, Lei Fang, Melanie Cornpropst, Sylvia Dobo, Phil Collis, William Sheridan, Marcus Maurer
Journal: Journal of Allergy and Clinical Immunology (2015)
Unusual effects of aspirin on ticlopidine induced thrombolysis
Authors: R J Gryglewski
Journal: Thorax (2000)

For hundreds of years salicylates have been used to treat fever and pain. Following the discovery that aspirin inhibits the biosynthesis of prostanoids,1 particularly thromboxane A2 (TXA2) in blood platelets, aspirin gained a new clinical indication as an antiplatelet and antithrombotic drug. Aspirin acetylates the serine 529 residue of cyclo-oxygenase 1 (COX-1) in platelets and megakaryocytes2; however, tyrosyl residues in inducible COX-2 are also acetylated.3 The anti-inflammatory action of aspirin depends on its interaction with COX-2 and subsequent removal of proinflammatory prostanoids or, possibly, on the appearance of cytoprotective 15-epi-lipoxins.4 Only diclofenac induced COX-2 remains insensitive to aspirin.5 Inhibition of nuclear factor kappa B (NFκB) activation is another mechanism of anti-inflammatory action of salicylates.6 Many unusual actions of aspirin are associated with its acetylating power that extends beyond serine residues in COX-1 or tyrosine residues in COX-2. For instance, the anti-cataract effect of aspirin seems to be associated with acetylation of cysteinyl residues of lens γ-crystallins which prevents the formation of opaque disulphide bonding.7 Aspirin affects the rheological properties of erythrocytes,8 decreases erythrocyte mediated activation of platelets,9 and modifies the functioning of haemoglobin by acetylation of its lysyl residues.10 Even platelet membranes possess protein sites available for acetylation by aspirin.11 In humans thrombinogenesis is inhibited by aspirin, possibly as a consequence of acetylation of either platelet membranes or active sites of prothrombin.12 The relation between sodium salicylate and aspirin is complex. Protective effects of sodium salicylate against inhibition of COX by aspirin have been reported in many systems including patients with aspirin induced asthma.13 On the other hand, both drugs enhance the generation of nitric oxide by activated murine macrophages14 or by cultured rat smooth muscle cells.15 

The antithrombotic activity of …
Prediction of <i>TP53</i> Status for Primary Cisplatin, Fluorouracil, and Leucovorin Chemotherapy in Ethmoid Sinus Intestinal-Type Adenocarcinoma
Authors: L. Licitra, S. Suardi, P. Bossi, L.D. Locati, L. Mariani, P. Quattrone, S. Lo Vullo, M. Oggionni, P. Olmi, G. Cantù, M.A. Pierotti, S. Pilotti
Journal: Journal of Clinical Oncology (2004)

Purpose To assess the role of TP53 status in predicting pathologic complete remission after primary chemotherapy in patients with ethmoidal intestinal-type adenocarcinoma (ITAC). Patients and Methods Thirty patients with ethmoidal ITAC enrolled onto a phase II study received chemotherapy with cisplatin, fluorouracil, and leucovorin (PFL) followed by surgery and radiation. On surgical specimens, absence of viable tumor cells was defined as pathologic complete remission (pCR). TP53 status/p53 function, analyzed on pretreatment biopsies, were retrospectively correlated with pathologic results and patient outcome. Results Twelve patients achieved a pCR; 18 patients did not (overall response rate, 40%). In patients with wild-type (wt) TP53 or functional p53 protein, the pCRs were 83% and 80%, respectively; in patients with mutated TP53 or impaired p53 protein, pCRs were 11% and 0%, respectively (P ≤ .0001). At a median 55-month follow-up, all pCR patients were disease-free; 44% of nonresponding patients experienced relapse (P = .0061). Conclusion The results indicate the existence of two genetic ITAC subgroups, defined by differences in TP53 mutational status or protein functionality, that strongly influence pathologic response to primary chemotherapy and, ultimately, prognosis. PFL seems to be highly effective in terms of pCR and disease-free survival in the presence of a wt or a still-efficient p53 protein, even when encoded by a mutated TP53 gene (eg, early-stop codon mutation), but ineffective in ITACs carrying a disabled p53 protein. Whether this model is extensible to other head and neck cancers needs appropriate investigation.
Localization of cystic fibrosis transmembrane conductance regulator in chloride secretory epithelia.
Authors: G M Denning, L S Ostedgaard, S H Cheng, A E Smith, M J Welsh
Journal: Journal of Clinical Investigation (1992)

Cystic fibrosis is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). To further our understanding of CFTR's function and regulation, we used confocal immunofluorescence microscopy to localize CFTR in cells stained with monoclonal antibodies against different regions of the protein: the R (regulatory) domain (M13-1), the COOH terminus (M1-4), and a predicted extracellular domain (M6-4). All three antibodies immunoprecipitated a 155-170-kD polypeptide from cells expressing CFTR. Each antibody stained HeLa and 3T3 cells expressing recombinant CFTR, but not cells lacking endogenous CFTR: HeLa, NIH-3T3, and endothelial cells. For localization studies, we used epithelial cell lines that express endogenous CFTR and have a cAMP-activated apical Cl- permeability: T84, CaCo2, and HT29 clone 19A. Our results demonstrate that CFTR is an apical membrane protein in these epithelial cells because (a) staining for CFTR resembled staining for several apical membrane markers, but differed from staining for basolateral membrane proteins; (b) thin sections of cell monolayers show staining at the apical membrane; and (c) M6-4, an extracellular domain antibody, stained the apical surface of nonpermeabilized cells. Our results do not exclude the possibility that CFTR is also located beneath the apical membrane. Increasing intracellular cAMP levels did not change the apical membrane staining pattern for CFTR. Moreover, insertion of channels by vesicle fusion with the apical membrane was not required for cAMP-mediated increases in apical membrane Cl- conductance. These results indicate that CFTR is located in the apical plasma membrane of Cl(-)-secreting epithelia, a result consistent with the conclusion that Cl TR is an apical membrane chloride channel.
Implantable Cardioverter-Defibrillators for Primary Prevention of Sudden Death in Heart Failure
Authors: Lynne Warner Stevenson
Journal: Circulation (2006)

2][3] The current cost, multiplied by the prevalence of heart failure deemed high-risk, threatens to make this one enterprise the highest priced intervention for the Medicare population.The elegant cost-effectiveness analysis contributed by Dr Mark and colleagues from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) in this issue of Circulation provides an exemplary insight into this challenge. 4These investigators' favorable conclusions are consistent with those from a meta-analysis by Sanders et al 5 and with the slightly more conservative implications from the recent cost-effectiveness analysis of the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II by Zwanziger et al. 6 Article p 135This editorial will offer an alternative conclusion based on both back-of-the-envelope estimations and scrutiny of model assumptions regarding different phases of survival for heart failure populations.ICDs for primary prevention of sudden death in the heart failure population may be less costeffective than other recommended heart failure therapies, which are prescribed to modify disease progression and symptoms, decreasing costly hospitalizations as well as mortality.
Clinical and Subclinical Macrovascular Disease as Predictors of Cognitive Decline in Older Patients With Type 2 Diabetes
Authors: Insa Feinkohl, Marketa Keller, Christine M. Robertson, Joanne R. Morling, Rachel M. Williamson, Lisa D. Nee, Stela McLachlan, Naveed Sattar, Paul Welsh, Rebecca M. Reynolds, Tom C. Russ, Ian J. Deary, Mark W.J. Strachan, Jackie F. Price
Journal: Diabetes Care (2013)

Macrovascular disease may contribute to increased risk of accelerated cognitive decline in patients with type 2 diabetes. We aimed to determine associations of measures of macrovascular disease with cognitive change in a cognitively healthy older population with type 2 diabetes.Eight hundred thirty-one men and women (aged 60-75 years) attended two waves of the prospective Edinburgh Type 2 Diabetes Study (ET2DS). At baseline, clinical and subclinical macrovascular disease was measured, including cardiovascular event history, carotid intima-media thickness (cIMT), ankle brachial index (ABI), and serum N-terminal probrain natriuretic peptide (NT-proBNP). Seven neuropsychological tests were administered at baseline and after 4 years; scores were combined to a standardized general ability factor (g). Adjustment of follow-up g for baseline g assessed 4-year cognitive change. Adjustment for vocabulary (estimated premorbid ability) was used to estimate lifetime cognitive change.Measures of cognitive decline were significantly associated with stroke, NT-proBNP, ABI, and cIMT, but not with nonstroke vascular events. The association of stroke with increased estimated lifetime cognitive decline (standardized β, -0.12) and of subclinical markers with actual 4-year decline (standardized β, -0.12, 0.12, and -0.15 for NT-proBNP, ABI, and cIMT, respectively) reached the Bonferroni-adjusted level of statistical significance (P < 0.006). Results altered only slightly on adjustment for vascular risk factors.Stroke and subclinical markers of cardiac stress and generalized atherosclerosis are associated with cognitive decline in older patients with type 2 diabetes. Further investigation into the potential use of subclinical vascular disease markers in predicting cognitive decline is warranted.
Nonclassic Endogenous Novel Regulators of Angiogenesis
Authors: Domenico Ribatti, Maria Teresa Conconi, Gastone G. Nussdorfer
Journal: Pharmacological Reviews (2007)

Angiogenesis, the process through which new blood vessels arise from preexisting ones, is regulated by several "classic" factors, among which the most studied are vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2). In recent years, investigations showed that, in addition to the classic factors, numerous endogenous peptides play a relevant regulatory role in angiogenesis. Such regulatory peptides, each of which exerts well-known specific biological activities, are present, along with their receptors, in the blood vessels and may take part in the control of the "angiogenic switch." An in vivo and in vitro proangiogenic effect has been demonstrated for erythropoietin, angiotensin II (ANG-II), endothelins (ETs), adrenomedullin (AM), proadrenomedullin N-terminal 20 peptide (PAMP), urotensin-II, leptin, adiponectin, resistin, neuropeptide-Y, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), and substance P. There is evidence that the angiogenic action of some of these peptides is at least partly mediated by their stimulating effect on VEGF (ANG-II, ETs, PAMP, resistin, VIP and PACAP) and/or FGF-2 systems (PAMP and leptin). AM raises the expression of VEGF in endothelial cells, but VEGF blockade does not affect the proangiogenic action of AM. Other endogenous peptides have been reported to exert an in vivo and in vitro antiangiogenic action. These include somatostatin and natriuretic peptides, which suppress the VEGF system, and ghrelin, that antagonizes FGF-2 effects. Investigations on "nonclassic" regulators of angiogenesis could open new perspectives in the therapy of diseases coupled to dysregulation of angiogenesis.