tbuckley/cabot-search huggingface dataset:
Tumor tissue levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) and survival following adjuvant chemotherapy in pre-menopausal lymph node-positive breast cancer patients (N=525).
Authors: A Schrohl, MP Look, ME Meijer-van Gelder, JA Foekens, N Brünner
Journal: Cancer Research (2009)

Abstract Abstract #6054 Predictive markers are needed to guide planning of adjuvant therapy for breast cancer patients. We have recently shown that high tumor tissue levels of TIMP-1 are associated with decreased response to chemotherapy in metastatic breast cancer (Schrohl et al, Clin Cancer Res, 2006) suggesting that TIMP-1 may be a predictive marker in breast cancer patients.&amp;#x2028; Purpose: This study investigates the association of tumor tissue TIMP-1 levels with response to adjuvant chemotherapy with CMF (cyclophosphamide/methotrexate/5-fluorouracil) or an anthracycline-based regimen.&amp;#x2028; Patients and Methods: 525 pre-menopausal lymph node-positive patients were included; 324 patients received adjuvant CMF, 99 received an adjuvant anthracycline-containing regimen and 102 had no adjuvant chemotherapy. Total TIMP-1 levels were measured using ELISA in cytosolic extracts of frozen primary tumors. Using the untreated patient group as a reference group we analyzed the benefit of adjuvant CMF and anthracyclines in TIMP-1 high and low patients, respectively. The median TIMP-1 concentration was used to dichotomize patients into high and low TIMP-1 groups. End points were disease-free and overall survival (DFS, OS).&amp;#x2028; Results: The median TIMP-1 level in the total patient group was 12,54 ng/mg of total protein (range, 0 – 112,9 ng/mg). TIMP-1 levels in subgroups according to adjuvant therapy were not significantly different (P=0,20). In a multivariate model including basic clinico-pathological parameters, TIMP-1 low and high patients benefited differentially from adjuvant CMF and anthracyclines when compared to untreated patients. In particular, patients with high tumor levels of TIMP-1 had little benefit from adjuvant anthracyclines. Hazard ratios (HR) and 95% confidence intervals (CI) are given in the table for the analysis of DFS. A similar pattern was seen in the analyses of OS. In the CMF-treated group, both TIMP-1 low and high patients had significantly better survival than untreated patients (P&amp;lt;0,01). Among anthracycline-treated patients those with TIMP-1 low tumors appeared to benefit more from the adjuvant therapy than TIMP-1 high patients although these results did not reach significance in the present analyses.&amp;#x2028; &amp;#x2028; Conclusion: This study suggests that high tumor tissue TIMP-1 levels are associated with decreased benefit from adjuvant chemotherapy. Especially in the group treated with anthracycline-based therapy there is a strong tendency for TIMP-1 high tumors to be less sensitive to the treatment. This group, however, is small and should be enlarged to confirm our results. In the group treated with CMF all patients benefit from the therapy with TIMP-1 high patients having slightly less benefit than TIMP-1 low patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6054.
Role of KATP channels in sepsis
Authors: J BUCKLEY, M SINGER, L CLAPP
Journal: Cardiovascular Research (2006)

Sepsis is an infection-induced inflammatory syndrome responsible for ∼10% of all deaths worldwide. While pathophysiological mechanisms remain to be fully unravelled, new insights and discoveries are yielding significant improvements in outcome, particularly in the high mortality conditions of shock and multi-organ failure. One potential target is the ATP-sensitive potassium (KATP) channel, an ion channel critical to the cardiovascular stress response. Excessive activation of the vascular channel is now recognised as a major cause of hypotension and vascular hyporesponsiveness to catecholamines in septic shock. Some researchers advocate therapeutic blockade of these channels; however, outside the vasculature, channel opening may actually represent a protective mechanism against cellular damage. In this review we critically examine the role of the KATP channel in sepsis.
The dishomeostasis of metal ions plays an important role for the cognitive impartment
Authors: Dehua Chui, Huan Yang, Hecheng Wang, Tuo Ji, Jia Yu, Shouzi Zhang, Zheng Chen, WeiZhong Xiao
Journal: Molecular Neurodegeneration (2013)

Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer’s disease (AD) and might underlie memory impairment. The homeostasis of metal ions plays an important role in health and neurodegenerative disease by influencing cellular biochemical pathways. The disturbance of some metal ions may have cytotoxic effects, which may cause cell death leading to neurodegenerative disorders such as AD. The aim of the present study was to investigate metal concentrations in whole blood from Chinese AD patients with APOE e4 allele carrier. Concentrations of metals (magnesium, calcium, manganese, iron, cobalt, copper, zinc, selenium, cadmium, mercury and lead) were determined in whole blood by inductively coupled plasma mass spectrometry (ICP-MS) in 40 Chinese people with different Mini-mental state examination (MMSE) score. Normal APP processing could be restored when magnesium was adjusted back to physiological concentration. Our findings suggest that supplementation of magnesium has a therapeutic potential for preventing AD. We observed that Plasma Mg, Zn and Se levels were found to be significantly lower in patients with AD compared with controls. Furthermore, there is a significant negative correlation between manganese and MMSE score. Whereas other metal ions have no association with MMSE score. These result suggests that dishomeostasis of metal ions may involve in the progress of AD pathology, and elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of AD and may have therapeutic potential for treating AD in humans.
A Genetic Algorithm Approach to Detecting Lineage-Specific Variation in Selection Pressure
Authors: Sergei L. Kosakovsky Pond, Simon D. W. Frost
Journal: Molecular Biology and Evolution (2004)

The ratio of nonsynonymous (dN) to synonymous (dS) substitution rates, omega, provides a measure of selection at the protein level. Models have been developed that allow omega to vary among lineages. However, these models require the lineages in which differential selection has acted to be specified a priori. We propose a genetic algorithm approach to assign lineages in a phylogeny to a fixed number of different classes of omega, thus allowing variable selection pressure without a priori specification of particular lineages. This approach can identify models with a better fit than a single-ratio model, and with fits that are better than (in an information theoretic sense) a fully local model, in which all lineages are assumed to evolve under different values of omega, but with far fewer parameters. By averaging over models which explain the data reasonably well, we can assess the robustness of our conclusions to uncertainty in model estimation. Our approach can also be used to compare results from models in which branch classes are specified a priori with a wide range of credible models. We illustrate our methods on primate lysozyme sequences and compare them with previous methods applied to the same data sets.
Identification of Severe Acute Respiratory Syndrome in Canada
Authors: Susan M Poutanen, Donald E Low, Bonnie Henry, Sandy Finkelstein, David Rose, Karen Green, Raymond Tellier, Ryan Draker, Dena Adachi, Melissa Ayers, Adrienne K Chan, Danuta M Skowronski, Irving Salit, Andrew E Simor, Arthur S Slutsky, Patrick W Doyle, Mel Krajden, Martin Petric, Robert C Brunham, Allison J McGeer
Journal: New England Journal of Medicine (2003)

BackgroundSevere acute respiratory syndrome (SARS) is a condition of unknown cause that has recently been recognized in patients in Asia, North America, and Europe. This report summarizes the initial epidemiologic findings, clinical description, and diagnostic findings that followed the identification of SARS in Canada.MethodsSARS was first identified in Canada in early March 2003. We collected epidemiologic, clinical, and diagnostic data from each of the first 10 cases prospectively as they were identified. Specimens from all cases were sent to local, provincial, national, and international laboratories for studies to identify an etiologic agent.ResultsThe patients ranged from 24 to 78 years old; 60 percent were men. Transmission occurred only after close contact. The most common presenting symptoms were fever (in 100 percent of cases) and malaise (in 70 percent), followed by nonproductive cough (in 100 percent) and dyspnea (in 80 percent) associated with infiltrates on chest radiography (in 100 percent). Lymphopenia (in 89 percent of those for whom data were available), elevated lactate dehydrogenase levels (in 80 percent), elevated aspartate aminotransferase levels (in 78 percent), and elevated creatinine kinase levels (in 56 percent) were common. Empirical therapy most commonly included antibiotics, oseltamivir, and intravenous ribavirin. Mechanical ventilation was required in five patients. Three patients died, and five have had clinical improvement. The results of laboratory investigations were negative or not clinically significant except for the amplification of human metapneumovirus from respiratory specimens from five of nine patients and the isolation and amplification of a novel coronavirus from five of nine patients. In four cases both pathogens were isolated.ConclusionsSARS is a condition associated with substantial morbidity and mortality. It appears to be of viral origin, with patterns suggesting droplet or contact transmission. The role of human metapneumovirus, a novel coronavirus, or both requires further investigation.
A Research Trail Over Half a Century
Authors: Robert F. Furchgott
Journal: The Annual Review of Pharmacology and Toxicology (1995)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More
Increases in physical activity is as important as smoking cessation for reduction in total mortality in elderly men: 12 years of follow-up of the Oslo II study
Authors: I Holme, S A Anderssen
Journal: British Journal of Sports Medicine (2015)

Physical activity (PA) at leisure by the elderly, and its relationship to cardiovascular (CV) and non-CV mortality, with and without competing risk, has been scarcely described. We determined the relationships between PA, smoking and 12-year CV, non-CV and all-cause mortality in elderly Oslo men screened for CV disease in 1972-1973 and 2000.Among 14,846 men born during 1923-1932 and participating in 1972-1973, there were 5738 participants in 2000. During the 12 years follow-up 2154 died. Cox regression modelling of mortality endpoints, with and without competing risk, was applied analysing PA variables hours per week of light or vigorous PA intensity and degree of PA at leisure. Comparisons of predictive ability between PA and smoking were done by receiver operating characteristics.Thirty minutes of PA per 6 days a week was associated with about 40% mortality risk reduction. There was a 5 years increased lifetime when comparing sedentary and moderate to vigorous physically active men. Associations to CV or non-CV mortality were slightly weakened, allowing competing risk. Conditional on the prevalence of smoking and PA, the degree of PA at leisure was almost as predictive as smoking with regard to the effects on mortality. Increase in PA was as beneficial as smoking cessation in reducing mortality.Even at the age of 73 years, PA is associated highly with mortality between groups of sedentary and active persons. Allowing for competing risk did not weaken these associations markedly. Public health strategies in elderly men should include efforts to increase PA in line with efforts to reduce smoking behaviour.
Phase II Trial of Docetaxel With Rapid Androgen Cycling for Progressive Noncastrate Prostate Cancer
Authors: Dana Rathkopf, Michael A. Carducci, Michael J. Morris, Susan F. Slovin, Mario A. Eisenberger, Roberto Pili, Samuel R. Denmeade, Moshe Kelsen, Tracy Curley, Melinda Halter, Connie Collins, Martin Fleisher, Glenn Heller, Sharyn D. Baker, Howard I. Scher
Journal: Journal of Clinical Oncology (2008)

We evaluated rapid androgen cycling in combination with docetaxel for men with progressive noncastrate prostate cancers.
Community-acquired methicillin-resistant <i>Staphylococcus aureus</i> : different populations, different results: reply from authors
Authors: P.D. Del Giudice
Journal: British Journal of Dermatology (2006)

Journal Article Community‐acquired methicillin‐resistant Staphylococcus aureus: different populations, different results: reply from authors Get access P.D. Del Giudice P.D. Del Giudice Unité d'Infectiologie–Dermatologie, Hôpital Bonnet, 83700 Fréjus, France E‐mail: del‐giudice‐p@frejus‐saint‐raphael.fr Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 155, Issue 6, 1 December 2006, Page 1299, https://doi.org/10.1111/j.1365-2133.2006.07544.x Published: 01 December 2006
IL-17 and tumour necrosis factor α combination induces a HIF-1α-dependent invasive phenotype in synoviocytes
Authors: Arnaud Hot, Saloua Zrioual, Vanina Lenief, Pierre Miossec
Journal: Annals of the Rheumatic Diseases (2012)

To examine the effect of interleukin-17 (IL-17) on rheumatoid arthritis (RA) synoviocyte migration and invasiveness.IL-17A and tumour necrosis factor α (TNFα)-induced messenger RNA expression in RA synoviocytes was analysed using Affymetrix U133A microarrays. The capacity of IL-17 alone or in combination with TNFα to induce synoviocyte migration and invasion was tested using Boyden and transwell Matrigel invasion chambers. A functional DNA binding assay was used to evaluate the regulation of the key hypoxia-related gene hypoxia-inducible factor 1 (HIF-1α) expression and activation. The role of metalloproteinase 2 (MMP2) in IL-17-induced invasiveness was assessed using small interfering RNA. Hypoxia pathway gene expression was measured in the blood of RA patients and healthy volunteers using Affymetrix microarrays.Among the genes induced by IL-17A in RA synoviocytes, a molecular pattern of inflammation hypoxia-related genes, including CXC chemokine receptor 4 (CXCR4) and MMP2 was identified. Using immunofluorescence microscopy, the expression of CXCR4 was confirmed on synoviocytes. IL-17A and TNFα induced synoviocyte migration and invasion through a CXCR4-dependent mechanism with a synergistic effect. Their combination activated HIF-1α through the nuclear factor κB pathway. IL-17 enhanced invasion through MMP2 induction as demonstrated using siRNA. Finally, hypoxia genes were overexpressed in the blood of RA patients.IL-17A, specifically when combined with TNFα may contribute to the progression of RA, notably through their effect on synoviocyte aggressiveness. Part of this effect results from activation of the CXCR4/stromal cell-derived factor 1 and hypoxia-mediated pathways.
The spectrum of bacterial resistance in the lower respiratory tract infections in Oradea Pneumology Hospital in 2011
Authors: Lavinia Davidescu, Natalia Zaporojean
Journal: European Respiratory Journal (2012)

Aim: Estimation of pathogen resistance (Enterobacteriaceae: Klebsiella, E. coli, Proteus, Enterobacter, Pseudomonas) isolated from different pathological products to antibiotics currently used in clinical practice: ampicillin, ampicillin + sulbactam, amoxicillin + clavulanic acid, cefotaxime, ceftazidime, ceftriaxone.  Material and method: sensitivity and resistance of these pathogens to antibiotics was determined by performing diffusion antibiogram from bacterial cultures isolated from pathological products collected from patients diagnosed with lower respiratory infections and admitted to the Pneumology Hospital Oradea in 2011. In carrying out our study were used 4358 bacterial cultures isolated from pathological products: sputum, bronchial lavage, bronchial aspirate.  Results and conclusions: From 4358 bacterial cultures, 128 were represented by Klebsiella, 68 of E. coli, 131 of Pseudomonas, 40 of Enterobacter, 98 of S. aureus, 8 of Proteus. At Meropenem, Pseudomonas spp became resistant, Klebsiella and Proteus sensitivity did not change, while Staphylococcus sensitivity decreased although it remained responsive to this antibiotic. E. coli has retained sensitivity to the action of Ampicillin +Sulbactam.In contrast to the others germs, that we found a tendency to the development resistance to Ampicillin + Sulbactam, only E. coli and Klebsiella species have intermediate sensitivity to Ampicillin + Sulbactam. At Klebsiella and Enterobacter we found tendency to installation of resistance to this antibiotic. We noticed a tendency to definitive Ampicillin resistance at the following pathogens: E. coli, Klebsiella ssp, Enterobacter spp, Proteus ssp.
Skeletal muscle oxygenation during exercise in patients with chronic respiratory failure
Authors: Kazuyuki Tabira, Jun Horie, Hiromasa Fujii, Toshio Aida
Journal: European Respiratory Journal (2012)

Background: Muscle oxygenation correlates with systemic oxygen uptake (VO2) in normal subjects, however whether this relationship exists chronic respiratory failure (CRF) patients remains unclear.

Objectives: The purpose of this study was to investigate the influence of skeletal muscle oxygenation on VO2 during exercise in CRF patients.

Methods: Ten chronic obstructive pulmonary disease and two sequelae of pulmonary tuberculosis patients performed an incremental cycle ergometer exercise test. We measured ventilation, pulmonary gas exchange and SaO2. We also measured tissue oxygen saturation (StO2) in the vastus lateralis with continuous-wave near-infrared spectroscopy. We calculated the muscle oxygen extraction rate (MOER) based on SaO2 and StO2. In addition, we performed regression analysis to examine the relationships between the VO2 obtained during exercise testing and the mean values of SaO2, StO2, heart rate (HR), and MOER for each 30-second interval of the tests. Finally, we analysed the relationships between the peak value of oxygen uptake (VO2peak) and the slopes of HR/VO2, SaO2/VO2, StO2/VO2, and MOER/VO2.

Results: With the increasing exercise intensity, many subjects showed a gradual decrease in StO2 and SaO2, but a gradual increase in HR and MOER. VO2 was negatively correlated with StO2 and SaO2, and was positively correlated with HR and MOER. However, VO2peak was not correlated with any of the slopes.

Conclusions: VO2 is highly influenced by oxygen utilization in exercising muscles, as well as by blood oxygenation levels and cardiac function. However, the impact of skeletal muscle utilization during exercise on VO2peak varied greatly among the patients.
Cause-Specific Survival for Women Diagnosed With Cancer During Pregnancy or Lactation: A Registry-Based Cohort Study
Authors: Hanne Stensheim, Bjørn Møller, Tini van Dijk, Sophie D. Fosså
Journal: Journal of Clinical Oncology (2008)

To assess if cancers diagnosed during pregnancy or lactation are associated with increased risk of cause-specific death.In this population-based cohort study using data from the Cancer Registry and the Medical Birth Registry of Norway, 42,511 women, age 16 to 49 years and diagnosed with cancer from 1967 to 2002, were eligible. They were grouped as not pregnant (reference), pregnant, or lactating at diagnosis. Cause-specific survival for all sites combined, and for the most frequent malignancies, was investigated using a Cox proportional hazards model. An additional analysis with time-dependent covariates was performed for comparison of women with and without a postcancer pregnancy. The multivariate analyses were adjusted for age at diagnosis, extent of disease, and diagnostic periods.For all sites combined, no intergroup differences in cause-specific death were seen, with hazard ratio (HR) of 1.03 (95% CI, 0.86 to 1.22) and HR 1.02 (95% CI, 0.86 to 1.22) for the pregnant and lactating groups, respectively. Patients with breast (HR, 1.95; 95% CI, 1.36 to 2.78) and ovarian cancer (HR, 2.23; 95% CI, 1.05 to 4.73) diagnosed during lactation had an increased risk of cause-specific death. Diagnosis of malignant melanoma during pregnancy slightly increased this risk. For all sites combined, the risk of cause-specific death was significantly decreased for women who had postcancer pregnancies.In general, the diagnosis of most cancer types during pregnancy or lactation does not increase the risk of cause-specific death. Breast and ovarian cancer diagnosed during lactation represents an exception. We confirmed the "healthy mother effect" for women with a postcancer pregnancy.
CXCR4 Inhibition Synergizes with Cytotoxic Chemotherapy in Gliomas
Authors: Navid Redjal, Jennifer A. Chan, Rosalind A. Segal, Andrew L. Kung
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The chemokine receptor CXCR4 is expressed in many different cancers. In malignant brain tumors, CXCR4 signaling has been implicated in tumor growth, survival, and migration, and pharmacologic inhibition of CXCR4 results in decreased tumor growth in preclinical models. To understand how CXCR4 inhibitors may be incorporated into clinical therapy, we examined determinants of responsiveness to CXCR4 inhibition. Because optimal use of CXCR4 inhibition will likely be a part of multimodality therapy, we also investigated the efficacy of CXCR4 inhibition combined with conventional cytotoxic chemotherapy. Experimental Design: CXCR4 protein levels and responsiveness to the CXCR4 inhibitor AMD3100 were determined in a panel of glioblastoma multiforme cell lines. The effects of AMD3100, alone or in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), on cell growth were determined for several of these cell lines in vitro. We used an orthotopic model of glioblastoma multiforme to evaluate the antitumor efficacy of AMD3100 combined with BCNU in vivo. Results: The level of CXCR4 protein expression in glioblastoma multiforme cells predicts the dose at which there is a response to AMD3100; cells that express higher levels of CXCR4 protein require higher doses for equivalent response. In all cell lines tested, treatment of glioblastoma multiforme cells with BCNU followed by AMD3100 results in synergistic antitumor efficacy in vitro. This synergy can also be seen in an orthotopic glioblastoma multiforme model. Treatment with subtherapeutic doses of BCNU in combination with AMD3100 results in tumor regression in vivo, and this reflects both increased apoptosis and decreased proliferation following combination therapy. Conclusion: These studies support testing CXCR4 inhibitors in patients with glioblastoma multiforme and establish that inhibition of CXCR4 synergizes with conventional cytotoxic therapies in a clinically relevant combinatorial strategy.
Role of the Ubiquitin Proteasome System in the Heart
Authors: Julia Pagan, Tiffany Seto, Michele Pagano, Antonio Cittadini
Journal: Circulation Research (2013)

Proper protein turnover is required for cardiac homeostasis and, accordingly, impaired proteasomal function appears to contribute to heart disease. Specific proteasomal degradation mechanisms underlying cardiovascular biology and disease have been identified, and such cellular pathways have been proposed to be targets of clinical relevance. This review summarizes the latest literature regarding the specific E3 ligases involved in heart biology, and the general ways that the proteasome regulates protein quality control in heart disease. The potential for therapeutic intervention in Ubiquitin Proteasome System function in heart disease is discussed.