tbuckley/cabot-search huggingface dataset:
Steroids induce a disequilibrium of secreted interleukin-1 receptor antagonist and interleukin-1 synthesis by human neutrophils
Authors: J.D. Langereis, E-J.D. Oudijk, R.C. Schweizer, J-W.J. Lammers, L. Koenderman, L.H. Ulfman
Journal: European Respiratory Journal (2010)

Chronic obstructive pulmonary disease (COPD) is characterised by neutrophilic inflammation in the airways and these neutrophils contribute to the production of inflammatory mediators. Dampening the production of proinflammatory mediators might be an important strategy to treat COPD and glucocorticosteroids are known to do so via inhibition of nuclear factor-κB. However, this pathway is important for the control of pro- and anti-inflammatory genes. We studied the effects of dexamethasone on production and secretion of pro-inflammatory interleukin (IL)-1β and anti-inflammatory secreted IL-1 receptor antagonist (sIL-1Ra) by human neutrophils activated with tumor necrosis factor (TNF)-α. In vitro , TNF-α-stimulated neutrophils produced significant amounts of IL-1β and sIL-1Ra; this production was inhibited by dexamethasone. However, synthesis and secretion of sIL-1Ra was inhibited at lower concentrations dexamethasone compared to IL-1β, which changed the IL-1β:sIL-1Ra ratio significantly. This altered ratio resulted in a more pro-inflammatory condition, as visualised by increased intercellular adhesion molecule-1 expression on human endothelial cells. In vivo , moderate-to-severe COPD patients using inhaled glucocorticosteroids have decreased plasma sIL-Ra levels compared with mild-to-moderate patients not on glucocorticosteroid treatment. In conclusion, dexamethasone induces a pro-inflammatory shift in the IL-1β:sIL-1Ra cytokine balance in neutrophils in vitro , which might contribute to a lack of endogenous anti-inflammatory signals to dampen inflammation in vivo .
Understanding the Estrogen Receptor-Positive Breast Cancer Genome: Not Even the End of the Beginning
Authors: B. A. Van Tine, M. J. Ellis
Journal: JNCI Journal of the National Cancer Institute (2011)

Global gene expression analysis has been used to subcategorize breast tumors into risk groups or intrinsic subtypes that have value clinically. However, our understanding of the cancer biology associated with these genes sets often remains obscure and, to add to the confusion, the same biology (eg, poor outcome on adjuvant tamoxifen therapy) can be predicted by different gene expression profiles with only partial overlap (1–3). Furthermore, the advent of massive parallel sequencing is adding another and even more startling level of complexity to the problem of biological interpretation (4,5). Careful well-powered molecular epidemiological studies are therefore necessary as a first step toward biological annotation to prioritize the genes and pathways most strongly associated with poor outcome. We also need high-fidelity models of breast cancer to efficiently and accurately test the roles of multiple genes in breast cancer biology. The ultimate goal of functional annotation efforts is to identify driver gene aberrations that can be targeted for therapy so that outcomes can be improved. In this issue of the Journal, Barone et al. (6) used current approaches for the identification and study of genes associated with tamoxifen resistance, a major issue in breast cancer therapy, by using genome-wide mRNA expression studies followed by pathway analysis in model systems. Their initial discovery effort, based on four primary tumors treated with tamoxifen that did not recur despite very long follow-up in comparison with five tumors from
Depression in Family Caregivers of Cancer Patients: The Feeling of Burden As a Predictor of Depression
Authors: Young Sun Rhee, Young Ho Yun, Sohee Park, Dong Ok Shin, Kwang Mi Lee, Han Jin Yoo, Jeong Hwa Kim, Soon Ok Kim, Ran Lee, Youn Ok Lee, Nam Shin Kim
Journal: Journal of Clinical Oncology (2008)

Purpose The purpose of this study was to explore the prevalence of and to identify the predictors of depression in family caregivers of cancer patients. Patients and Methods We enrolled 310 caregivers of cancer patients from the National Cancer Center, Korea, on this study and obtained demographic information for both patients and caregivers. To assess caregiver depression and its predictors, we used the Beck Depression Inventory (BDI), the Caregiver Quality of Life Index–Cancer, and the Family Impact Questionnaire. We used logistic regression analysis to identify independent predictors of caregiver depression. Results The majority (67%) of caregivers had high depression scores (BDI &gt; 13), and 35% had very high depression scores (BDI &gt; 21). In a multiple logistic regression model, caregivers who were women, the spouse of the patient, in poor health, feeling burdened, adapting poorly, unable to function normally, or caring for a patient with poor Eastern Cooperative Oncology Group performance status were more likely to experience depression (P &lt; .01 for all values). Conclusion Depression was highly prevalent among cancer patient family caregivers, and care burden was its best predictor. Interventions aimed at reducing the psychiatric effects of cancer should focus not only on the patient but also on the caregiver.
Cigarette smoke inhibits lung fibroblast proliferation by translational mechanisms
Authors: N. Miglino, M. Roth, D. Lardinois, C. Sadowski, M. Tamm, P. Borger
Journal: European Respiratory Journal (2011)

Cigarette smoke is a major cause of chronic obstructive pulmonary disease (COPD) and emphysema. Although cigarette smoke represses cellular proliferation, the molecular mechanisms underlying this phenomenon are unknown. CCAAT/enhancer-binding proteins (C/EBPs) are key regulators of cell cycle progression, differentiation and pro-inflammatory gene expression, are regulated predominantly at the translational level and may be involved in the pathogenesis of COPD. The aim of this study was to assess the effect of cigarette smoke on proliferation and the expression and translational regulation of C/EBPα and C/EBPβ in nondiseased primary human lung fibroblasts. Fibroblasts were exposed to cigarette smoke-conditioned medium (10% and 20% for 24 h). Proliferation was determined by [ 3 H]thymidine incorporation. Protein expression levels were determined by immunoblotting and translation was monitored using a translation control reporter system. Cigarette smoke significantly reduced fibroblast proliferation and significantly upregulated full-length C/EBPα and C/EBPβ proteins due to a shift in the translational control of CEBPA and CEBPB mRNAs. This shift involved the re-initiation of mRNA translation via the regulatory upstream open reading frame, which coincided with increased interleukin-8 release and a decrease in functional elastin level. These findings provide a novel mechanism to understanding the tissue remodelling observed in the lungs of COPD patients.
Catechol-O-Methyltransferase and Blood Pressure in Humans
Authors: Jens Jordan, Axel Lipp, Jens Tank, Christoph Schröder, Mandy Stoffels, Gabriele Franke, Andre Diedrich, Guy Arnold, David S. Goldstein, Arya M. Sharma, Friedrich C. Luft
Journal: Circulation (2002)

Background — Whether catechol-O-methyltransferase (COMT), the enzyme that metabolizes extraneuronal norepinephrine, contributes to blood pressure regulation in humans is unknown. Methods and Results — We studied incremental doses of the COMT inhibitor entacapone, the sympathetic stimulant yohimbine, and placebo in 7 patients with multiple system atrophy (Shy Drager syndrome). We selected these unique subjects because norepinephrine exerts an exaggerated increase in blood pressure in these patients. Autonomic regulation was characterized with intravenous phenylephrine, nitroprusside, and trimethaphan. Patients were extremely hypersensitive to phenylephrine and nitroprusside. Trimethaphan elicited a profound depressor response. Phenylephrine sensitivity increased only slightly during ganglionic blockade. Entacapone increased systolic blood pressure dose-dependently; however, the pressor response to yohimbine was ≈3.5 times greater than the maximal response to entacapone. Conclusions — COMT inhibition elicits a moderate, dose-dependent pressor response in the setting of severely impaired baroreflex buffering. Patients with multiple system atrophy allow for the characterization of subtle manipulations of norepinephrine turnover and blood pressure regulation in small numbers of subjects.
A Phase II Clinical Trial of ENMD-2076 in Metastatic Triple-Negative Breast Cancer: Translating a P53-Based Biomarker from Bench to Bedside
Authors: J.R. Diamond, A.C. Tan, T.M. Pitts, A. van Bokhoven, D. Aisner, A.D. Elias, V.F. Borges, K.D. Miller, S.G. Eckhardt, J.J. Tentler
Journal: Annals of Oncology (2013)
Cost Effectiveness of Ixabepilone Plus Capecitabine for Metastatic Breast Cancer Progressing After Anthracycline and Taxane Treatment
Authors: Shelby D. Reed, Yanhong Li, Kevin J. Anstrom, Kevin A. Schulman
Journal: Journal of Clinical Oncology (2009)

Using data from a recent randomized trial, we evaluated the cost effectiveness of ixabepilone plus capecitabine versus capecitabine alone in patients with predominantly metastatic breast cancer considered to be taxane-resistant and previously treated with or resistant to an anthracycline.We developed a stochastic decision-analytic model to represent data collected in the trial on medical resource use, health-related quality of life, and clinical outcomes. Estimates of overall survival were conditional on level of tumor response. We assigned monthly costs and utility weights according to periods defined by the duration of study treatment, time from discontinuation of the study drug until disease progression, and from progression until death and were specific to the level of response and receipt of subsequent therapy. Medical resources were valued in 2008 US dollars. We performed Monte Carlo simulations and sensitivity analyses to evaluate model uncertainty.Overall survival was significantly associated with level of tumor response (P < .001). Total costs were estimated at $60,900 for patients receiving ixabepilone plus capecitabine and $30,000 for patients receiving capecitabine alone. The estimated gain in life expectancy with ixabepilone was 1.96 months (95% CI, 1.36 to 2.64 months); the estimated gain in quality-adjusted survival was 1.06 months (95% CI, 0.09 to 2.03 months). The resulting incremental cost-effectiveness ratio was $359,000 per quality-adjusted life-year (95% CI, $183,000 to $4,030,000). In sensitivity analyses, the results were robust to changes in numerous inputs and assumptions.Addition of ixabepilone to capecitabine adds approximately $31,000 to overall medical costs and affords approximately 1 additional month of quality-adjusted survival.
Effectiveness of oral moxifloxacin in standard first-line therapy in community-acquired pneumonia
Authors: A. Torres, J-F. Muir, P. Corris, R. Kubin, I. Duprat-Lomon, P-P. Sagnier, G. Höffken
Journal: European Respiratory Journal (2003)

Based on recent guidelines for the management of community-acquired pneumonia, this study was designed to evaluate the effectiveness of a new fluoroquinolone compared with standard antimicrobial regimens, in conditions relating as closely as possible to the real world setting. In this study, 564 patients were randomised to either oral moxifloxacin (400 mg o.d .) or to standard oral therapy (amoxicillin 1 g t.i.d. or clarithromycin 500 mg b.i.d. alone or in combination) for up to 14 days using a double-blind procedure. The choice between the three standard regimens was made by the clinician prior to randomisation. Clinical response, quality of life, symptoms, healthcare resources and safety were assessed. In the per-protocol population, clinical success was reported for 201 of 215 (93.5%) and 217 of 231 (93.9%) in the moxifloxacin and standard groups, respectively, at 7–10 days post-therapy. At 28–35 days follow-up, continued clinical cure was observed in 183 of 192 (95.3%) moxifloxacin and 207 of 221 (93.7%) standard groups. Drug-related adverse events were reported in 55 of 274 (20%) moxifloxacin and 86 of 279 (31%) standard patients with diarrhoea &gt;5%. Oral moxifloxacin monotherapy was as effective as, and better tolerated than, optimal antibiotic strategy represented either by mono- or combination therapy (amoxicillin and/or clarithromycin) in community-acquired pneumonia management.
Radiation enhances silica translocation to the pulmonary interstitium and increases fibrosis in mice.
Authors: I Y Adamson
Journal: Environmental Health Perspectives (1992)

The effects of whole body irradiation (WBR) on particle clearance and the development of pulmonary fibrosis have been investigated. Using carbon, clearance is accomplished by polymorphonuclear leukocytes (PMN) and alveolar macrophages (AM), and only a few particles reach the interstitum. However, in preirradiated mice, the usual eflux of inflammatory cells is much delayed so that more free carbon remains in the alveoli, and by 1 week, many particles cross the epithelium to be phagocytized by interstitial macrophages. Carbon is found in the peribronchiolar interstitium 6 months later with no evidence of fibrosis. In the present study, mice received 1 mg silica intratracheally 2 days after 6.5 Gy WBR when the white blood cell count was low. A much-reduced AM and PMN response was found in the following 2 weeks compared to the reaction to silica alone, and many silica particles reached interstitial macrophages. In this case, macrophage activation by silica was associated with fibroblast proliferation, and by 16 weeks, much more pulmonary fibrosis was produced than after silica or irradiation only. This was measured biochemically and correlated with a large increase in retained silica in the irradiation-silica group. The results indicate that radiation inhibits the inflammatory response to particle instillation, resulting in greater translocation of free particles to the pulmonary interstitium. In the case of silica, the greater, prolonged interaction with interstitial macrophages leads to a much exaggerated fibrotic reaction.
Cardioprotection by <i>N</i> -Acetylglucosamine Linkage to Cellular Proteins
Authors: Steven P. Jones, Natasha E. Zachara, Gladys A. Ngoh, Bradford G. Hill, Yasushi Teshima, Aruni Bhatnagar, Gerald W. Hart, Eduardo Marbán
Journal: Circulation (2008)

Background— The modification of proteins with O -linked β- N -acetylglucosamine ( O -GlcNAc) represents a key posttranslational modification that modulates cellular function. Previous data suggest that O -GlcNAc may act as an intracellular metabolic or stress sensor, linking glucose metabolism to cellular function. Considering this, we hypothesized that augmentation of O -GlcNAc levels represents an endogenously recruitable mechanism of cardioprotection. Methods and Results— In mouse hearts subjected to in vivo ischemic preconditioning, O -GlcNAc levels were significantly elevated. Pharmacological augmentation of O -GlcNAc levels in vivo was sufficient to reduce myocardial infarct size. We investigated the influence of O -GlcNAc levels on cardiac injury at the cellular level. Lethal oxidant stress of cardiac myocytes produced a time-dependent loss of cellular O -GlcNAc levels. This pathological response was largely reversible by pharmacological augmentation of O -GlcNAc levels and was associated with improved cardiac myocyte survival. The diminution of O -GlcNAc levels occurred synchronously with the loss of mitochondrial membrane potential in isolated cardiac myocytes. Pharmacological enhancement of O -GlcNAc levels attenuated the loss of mitochondrial membrane potential. Proteomic analysis identified voltage-dependent anion channel as a potential target of O -GlcNAc modification. Mitochondria isolated from adult mouse hearts with elevated O -GlcNAc levels had more O -GlcNAc–modified voltage-dependent anion channel and were more resistant to calcium-induced swelling than cardiac mitochondria from vehicle mice. Conclusions— O -GlcNAc signaling represents a unique endogenously recruitable mechanism of cardioprotection that may involve direct modification of mitochondrial proteins critical for survival such as voltage-dependent anion channel.
Fatal peptic ulcer complications and the use of non-steroidal anti-inflammatory drugs, aspirin, and corticosteroids.
Authors: D A Henry, A Johnston, A Dobson, J Duggan
Journal: BMJ (1987)

Although non-steroidal anti-inflammatory drugs are known to cause peptic ulcer and its complications, controversy exists about the number of deaths from ulcer which are attributable to their use. A case-control study was therefore performed to determine whether prior use of non-steroidal and other anti-inflammatory compounds was associated with an increased case fatality rate from complications of peptic ulcer. Non-steroidal anti-inflammatory drugs were used by 39% of a series of 80 patients who had died from peptic ulcer complications and by 37% of 160 controls who were survivors matched for sex, age, ulcer site, and nature of complication (odds ratio 1.1; 95% confidence interval 0.6 to 2.1). Similarly, the rates of prior use of aspirin by cases and controls were almost identical (odds ratio 1.2; 95% confidence interval 0.5 to 1.9). Thus neither nonsteroidal anti-inflammatory drugs nor aspirin were associated with increased case fatality rates from peptic ulcer complications. In contrast, corticosteroids were associated with an increased mortality (odds ratio 4.2; 95% confidence interval 0.9 to 25.6). Although this increase in the estimated relative risk was not statistically significant, a review of the case records indicated that most deaths in steroid users were due to serious sepsis, indicating that there might be a causal association between use of the drugs and the mode of death.
Dual Therapy of Ovarian Cancer Using Measles Viruses Expressing Carcinoembryonic Antigen and Sodium Iodide Symporter
Authors: Kosei Hasegawa, Linh Pham, Michael K. O'Connor, Mark J. Federspiel, Stephen J. Russell, Kah-Whye Peng
Journal: Clinical Cancer Research (2006)

Abstract Purpose: MV-CEA is an oncolytic measles virus currently being tested in patients with ovarian cancer and whose propagation can be monitored by measuring blood carcinoembryonic antigen (CEA) levels. MV-NIS is an oncolytic measles virus coding for the thyroidal sodium iodide symporter (NIS) whose propagation can be mapped by serial radioiodine imaging. Expression of both CEA and NIS genes from a single virus would combine sensitive, quantitative expression monitoring (CEA) with radioisotopic expression mapping (NIS). Because of the unfavorable replication kinetics of measles viruses expressing both CEA and NIS, we explored the feasibility of combining MV-CEA with MV-NIS for comprehensive virotherapy monitoring in ovarian cancer. Experimental Design and Results: Mice implanted with i.p. SKOV3ip.1 ovarian cancer xenografts received MV-CEA alone, MV-NIS alone, or a combination of MV-CEA plus MV-NIS. Viral gene expression was monitored by measuring blood CEA levels, and the location of virus-infected cells was monitored by gamma camera imaging. Surprisingly, mice receiving the combination of MV-CEA plus MV-NIS showed greatly superior responses to therapy, but this was associated with 10-fold lower plasma levels of CEA compared with mice treated with MV-CEA alone. In vitro studies showed superior replication kinetics of MV-NIS relative to MV-CEA. The gamma camera scans were considerably less sensitive than the plasma CEA marker for monitoring virus infection. Conclusions: Dual therapy with MV-CEA and MV-NIS is superior to treatment with either virus alone, and it allows noninvasive monitoring of virotherapy via soluble marker peptide and gamma camera imaging. This has important implications for the clinical development of oncolytic measles viruses.
Evaluation of New Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer: A Phase III Trial of the Gynecologic Cancer InterGroup
Authors: Michael A. Bookman, Mark F. Brady, William P. McGuire, Peter G. Harper, David S. Alberts, Michael Friedlander, Nicoletta Colombo, Jeffrey M. Fowler, Peter A. Argenta, Koen De Geest, David G. Mutch, Robert A. Burger, Ann Marie Swart, Edward L. Trimble, Chrisann Accario-Winslow, Lawrence M. Roth
Journal: Journal of Clinical Oncology (2009)

To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel.
Increased salivary exoglycosidase activity during critical illness.
Authors: M O Quinn, V E Miller, A R Dal Nogare
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

Exoglycosidases remove peripheral monosaccharides from oligosaccharides and hence are capable of altering respiratory epithelial cell surface carbohydrates. We obtained saliva and tracheal secretions from 34 critically ill patients and saliva from 23 healthy subjects. Compared with the normal subjects, the ill patients had large amounts of mannosidase, fucosidase, hexosaminidase, and sialidase activity. Sialidase increased adherence of several gram-negative bacteria to epithelial cell monolayers and pure glycoproteins. Pretreatment of glycoproteins with some of the patients' saliva samples also increased bacterial adherence to the glycoproteins. We conclude that respiratory tract exoglycosidase activity increases during critical illness. By altering normal cell surface carbohydrates, exoglycosidases may facilitate bacterial adherence and respiratory tract colonization.
Validation of a Novel Screening Device (NeuroQuick) for Quantitative Assessment of Small Nerve Fiber Dysfunction as an Early Feature of Diabetic Polyneuropathy
Authors: Dan Ziegler, Ewa Siekierka-Kleiser, Bernd Meyer, Michael Schweers
Journal: Diabetes Care (2005)

OBJECTIVE—To validate a handheld screening device (NeuroQuick) for an early detection of diabetic distal symmetric polyneuropathy (DSP) by quantitative testing of cold sensation based on the wind chill factor (NeuroQuick threshold [NQT]). RESEARCH DESIGN AND METHODS—NQT was measured on the dorsum of the foot in 160 healthy subjects as well as 60 and 128 diabetic patients without and with DSP, respectively. DSP was diagnosed by a neurological examination, motor and sensory nerve conduction velocity, vibration perception threshold, and warm and cold thermal perception threshold (TPT) (TPT Medoc). In addition, a C-64 Hz tuning fork and TipTherm device were used as screening instruments. RESULTS—In the diabetic cohort, NQT correlated significantly with all nerve function tests, with the highest correlation coefficients being found on the foot versus Medoc warm TPT (r = 0.618, P &amp;lt; 0.001) and cold TPT (r = 0.529, P &amp;lt; 0.001). Among patients with DSP, NQT was abnormal, whereas Medoc warm TPT was normal in 34%, whereas only 5% showed the opposite constellation (P &amp;lt; 0.05). Likewise, the corresponding percentages for Medoc cold TPT were 32 and 11%, for TipTherm 47 and 2%, and for the tuning fork 29 and 10% (all P &amp;lt; 0.05), whereas no significant differences were noted when comparing NQT with peroneal motor nerve conduction velocity, sural sensory nerve conduction velocity, and malleolar vibration perception threshold. The coefficients of variation for repeated NQT measurements in 41 control and 41 diabetic subjects were 20.4 and 8.5%, respectively. CONCLUSIONS—The NeuroQuick is a valid and reliable screening tool for quantitative assessment of small nerve fiber dysfunction. This device appears to be more sensitive in detecting early diabetic polyneuropathy than both elaborate thermal testing and screening tests such as the tuning fork.