tbuckley/cabot-search huggingface dataset:
Gene-Environment Interactions in Asthma and Other Respiratory Diseases
Authors: Steven R. Kleeberger, David Peden
Journal: Annual Review of Medicine (2004)

It is generally agreed that many lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) have polygenic inheritance, and that the association of a specific genotype or genotypes with the disease is likely to vary between populations. Furthermore, it is recognized that the etiology of many lung diseases involves a complex interplay between genetic background and exposure to multiple environmental stimuli, and understanding the mechanisms through which genes and environment interact represents a major challenge for pulmonary researchers. We discuss experimental approaches and challenges that must be overcome to identify disease genes for asthma, COPD and chronic bronchitis, and occupational lung diseases. In particular, common polymorphisms in CD14, glutathione S-transferase, and tumor necrosis factor alpha have been found to be important in gene-environment interaction and asthma pathogenesis. An understanding of gene-environment interactions in complex lung diseases is essential to the development of new strategies for lung disease prevention and treatment.
Calcium-Binding Proteins S100A8 and S100A9 as Novel Diagnostic Markers in Human Prostate Cancer
Authors: Alexander Hermani, Jochen Hess, Barbara De Servi, Senad Medunjanin, Rainer Grobholz, Lutz Trojan, Peter Angel, Doris Mayer
Journal: Clinical Cancer Research (2005)

Abstract Purpose: S100 proteins comprise a family of calcium-modulated proteins that have recently been associated with epithelial tumors. We examined the expression of two members of this family, S100A8 and S100A9, together with the S100 receptor RAGE (receptor for advanced glycation end products) in human prostate adenocarcinomas and in prostatic intraepithelial neoplasia. Experimental Design: Tissue specimens of 75 patients with organ-confined prostate cancer of different grades were analyzed by immunohistochemistry for expression of S100A8, S100A9, and RAGE. In addition, in situ hybridization of S100A8 and S100A9 was done for 20 cases. An ELISA was applied to determine serum concentrations of S100A9 in cancer patients compared with healthy controls or to patients with benign prostatic hyperplasia (BPH). Results: S100A8, S100A9, and RAGE were up-regulated in prostatic intraepithelial neoplasia and preferentially in high-grade adenocarcinomas, whereas benign tissue was negative or showed weak expression of the proteins. There was a high degree of overlap of S100A8 and S100A9 expression patterns and of S100A8 or S100A9 and RAGE, respectively. Frequently, a gradient within the tumor tissue with an increased expression toward the invaded stroma of the prostate was observed. S100A9 serum levels were significantly elevated in cancer patients compared with BPH patients or healthy individuals. Conclusion: Our data suggest that enhanced expression of S100A8, S100A9, and RAGE is an early event in prostate tumorigenesis and may contribute to development and progression or extension of prostate carcinomas. Furthermore, S100A9 in serum may serve as useful marker to discriminate between prostate cancer and BPH.
Effects of an inotropic agent, RO 2-2985 (X-537A), on regional blood flow and myocardial function in chronically instrumented conscious dogs and anesthetized dogs.
Authors: H G Hanley, R M Lewis, C J Hartley, D Franklin, A Schwartz
Journal: Circulation Research (1975)

RO 2-2985 produced a marked positive inotropic effect in unanesthetized, chronically instrumented dogs, measured as an increase in left ventricular dP/ dt and an increase in maximum velocity of myocardial fiber shortening. Similar changes produced in dogs in hemorrhagic shock lasted for 2-3 hours. RO 2-2985 increased peripheral blood flow and caused marked increases in both coronary and renal blood flows. The drug altered the response of the renal vascular bed to subsequent norepinephrine administration. After administration of a single dose of RO 2-2985, norepinephrine produced sustained increases in renal blood flow, and this altered responsiveness to norepinephrine persisted for periods ranging from 1 to 3 weeks.
AMPK: A Contextual Oncogene or Tumor Suppressor?
Authors: Jiyong Liang, Gordon B. Mills
Journal: Cancer Research (2013)

The AMP-activated protein kinase (AMPK) functions to monitor and maintain energy homeostasis at the cellular and organism level. AMPK was perceived historically primarily as a component of the LKB1/STK11 tumor suppressor (LKB1 mutations cause the Peutz-Jegher cancer predisposition syndrome) cascade upstream of the TSC1/2/mTOR pathway and thus likely to be a tumor suppressor. However, AMPK has recently been shown to promote cancer cell survival in the face of extrinsic and intrinsic stressors including bioenergetic, growth factor, and oncogene stress compatible with studies showing that AMPK is required for oncogenic transformation. Thus, whether AMPK acts as a bona fide tumor suppressor or a contextual oncogene and, of particular importance, whether AMPK should be targeted for activation or inhibition during cancer therapy, is controversial and requires clarification. We aim to initiate discussions of these critical questions by reviewing the role of AMPK with an emphasis on cancer cell adaptation to microenvironment stress and therapeutic intervention.
The effect of inhaled leukotriene D4 and methacholine on sputum cell differentials in asthma.
Authors: Z Diamant, J T Hiltermann, E L van Rensen, P M Callenbach, M Veselic-Charvat, H van der Veen, J K Sont, P J Sterk
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The cysteinyl leukotriene LTE4 has been shown to induce airway eosinophilia in asthmatics in vivo. This phenomenon has not yet been reported for LTD4. Hence, we examined the effect of inhaled LTD4 and a control bronchoconstrictor agent, methacholine, on cell differentials in hypertonic saline-induced whole sputum samples of 12 nonsmoking atopic asthmatic subjects (three women, nine men; 21 to 29 yr of age; FEV1, 74 to 120% pred; PC20FEV1 methacholine < 9.6 mg/ml). The study had a cross-over, placebo-controlled design consisting of 4 d separated by > or = 1 wk. On each randomized study day, the subjects inhaled five serial doses of either LTD4 (mean cumulative concentration: 95.7 microM) or methacholine (mean cumulative concentration: 542 mM) or five doses of their respective diluents (PBS/ethanol or PBS). The airway response was measured by FEV1, followed by sputum induction with 4.5% NaCl, 4 h postchallenge. Inflammatory cells (> or = 250) were counted twice on coded cytospins and expressed as percentages of nonsquamous cells. There was no significant difference in the maximal percent fall in FEV1 from baseline between LTD4 (mean +/- SEM, 49.5 +/- 4.4% fall) and methacholine (mean +/- SEM, 55.9 +/- 3.4% fall) (p = 0.11). LTD4 induced a significant increase in the percentage of sputum eosinophils as compared with its diluent (mean +/- SD, 26.6 +/- 21.3% and 10.2 +/- 8.8%, respectively; p = 0.025), whereas a similar trend for methacholine failed to reach significance (mean +/- SD, 19.1 +/- 22.9% and 7.8 +/- 5.8%, respectively; p = 0.11). There was no significant difference in the changes in the percentage of sputum eosinophils between LTD4 and methacholine (mean difference +/- SD, 7.5 +/- 12.5% eosinophils; p = 0.09). We conclude that LTD4 induces eosinophilia in sputum of asthmatic subjects 4 h after inhalation. Our data suggest that LTD4 recruits eosinophils into the airways of asthmatics in vivo, possibly by virtue of direct or indirect chemotactic properties, whereas an additional effect of vigourous airway narrowing per se cannot be excluded.
LFA-1 expression by blood eosinophils is increased in atopic asthmatic children and is involved in eosinophil locomotion
Authors: S Lantero, G Alessandri, D Spallarossa, L Scarso, GA Rossi
Journal: European Respiratory Journal (1998)

Allergic asthma is characterized by eosinophil migration in the airways, which is strictly dependent on the expression of adhesion molecules. This study investigated whether the expression of adhesion molecules on eosinophils is increased and associated with disease activity in allergic asthma. Twenty atopic asthmatic (AA) subjects and nine controls were studied and the expression of lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18), Mac-1 (CD11b/CD18) and very late antigen-4 (VLA-4; CD49d/CD29) on blood eosinophils was evaluated by specific monoclonal antibody (Mab) staining and flow-cytometric analysis. Compared with controls, eosinophils from AA showed increased expression of LFA-1 (p&lt;0.005), but not of Mac-1 or VLA-4 (p&gt;0.1). In addition, LFA-1 expression correlated positively with blood eosinophil number (r=0.792, p&lt;0.05), while no correlations were observed between Mac-1 or VLA-4 expression and blood eosinophil number. The migration of eosinophils through human umbilical vein endothelial cells with or without anti-LFA-1, Mac-1 and VLA-4-blocking Mab was studied. Compared with controls, eosinophils from AA showed increased migration toward C5a (p&lt;0.01). Cell migration was totally inhibited by preincubating eosinophils with anti-LFA-1 (p&lt;0.05), while anti-Mac-1 had no effect (p&gt;0.1). Thus, the expression of lymphocyte function-associated antigen-1 by blood eosinophils is increased in atopic asthmatics and seems to modulate the enhanced eosinophil migration observed in allergic asthma.
Dendritic Cell Survival and Maturation Are Regulated by Different Signaling Pathways
Authors: Maria Rescigno, Manuela Martino, Claire L. Sutherland, Michael R. Gold, Paola Ricciardi-Castagnoli
Journal: The Journal of Experimental Medicine (1998)

Although dendritic cell (DC) activation is a critical event for the induction of immune responses, the signaling pathways involved in this process have not been characterized. In this report, we show that DC activation induced by lipopolysaccharide (LPS) can be separated into two distinct processes: first, maturation, leading to upregulation of MHC and costimulatory molecules, and second, rescue from immediate apoptosis after withdrawal of growth factors (survival). Using a DC culture system that allowed us to propagate immature growth factor–dependent DCs, we have investigated the signaling pathways activated by LPS. We found that LPS induced nuclear translocation of the nuclear factor (NF)-κB transcription factor. Inhibition of NF-κB activation blocked maturation of DCs in terms of upregulation of major histocompatibility complex and costimulatory molecules. In addition, we found that LPS activated the extracellular signal–regulated kinase (ERK), and that specific inhibition of MEK1, the kinase which activates ERK, abrogated the ability of LPS to prevent apoptosis but did not inhibit DC maturation or NF-κB nuclear translocation. These results indicate that ERK and NF-κB regulate different aspects of LPS-induced DC activation: ERK regulates DC survival whereas NF-κB is responsible for DC maturation.
Sports injuries of the knee ligaments--a prospective stress radiographic study.
Authors: A Hede, N Hejgaard, H Sandberg, K Jacobsen
Journal: British Journal of Sports Medicine (1985)

Forty-six patients were entered into a prospective clinical and stress radiographic study done to assess the value of acute surgical treatment of injuries to the knee ligaments sustained during sports activities. After an average follow-up period of 5 1/2 years (range 4-6 1/2 years) medial instability was found only in two patients, both of whom were in the group with isolated rupture of the medial collateral ligament. Nine of the 29 patients in this group developed rotatory instability, but it was moderate and did not give rise to symptoms. Among the 17 patients with either injuries to the anterior cruciate ligament or combined injuries, anterior drawer instability persisted in seven, with an insufficient functional result in five. None of these 17 patients were able to resume competitive sport. Those patients who had not exercised physically just before the injury proved to have a significantly greater total instability than those who had. Therefore, routine limbering-up is recommended before sports activities.
Toward Proteomics in Uroscopy: Urinary Protein Profiles after Radiocontrast Medium Administration
Authors: DIERK J. HAMPEL, CHRISTINE SANSOME, MA SHA, SERGEY BRODSKY, WILLIAM E. LAWSON, MICHAEL S. GOLIGORSKY
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Previous attempts to use urinary protein profiles for diagnostic purposes have been rather disappointing with respect to their clinical validity, in part because of the insufficient reproducibility, sensitivity, and rapidity of available techniques. Therefore, a newly developed, high-throughput technique, namely surface-enhanced laser desorption/ionization (SELDI) ProteinChip array-time of flight mass spectrometry, was studied, to assess its applicability for protein profiling of urine and to exemplify its use for a group of patients receiving radiocontrast medium. Assessment of the accuracy, sensitivity, and reproducibility of SELDI in test urinary protein profiling was performed. Renal function was studied in 20 male Sprague-Dawley rats before and after intravenous administration of either 1.25 g/kg ioxilan ( n = 10) or hypertonic saline solution ( n = 10) as a control. Urine samples from 25 patients undergoing cardiac catheterization were obtained before, immediately after, and 6 to 12 h after the procedure. Administration of ioxilan to rats resulted in changes in the abundance of proteins of 9.9, 18.7, 21.0, and 66.3 kD. For patients, even in uncomplicated cases of radiocontrast medium infusion during cardiac catheterization, perturbations in the protein composition occurred but returned to baseline values after 6 to 12 h. Proteins with molecular masses of 9.75, 11.75, 23.5, and 66.4 kD changed in abundance. For patients with impaired renal function, these changes were not reversible within 6 to 12 h. As a proof of principle, one of the peaks, i.e. , that at 11.75 kD, was identified as β 2 -microglobulin. SELDI is a promising tool for the detection, identification, and characterization of trace amounts of proteins in urine. Even for patients without renal complications, proteins with a broad range of molecular masses either appear in or disappear from the urine. Some of these might represent markers of impending nephropathy.
The effects of surgically treated pulmonary stenosis on lung growth and cardiopulmonary function in children during rest and exercise
Authors: M Rosenthal, A Bush
Journal: European Respiratory Journal (1999)

The effects of high pulmonary blood flow and pressure on pulmonary development are well understood, but the effect of low pulmonary flow/pressure is not. Pulmonary stenosis (PS) was therefore used as a model to determine its effect on lung development, which was assessed noninvasively by carbon monoxide transfer at rest and during exercise. One hundred and six control children (55 males, 8-16 yrs) and 11 children with isolated valvar or subvalvar PS surgically corrected &gt; or =10 yrs prior to the study without residual stenosis/regurgitation were evaluated. Measurements of effective pulmonary blood flow, stroke volume, arteriovenous oxygen difference (AVO), transfer factor and transfer constant, alveolar ventilation and anaerobic threshold were performed using a mass spectrometer. Data from the normal children allowed calculation of z-scores for the study group matched for age, sex, pubertal stage and surface area. PS children at rest had a significantly lower forced expired volume in one second, cardiac frequency and transfer constant with a raised oxygen consumption and AVO which persisted on exercise. During exercise, the cardiac frequency was 12 beats x min(-1) slower and AVO 0.017 L greater than controls (p&lt;0.05). A persistently mildly raised effective functional residual capacity (0.2 L x m(-2)) during exercise led to a reduced transfer constant (0.35 mmol x min(-1) x kPa(-1) x L(-1)), although the percentage rise (28%) from rest to peak exercise was normal. The percentage fall in stroke volume from the penultimate exercise stage to peak exercise stage was greater in PS children (24%, 95% confidence interval 11-37) than control children (2.4, -2-10, p&lt;0.005). In conclusion, although the effects are small, pulmonary stenosis does affect cardiopulmonary function after surgery. This needs to be considered when contemplating the timing of treatment.
Potential role for adenosine in the pathogenesis of the vascular complications of hyperhomocysteinemia
Authors: N RIKSEN, G RONGEN, H BLOM, F RUSSEL, G BOERS, P SMITS
Journal: Cardiovascular Research (2003)

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Most previous investigations focused on the role of homocysteine as direct pathogenetic factor for these adverse vascular events. However, the exact pathophysiological mechanism is still unknown. In this review we discuss the hypothesis that a decreased extracellular concentration of adenosine could contribute to the adverse cardiovascular effects of hyperhomocysteinemia. Fundamental to this hypothesis is that, in vivo, any increase in the plasma concentration of homocysteine reflects an increased intracellular homocysteine concentration, which inevitably will result in a decrease in the adenosine concentration. In this situation, the hydrolase reaction catalysed by S-adenosylhomocysteine hydrolase will reverse and S-adenosylhomocysteine will accumulate at the expense of adenosine. Stimulation of adenosine receptors by adenosine results in various cardio- and vasoprotective actions, like modulation of vascular resistance, presynaptic inhibition of norepinephrine release, ischaemic preconditioning, inhibition of platelet aggregation, modulation of inflammation and regulation of vascular cell proliferation and death. In this respect, a decrease in the adenosine concentration could contribute significantly to the cardiovascular effects of hyperhomocysteinemia.
Bile salt metabolism in tropical sprue
Authors: G. Bevan, R. Engert, F. A. Klipstein, N. Maldonado, A. Rubulis, M. D. Turner
Journal: Gut (1974)

Mean and peak jejunal bile salt concentrations during digestion of a standard fat meal were found to be significantly lower in six Puerto Rican patients with untreated tropical sprue, all of whom had steatorrhoea, than in six asymptomatic subjects who had normal fat absorption. Bile salt pool size and turnover time did not differ significantly in the two groups.It is suggested that bile salt concentrations may be reduced in the proximal small intestine of patients with tropical sprue as a result of excessive dilution by intestinal fluid. The finding of low bile salt concentrations in two asymptomatic subjects indicates that bile salt lack alone may not be sufficient to produce steatorrhoea.
Neutralization of Macrophage-Stimulating Protein Ameliorates Renal Injury in Anti–Thy 1 Glomerulonephritis
Authors: Teresa Rampino, Grazia Soccio, Marilena Gregorini, Cristina Guidetti, Maddalena Marasa[Combining Grave Accent], Milena Maggio, Vincenzo Panichi, Massimiliano Migliori, Carmelo Libetta, Antonio Dal Canton
Journal: Journal of the American Society of Nephrology (2007)

Macrophage-stimulating protein (MSP) is a scatter factor that causes cell proliferation and migration, and receptor origin nantaise (RON) is its receptor. RON is expressed in macrophages and mesangial cells, and MSP is produced by renal tubular cells. This study investigated whether MSP/RON participate in the pathogenesis of anti-Thy 1 nephritis, a glomerular disease that is characterized by invasion of circulating monocytes into glomeruli and migration and proliferation of mesangial cells. In vivo, renal function and histopathology were studied in rats that had anti-Thy 1 disease and were untreated and treated with a neutralizing anti-MSP antibody. In vitro, whether monocytes express RON and whether MSP has a chemotactic effect on monocytes were studied. In vivo, in anti-Thy 1 disease, MSP was expressed de novo in glomeruli, and neutralization of MSP attenuated the rise in serum creatinine and proteinuria, stopped glomerular neutrophil and monocyte influx, protected from glomerular injury, and lessened mesangial cell overgrowth. In vitro, unstimulated monocytes did not express RON, but the stimulation with LPS induced de novo RON expression. LPS-stimulated monocytes were attracted by MSP. These results demonstrate a pathogenic role of the MSP/RON system in anti-Thy 1 nephritis.
Rising Incidence of Renal Cell Cancer in the United States
Authors: Wong-Ho Chow
Journal: JAMA (1999)

ContextClinical surveys have revealed that incidental detection of renal cell carcinoma is rising because of increased use of imaging procedures.ObjectiveTo examine incidence, mortality, and survival trends of renal cell and renal pelvis cancers by age, sex, race, and tumor stage at diagnosis.DesignCalculation of age-adjusted incidence and mortality rates, along with 5-year relative survival rates, using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program.Setting and ParticipantsPatients diagnosed as having kidney cancer from 1975 through 1995 in the 9 geographic areas covered by tumor registries in the SEER program, which represent about 10% of the US population.Main Outcome MeasuresIncidence, mortality, and 5-year relative survival rates by time periods.ResultsThe age-adjusted incidence rates for renal cell carcinoma between 1975 and 1995 for white men, white women, black men, and black women were 9.6, 4.4, 11.1, and 4.9 per 100,000 person-years, respectively. The corresponding rates for renal pelvis cancer were 1.5, 0.7, 0.8, and 0.5 per 100,000 person-years. Renal cell cancer incidence rates increased steadily between 1975 and 1995, by 2.3% annually among white men, 3.1% among white women, 3.9% among black men, and 4.3% among black women. Increases were greatest for localized tumors but were also seen for more advanced and unstaged tumors. In contrast, the incidence rates for renal pelvis cancer declined among white men and remained stable among white women and blacks. Although 5-year relative survival rates for patients with renal cell cancer improved among whites but not among blacks, kidney cancer mortality rates increased in all race and sex groups.ConclusionsIncreasing detection of presymptomatic tumors by imaging procedures, such as ultrasonography, computed tomography, and magnetic resonance imaging, does not fully explain the upward incidence trends of renal cell carcinoma. Other factors may be contributing to the rapidly increasing incidence of renal cell cancer in the United States, particularly among blacks.