tbuckley/cabot-search huggingface dataset:
Effect of proteasome inhibitors on proliferation and apoptosis of human cutaneous melanoma-derived cell lines
Authors: A. Sorolla, A. Yeramian, X. Dolcet, A.M. Pérez de Santos, D. Llobet, J.A. Schoenenberger, J.M. Casanova, X. Soria, R. Egido, A. Llombart, R. Vilella, X. Matias-Guiu, R.M. Marti
Journal: British Journal of Dermatology (2008)

Background Cutaneous malignant melanoma is an aggressive type of skin cancer which causes disproportionate mortality in young and middle-aged adults. Once disseminated, melanoma can be considered an incurable disease, highly resistant to standard antineoplastic treatment, such as chemotherapy or radiation therapy. The proteasome represents a novel target for cancer therapy that can potentially be used in melanoma. Objectives To assess the effect of four structurally different proteasome inhibitors on human cutaneous melanoma-derived cell lines. Methods Sixteen human cutaneous melanoma-derived cell lines which are original were obtained from patients who were treated by two of the authors. Cells were cultured, exposed to proteasome inhibitors (bortezomib, ALLN, MG-132 and epoxomicin) and then assayed for cell cycle and cell death analyses. Results Proteasome inhibitors inhibited the in vitro growth of melanoma cells, and this effect was due to a reduction in cell proliferation rate and an induction of both caspase-dependent and caspase-independent cell death. Moreover, release of apoptosis-inducing factor was observed in the presence of the broad-specificity caspase inhibitor BAF (Boc-D-fmk). In addition, the four different proteasome inhibitors induced caspase 2 processing. Conclusions This study provides information regarding the in vitro effects of proteasome inhibitors on melanoma cell lines, and the molecular mechanisms involved. It also gives support to the future use of such inhibitors in the treatment of patients with melanoma, either administered alone or in combination with other drugs.
Hemodynamics of arterial stenoses at elevated flow rates.
Authors: D F Young, N R Cholvin, R L Kirkeeide, A C Roth
Journal: Circulation Research (1977)

This study is concerned with the pressure drop that develops across an arterial stenosis, with particular emphasis on the effect of the stenosis at high blood flow rates induced by a locally administered vasodilator drug. Stenoses, ranging in severity from 55.7% to 91.0% reduction in lumen area were artificially induced in the femoral and carotid arteries of large mongrel dogs. Instantaneous flow rates and pressure drops were measured over a wide range of flow conditions. Mean velocities varied from 3.9 to 88.8 cm/sec. Experimental data support the applicability of a relatively simple equation for predicting the pressure drop over this wide range of velocities and stenosis geometries. Results show that blood flow through a particular artery can increase by a large factor, in the range of 4-5, under conditions of vasodilation with a corresponding large decrease in pressure distal to the stenosis. The pressure drop increases in a nonlinear manner with velocity and thereby accentuates the importance of the stenosis at elevated flow rates. We suggest that a critical stenosis be defined in terms of its effect on maximal flow rather than resting flow.
Inflammasomes in COPD and neutrophilic asthma
Authors: Richard Y Kim, James W Pinkerton, Peter G Gibson, Matthew A Cooper, Jay C Horvat, Philip M Hansbro
Journal: Thorax (2015)

Inflammasomes have recently been identified to be critical and potent inducers of inflammation that when overactive may be targeted therapeutically in inflammatory diseases. Inflammasomes are multiprotein signalling complexes that control the maturation and release of pro-inflammatory cytokines in response to numerous exogenous, endogenous and pathogenic danger signals (figure 1).1 They mediate host responses, particularly interleukin (IL)-1β release and neutrophilic inflammatory responses, which are essential for protection against infection. However, recent evidence demonstrates that excessive inflammasome activation is a feature of numerous inflammatory diseases including COPD, neutrophilic asthma, idiopathic pulmonary fibrosis, cystic fibrosis, acute respiratory distress syndrome (ARDS) and respiratory infections (table in figure 1). Infections are the most widely recognised activators of inflammasomes; however, this field has recently been reviewed extensively and is beyond the scope of this article. Their roles in ARDS and potential for therapeutic targeting are well established.2 It is now emerging that inflammasomes are likely involved in the pathogenesis of COPD and asthma, and further investigation is urgently needed.



Figure 1 
Potential role for inflammasome activation in COPD and neutrophilic asthma. Numerous exogenous, endogenous and pathogenic danger signals (eg, ATP, monosodium urate crystals (MSU)) in the airways induce the assembly and activation of the inflammasome complex and synthesis of pro-interleukin (IL)-1β. Inflammasome activation by pathogen-associated molecular patterns (PAMPs) (eg, lipopolysaccharide (LPS) and peptidoglycan) results in proteolytic cleavage and activation of pro-caspase-1. Active caspase-1 in turn mediates the subsequent cleavage of pro-IL-1β that leads to the production and release of IL-1β and other pro-inflammatory mediators and cellular contents, including IL-18 and adaptor protein apoptosis-associated speck-like containing a caspase recruitment domain (ASC) specks. Excessive release of active IL-1β and ASC specks promotes neutrophil-dominated inflammatory responses in the airways that contribute to the pathogenesis of COPD and neutrophilic asthma. Complex interactions between inflammasomes, IL-1β, its receptors and intracellular …
Specific major mental disorders and criminality: a 26-year prospective study of the 1966 northern Finland birth cohort
Authors: J Tiihonen, M Isohanni, P Räsänen, M Koiranen, J Moring
Journal: American Journal of Psychiatry (1997)

Objective: The purpose of the study was to examine the quantitative risk of criminal behavior associated with specific mental disorders.Method: An unselected 1966 birth cohort (N=12,058) in Northern Finland was prospectively studied until the end of 1992.The investigation started during the mothers' pregnancy, and the data on the subjects' family characteristics, mental and physical development, living habits, psychiatric morbidity, and criminal records were gathered at various times.Results: The prevalence of offenses was the highest among males with alcohol-induced psychoses and male schizophrenic subjects with coexisting alcohol abuse, and more than half of the schizophrenic offenders also had problems with alcohol.Eleven (7%) of the 165 subjects who committed violent crimes were diagnosed as psychotic.Male schizophrenic subjects had a moderately high risk for violent offenses, but the risk for other types of crimes was not elevated significantly.Odds ratios for criminal behavior were adjusted according to the socioeconomic status of the childhood family and were the same as or slightly lower than the crude odds ratios for all disorders except schizophrenia and mood disorders with psychotic features.Conclusions: The results indicate that the risk of criminal behavior was significantly higher among subjects with psychotic disorders, even though the socioeconomic status of the childhood family was controlled.The higher risk for violent behavior was associated especially with alcohol-induced psychoses and with schizophrenia with coexisting substance abuse.The results suggest that schizophrenia without substance abuse may also be associated with a higher risk of offenses, but this finding is tentative and requires further investigation.
mSYD1A, a Mammalian Synapse-Defective-1 Protein, Regulates Synaptogenic Signaling and Vesicle Docking
Authors: Corinna Wentzel, Julia E. Sommer, Ramya Nair, Adeline Stiefvater, Jean-Baptiste Sibarita, Peter Scheiffele
Journal: Neuron (2013)
Spontaneous and induced sputum to measure indices of airway inflammation in asthma.
Authors: M M Pizzichini, T A Popov, A Efthimiadis, P Hussack, S Evans, E Pizzichini, J Dolovich, F E Hargreave
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Inhalation of hypertonic saline to induce sputum may alter cells and fluid-phase markers in sputum. We have compared indices of inflammation in sputum produced spontaneously with sputum induced by an aerosol of hypertonic saline. Twenty-three asthmatics produced spontaneous followed by induced sputum on the same day. The sputum specimen was separated from saliva within 2 h, dispersed with dithiothreitol (DTT) and processed to obtain cytospins and supernatant. The statistical power to detect a 20% difference in sputum parameters was > 90%. Results are expressed as median and interquartile range [IQR]. Induced sputum had a higher proportion of viable cells (77.0 [19.0] versus 47.0 [38.0]%, p < 0.001), less squamous cell contamination (1.0 [1.2] versus 1.8 [34.0]%, p < 0.001) and better quality cytospins (score of 8.0 [4.0] versus 4.0 [2.0], p < 0.001). It also had lower fluid-phase levels of eosinophil cationic protein (ECP) (1,358 [1,102] versus 1,574 [2,479] microg/L) and fibrinogen (1,560.0 [3,130.0] versus 4,350.0 [5,970.0] ng/ml) but only the latter was significantly different (p = 0.02). Induced sputum was similar to spontaneous sputum in weight (200.0 [219.0] versus 270.0 [227.0] mg), total cell count (3.3 [4.1] versus 3.5 [4.5] x 10(6)/ml), proportion of nonsquamous cells, and levels of tryptase. The agreement between induced and spontaneous measurements was good, but fluid-phase levels were affected by the low viability of some spontaneous samples. We conclude that for the indices measured in asthmatic subjects, induced sputum separated from saliva is similar to lower respiratory secretions expectorated spontaneously and has the advantage of better cell viability.
Inflammation as a Cardiovascular Risk Factor
Authors: James T. Willerson, Paul M. Ridker
Journal: Circulation (2004)

Inflammation occurs in the vasculature as a response to injury, lipid peroxidation, and perhaps infection. Various risk factors, including hypertension, diabetes, and smoking, are amplified by the harmful effects of oxidized low-density–lipoprotein cholesterol, initiating a chronic inflammatory reaction, the result of which is a vulnerable plaque, prone to rupture and thrombosis. Epidemiological and clinical studies have shown strong and consistent relationships between markers of inflammation and risk of future cardiovascular events. Inflammation can potentially be detected locally by imaging techniques as well as emerging techniques, such as identification of temperature or pH heterogeneity. It can be detected systemically by measurement of inflammatory markers. Of these, the most reliable and accessible for clinical use is currently high-sensitivity C-reactive protein. A combination of methods may provide the best identification of persons at risk for cardiovascular events who would benefit from treatment. In randomized, controlled trials, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, in the form of statins, have been shown to provide effective therapy for lowering CRP, in conjunction with their lipid-lowering effects. Although the magnitude of risk reduction associated with statin use appears to be largest for those with the highest serum levels of CRP, whether CRP reduction per se lowers cardiovascular risk is unknown.
Recent advances in the endoscopic management of variceal bleeding.
Authors: S G Williams, D Westaby
Journal: Gut (1995)

For the first time the endoscopist has more than one option for the management of gastro-oesophageal varices. It is now feasible to select the appropriate therapy on the basis of the clinical setting. Acute injection sclerotherapy remains a quick and simple technique for the control of active bleeding from oesophageal varices, and could be followed two or three days later by banding ligation. Earlier obliteration of varices with this technique may offer the prospect of only two or three sessions of therapy. The availability of the tissue adhesives and thrombin as injectates for fundal gastric varices provide the option of an initial attempt at endoscopic therapy in this high risk group.
The Incidence of Pediatric Cardiomyopathy in Two Regions of the United States
Authors: Steven E. Lipshultz, Lynn A. Sleeper, Jeffrey A. Towbin, April M. Lowe, E. John Orav, Gerald F. Cox, Paul R. Lurie, Kristina L. McCoy, Melissa A. McDonald, Jane E. Messere, Steven D. Colan
Journal: New England Journal of Medicine (2003)

Population-based data on the incidence of pediatric cardiomyopathy are rare because of the lack of large, prospective studies.Since 1996 the Pediatric Cardiomyopathy Registry sponsored by the National Heart, Lung, and Blood Institute has collected data on all children with newly diagnosed cardiomyopathy in New England and the Central Southwest region (Texas, Oklahoma, and Arkansas) of the United States. We report on all children in these regions who received this diagnosis between 1996 and 1999.We identified 467 cases of cardiomyopathy, for an overall annual incidence of 1.13 per 100,000 children (95 percent confidence interval, 1.03 to 1.23). The incidence was significantly higher among infants younger than 1 year old than among children and adolescents who were 1 to 18 years old (8.34 vs. 0.70 per 100,000, P<0.001). The annual incidence of cardiomyopathy was lower among white children (upper-bound estimate, 1.06 cases per 100,000) than among black children (lower-bound estimate, 1.47 per 100,000; P=0.02) and higher among boys than among girls (1.32 vs. 0.92 per 100,000, P<0.001). The incidence also varied significantly by region: 1.44 cases per 100,000 in New England and 0.98 per 100,000 in the Central Southwest region (P<0.001). When categorized according to type, dilated cardiomyopathy made up 51 percent of the cases, hypertrophic cardiomyopathy 42 percent, and restrictive or other types 3 percent; 4 percent were unspecified. There was no significant difference in the incidence rates according to the year.The estimated incidence of pediatric cardiomyopathy in two large regions of the United States is 1.13 cases per 100,000 children. Most cases are identified at an early age, and the incidence varies according to sex, region, and racial or ethnic origin.
Vasoactive intestinal polypeptide-induced chloride secretion by a colonic epithelial cell line. Direct participation of a basolaterally localized Na+,K+,Cl- cotransport system.
Authors: K Dharmsathaphorn, K G Mandel, H Masui, J A McRoberts
Journal: Journal of Clinical Investigation (1985)

We have used a well-differentiated human colonic cell line, the T84 cell line, as a model system to study the pathways of cellular ion transport involved in vasoactive intestinal polypeptide (VIP)-induced chloride secretion. A modified Ussing chamber was used to study transepithelial Na+ and Cl- fluxes across confluent monolayer cultures of the T84 cells grown on permeable supports. In a manner analogous to isolated intestine, the addition of VIP caused an increase of net Cl- secretion which accounted for the increase in short circuit current (Isc). The effect of VIP on Isc was dose dependent with a threshold stimulation at 10(-10) M VIP, and a maximal effect at 10(-8) M. Bumetanide prevented or reversed the response to VIP. Inhibition by bumetanide occurred promptly when it was added to the serosal, but not to the mucosal bathing media. Ion replacement studies demonstrated that the response to VIP required the simultaneous presence of Na+, K+, and Cl- in the serosal media. Utilizing cellular ion uptake techniques, we describe an interdependence of bumetanide-sensitive 22Na+, 86Rb+, and 36Cl- uptake, which is indicative of a Na+,K+,Cl- cotransport system in this cell line. This transport pathway was localized to the basolateral membrane. Extrapolated initial velocities of uptake for each of the three ions was consistent with the electroneutral cotransport of 1 Na+:1 K+ (Rb+):2 Cl-. Our findings indicate that VIP-induced Cl- secretion intimately involves a bumetanide-sensitive Na+,K+,Cl- cotransport system which is functionally localized to the basolateral membrane.
Effect of Platelet Activation on Coronary Collateral Blood Flow
Authors: James W. Kinn, Robert J. Bache
Journal: Circulation (1998)

Background —The platelet products thromboxane A 2 and serotonin have been shown to cause constriction of well-developed coronary collateral vessels. This study was performed to determine whether intravascular platelet activation produced with platelet activating factor (PAF) can cause a decrease in coronary collateral blood flow. Methods and Results —Collateral vessel growth was induced by embolization of a hollow stainless steel plug into the left anterior descending coronary artery (LAD) of adult dogs. The animals were returned to the laboratory 3 to 6 weeks later for surgical instrumentation and measurement of collateral blood flow. Collateral flow was assessed by measuring retrograde blood flow from the cannulated collateral-dependent artery. PAF (10 nmol) was injected into the left main coronary artery to allow products of platelet activation to reach collateral vessels arising from the left coronary system. PAF caused a vasoconstrictor response, which became maximal 3 minutes after injection and resulted in a 40.3±7.4% decrease in retrograde blood flow (32.1±2.1 to 19.6±3.2 mL/min; P &lt;0.05). By 15 minutes after the PAF injection, both retrograde blood flow and transcollateral resistance had returned to normal. After pretreatment with the thromboxane A 2 receptor antagonist SQ30,741, the vasoconstrictor response to PAF was abolished and, in contrast to the decrease in retrograde blood flow from PAF alone, a weak vasodilator effect was unmasked. Conclusions —PAF caused a decrease in coronary collateral blood flow. This vasoconstrictor response required the participation of thromboxane A 2 .
Tumor-Associated Neutrophils: New Targets for Cancer Therapy
Authors: Alyssa D. Gregory, A. McGarry Houghton
Journal: Cancer Research (2011)

Studies have begun to emerge showing critical roles for neutrophils in tumorigenesis. Neutrophils can have a significant impact on the tumor microenvironment via their production of cytokines and chemokines, which influence inflammatory cell recruitment and activation. Additionally, products secreted from neutrophils, such as reactive oxygen species and proteinases, have defined and specific roles in regulating tumor cell proliferation, angiogenesis, and metastasis. Although evidence suggests that neutrophils act in a decidedly protumor capacity in vivo, recent studies indicate that neutrophils may be manipulated to exhibit cytotoxicity against tumors. Herein, we explore the idea of targeting tumor-associated neutrophils as a means of antitumor therapy and the important ramifications such manipulation could pose to host tissues.
Variant human phosphoribosylpyrophosphate synthetase altered in regulatory and catalytic functions.
Authors: M A Becker, K O Raivio, B Bakay, W B Adams, W L Nyhan
Journal: Journal of Clinical Investigation (1980)

An inherited, structurally abnormal and superactive form of the enzyme 5-phosphoribosyl 1-pyrophosphate (PP-ribose-P) synthetase (EC 2.7.6.1) has been characterized in fibroblasts cultured from a 14-yr-old male (S.M.) with clinical manifestations of uric acid overproduction present since infancy. PP-ribose-P synthetase from the cells of this child showed four- to fivefold greater than normal resistance to purine nucleotide (ADP and GDP) feedback inhibition of enzyme activity and hyperbolic rather than sigmoidal inorganic phosphate (Pi) activation in incompletely dialyzed extracts. Excessive maximal velocity of the enzyme reaction catalyzed by the mutant enzyme was indicated by: enzyme activities twice those of normal at all concentrations of Pi in chromatographed fibroblast extracts; normal affinity constants for substrates and for the activator, Mg2+; and twofold greater than normal activity per immunoreactive enzyme molecule. The mutant enzyme thus possessed deficient regulatory and superactive catalytic properties, two mechanisms previously demonstrated individually to underlie the excessive PPRribose-P and uric acid synthesis of affected members of families with superactive PP-ribose-P synthetases. Increased PP-ribose-P concentration (4-fold) and generation (2.7-fold) and enhanced rates of PP-ribose-P dependent purine synthetic reactions, including purine synthesis de novo, in S.M. fibroblasts confirmed the functional significance of this patient's mutant enzyme. Diminished stability of the variant PP-ribose-P synthetase was manifested in vitro by increased thermal lability and in vivo by deficiency of enzyme activity at Pi concentrations greater than 0.3 mM in hemolysates and by an accelerated, age-related decrement in enzyme activity in lysates of erythrocytes separated by specific density. Despite the diminished amount of PP-ribose-P synthetase in the S.M. erythrocyte population, S.M. erythrocytes had increased PP-ribose-P concentration and increased rates of incorporation of [14C]adenine and hypoxanthine into acid-soluble nucleotides during incubation at 1 mM Pi. These findings provided further confirmation of the extent to which PP-ribose-P synthesis is modulated in the normal cell at physiological Pi concentration by purine nucleotide inhibition of PP-ribose-P synthetase. The activity and kinetic characteristics of PP-ribose-P synthetase from fibroblasts of the mother of patient S.M. indicated that this woman was a heterozygous carrier of the enzyme defect expressed in hemizygous manner by her son.
Identification of an angiotensin receptor in rabbit renomedullary interstitial cells in tissue culture. Correlation with prostaglandin biosynthesis.
Authors: C A Brown, R M Zusman, E Haber
Journal: Circulation Research (1980)

High affinity binding sites of angiotensin II (A II) have been characterized in rabbit renomedullary interstitial cells in tissue culture. Binding was rapid, specific, and saturable. Scatchard analysis of steady state saturation binding data at 22 degrees C indicated a single binding site with an equilibrium dissociation constant of 3.1 mM. The binding inhibition activities of analogues of angiotensin II correlated with their biological potencies: [Sar1, Ala8]A II greater than [des-Asp1]A II greater than greater than 3--8 hexapeptide. The biologically inactive 1--7 heptapeptide failed to displace the labeled angiotensin II from its binding sites. Angiotensin II directly stimulated prostaglandin E2 biosynthesis by the rabbit renomedullary interstitial cells in tissue culture. The concentration of angiotensin II that resulted in half maximal stimulation of prostaglandin E2 biosynthesis (6.5 nM) correlated with the concentration of angiotensin II that resulted in half maximal occupancy of binding sites (3.1 nM). The relative potency of [des-Asp1] A II as a stimulus for prostaglandin E2 biosynthesis was proportional to its relative binding inhibition activity. These findings demonstrate the biological significance of the angiotensin II binding sites in the rabbit renomedullary interstitial cells in tissue culture and suggest that the cells may provide a homogeneous model tissue for the study of the angiotensin receptor.