tbuckley/cabot-search huggingface dataset:
A Selective Small Molecule c-MET Inhibitor, PHA665752, Cooperates with Rapamycin
Authors: Patrick C. Ma, Erik Schaefer, James G. Christensen, Ravi Salgia
Journal: Clinical Cancer Research (2005)

Abstract Purpose: c-MET is believed to be an attractive receptor target for molecular therapeutic inhibition. TPR-MET, a constitutively active oncogenic variant of MET, serves as excellent model for testing c-MET inhibitors. Here, we characterized a small molecule c-MET inhibitor, PHA665752, and tested its cooperation with the mammalian target of rapamycin inhibitor as potential targeted therapy. Experimental Design: The effect of PHA665752 treatment was determined on cell growth, motility and migration, apoptosis, and cell-cycle arrest of TPR-MET-transformed cells. Moreover, the effect of PHA665752 on the phosphorylation on MET, as well as its downstream effectors, p-AKT and p-S6K, was also determined. Finally, growth of TPR-MET-transformed cells was tested in the presence of PHA665752 and rapamycin. H441 non–small cell lung cancer (NSCLC) cells (with activated c-Met) were also tested against both PHA665752 and rapamycin. Results: PHA665752 specifically inhibited cell growth in BaF3. TPR-MET cells (IC50 &amp;lt; 0.06 μmol/L), induced apoptosis and cell cycle arrest. Constitutive cell motility and migration of the BaF3. TPR-MET cells was also inhibited. PHA665752 inhibited specific phosphorylation of TPR-MET as well as phosphorylation of downstream targets of the mammalian target of rapamycin pathway. When combined with PHA665752, rapamycin showed cooperative inhibition to reduce growth of BaF3. TPR-MET- and c-MET-expressing H441 NSCLC cells. Conclusions: PHA665752 is a potent small molecule–selective c-MET inhibitor and is highly active against TPR-MET-transformed cells both biologically and biochemically. PHA665752 is also active against H441 NSCLC cells. The c-MET inhibitor can cooperate with rapamycin in therapeutic inhibition of NSCLC, and in vivo studies of this combination against c-MET expressing cancers would be merited.
Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis
Authors: N Oikonomou, A Thanasopoulou, A Tzouvelekis, V Harokopos, T Paparountas, I Nikitopoulou, W Witke, A Karameris, A Kotanidou, D Bouros, V Aidinis
Journal: Thorax (2009)

Despite intense research efforts, the aetiology and pathogenesis of idiopathic pulmonary fibrosis remain poorly understood. Gelsolin, an actin-binding protein that modulates cytoskeletal dynamics, was recently highlighted as a likely disease modifier through comparative expression profiling and target prioritisation.To decipher the possible role of gelsolin in pulmonary inflammation and fibrosis, immunocytochemistry on tissue microarrays of human patient samples was performed followed by computerised image analysis. The results were validated in the bleomycin-induced animal model of pulmonary inflammation and fibrosis using genetically-modified mice lacking gelsolin expression. Moreover, to gain mechanistic insights into the mode of gelsolin activity, a series of biochemical analyses was performed ex vivo in mouse embryonic fibroblasts.Increased gelsolin expression was detected in lung samples of patients with idiopathic interstitial pneumonia as well as in modelled pulmonary inflammation and fibrosis. Genetic ablation of gelsolin protected mice from the development of modelled pulmonary inflammation and fibrosis attributed to attenuated epithelial apoptosis.Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis, while the caspase-3-mediated gelsolin fragmentation was shown to be an apoptotic effector mechanism in disease pathogenesis and a marker of lung injury.
BIOCOLLOIDS OF URINE IN HEALTH AND IN CALCULOUS DISEASE. II. ELECTROPHORETIC AND BIOCHEMICAL STUDIES OF A MUCOPROTEIN INSOLUBLE IN MOLAR SODIUM CHLORIDE 1
Authors: William H. Boyce, Marjorie Swanson
Journal: Journal of Clinical Investigation (1955)

A method for recovering the total biocolloids of urine by a combination of dialysis and ultrafiltration has been described (1). These biocolloids have been separated into two groups on the basis of their solubility in molar sodium chloride. The electrophoretic properties of those components which are soluble in molar sodium chloride have been reported, both for normal subjects and for patients with developing renal calculi (2). The urinary biocolloids which are insoluble in molar sodium chloride form the subject for the present study.
Aspirin ingestion and perforated peptic ulcer
Authors: J. M. Duggan
Journal: Gut (1972)

The results of a prospective inquiry into the aspirin taking habits of a consecutive series of 118 patients admitted to a large general hospital with acute perforation of peptic ulcer are presented. The series shows considerable increase in the proportion of females to males and of ulcers of the stomach compared to pyloro-duodenal perforations in contrast to British experience. Forty-five per cent of males and 75% of females were accustomed to taking at least two doses of an aspirin preparation weekly and most of the women took at least two doses daily. There was a highly significant association of heavy aspirin intake with ulcers of the stomach. The data support the theory that aspirin abuse is a cause of chronic gastric ulcer. It also supports the hypothesis that aspirin is the environmental factor responsible for the epidemic of gastric ulcers in middle-aged women in eastern Australia.
Antimyenteric neuronal antibodies in scleroderma.
Authors: S Howe, E Y Eaker, J E Sallustio, C Peebles, E M Tan, R C Williams
Journal: Journal of Clinical Investigation (1994)

The pathogenesis of gastrointestinal (GI) dysmotility in scleroderma is incompletely understood, although previous studies have proposed a neuropathic mechanism. We studied patients with scleroderma as compared with other connective tissue disease patients and normal controls for the presence of circulating antibodies to myenteric neurons. Serial dilutions of sera were overlaid on rat intestine, double-labeled with antineurofilament antibody as a myenteric plexus marker, and imaged using indirect immunofluorescence techniques. High titer sera (> or = 1:50) from 19 out of 41 scleroderma patients stained myenteric neurons, whereas none of 22 normals or 5 patients with idiopathic GI dysmotility were positive. Although 6 out of 20 SLE and 6 out of 10 mixed connective tissue disease patients' sera stained myenteric plexus neurons, when positive sera were absorbed with calf thymus extract to remove antinuclear antibody, 15 scleroderma sera, 0 SLE, and 2 mixed connective tissue disease patients retained positive staining of myenteric neurons. Western blotting using actin and neuronal intermediate filament preparations failed to show immunoreactivity with scleroderma sera containing antimyenteric neuronal antibodies. Paraneoplastic sera associated with GI dysmotility stained myenteric neurons in a different pattern than seen with scleroderma sera. A positive correlation between the presence of Raynaud's phenomenon and antimyenteric neuronal antibodies was observed in scleroderma patients. Our results indicate that IgG antibodies reacting with myenteric neurons are present in many patients with scleroderma. Although the neuronal antigen has not yet been identified, the presence of myenteric neuronal antibodies in patients with GI dysmotility and scleroderma suggests a neuropathic process.
Usefulness of lactate dehydrogenase and its isoenzymes as indicators of lung damage or inflammation
Authors: M Drent, NA Cobben, RF Henderson, EF Wouters, M van Dieijen-Visser
Journal: European Respiratory Journal (1996)

This review describes the usefulness of monitoring the activity level of lactate dehydrogenase (LDH) and its isoenzyme pattern as indicators of pathological conditions in the lungs, such as cell damage or inflammation. Cytoplasmatic cellular enzymes, like LDH, in the extracellular space, although of no further metabolic function in this space, are still of benefit because they serve as indicators suggestive of disturbances of the cellular integrity induced by pathological conditions. Since LDH is an enzyme present in essentially all major organ systems, serum LDH activity is abnormal in a large number of disorders. Although the increase in total serum LDH activity is rather nonspecific, it is proposed that measurement of LDH activity levels and its isoenzyme pattern in pleural effusion and, more recently, in bronchoalveolar lavage fluid may provide additional information about lung and pulmonary endothelial cell injury.
Therapeutic approaches for the treatment of renal disease in juvenile systemic lupus erythematosus: an international multicentre PRINTO study
Authors: Paivi M Miettunen, Angela Pistorio, Elena Palmisani, Angelo Ravelli, Earl Silverman, Sheila Oliveira, Maria Alessio, Ruben Cuttica, Dimitrina Mihaylova, Graciela Espada, Srdjan Pasic, Antonella Insalaco, Seza Ozen, Oscar Porras, Flavio Sztajnbok, Dragana Lazarevic, Alberto Martini, Nicolino Ruperto
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> To evaluate therapeutic approaches and response to therapy in juvenile systemic lupus erythematosus (SLE) with renal involvement in a large prospective international cohort from four geographic areas. <h3>Methods</h3> New onset and flared patients with active renal disease (proteinuria ≥0.5 g/24 h) were enrolled in 2001–2004. Therapeutic approaches and disease activity parameters were analysed at baseline, 6, 12 and 24 months. Response was assessed by the PRINTO/ACR criteria. <h3>Results</h3> 218/557 (79.8% female subjects, 117 new onset and 101 flared) patients with active renal disease were identified; 66 patients were lost to follow-up and 11 died. Mean age at disease onset for new onset group was higher than for flared group (13.1 vs 10.2 years, p&lt;0.0001). At baseline, both groups had similar renal activity with similar median doses of corticosteroids (1.0–0.76 mg/kg/day). Cyclophosphamide (43.1%) and azathioprine (22%) were the most common immunosuppressive drugs. At baseline, South American patients received higher doses of corticosteroids than in other areas in new onset (median 1.16 vs 0.8–1 mg/kg/day) while cyclophosphamide use was similar in all four regions in the new onset group. There were no differences regarding the use of azathioprine or mycophenolate mofetil worldwide. PRINTO 70 response was reached in a greater percentage of new onset versus flared patients (74.8% vs 53.3%; p=0.005) at 6 months while at 24 months ACR 90 was reached by 69.9% and 56.1%, respectively. <h3>Conclusions</h3> New onset and flared juvenile SLE improved similarly over 24 months with minimal differences in therapeutic approaches worldwide.
ROENTGEN RAY INTOXICATION
Authors: S. L. Warren, G. H. Whipple
Journal: The Journal of Experimental Medicine (1922)

Roentgen radiation in lethal dosage, given over the abdomen of a normal dog, is followed by a physiological reaction of remarkable uniformity. The first 24 hour period following the exposure is negative clinically and anatomically, but histologically we see frank changes in the bone marrow, spleen, lymph glands, and ovaries. There are definite nuclear changes with degeneration in the crypt epithelium of the small intestine. The second 24 hour period shows slight clinical disturbances of gastrointestinal nature (vomitus and diarrhea). The mucosa of the small intestine shows scattered ecchymoses, but the histology of the small intestine is important. The necrosis of the crypt epithelium may be almost complete, while the epithelium of the villi remains practically intact. There are a little edema and invasion of wandering cells. The third 24 hour period shows increasing clinical disturbance with vomiting and bloody diarrhea. Anatomically the small intestine from the edge of the pylorus to the rim of the ileocecal valve looks raw, red, and inflamed. The crypt and villous epithelium has in large part vanished, leaving a collapsed framework of the mucosa showing a little edema and invasion of wandering cells. The 4th day marks the peak of the intoxication, and death usually takes place at this time, preceded by coma. Anatomically and histologically the picture is like that of the 3rd day. There is more evidence of mitosis and efforts of repair on the part of the intestinal epithelium. The stomach is not concerned in this reaction, but the colon may show evidences of a slight injury. The colon is obviously much more resistant than is the small intestine. We believe the evidence is conclusive that the injury done the epithelium of the small intestine is wholly responsible for the stormy clinical picture and fatal intoxication.
Systematic bioinformatic analysis of expression levels of 17,330 human genes across 9,783 samples from 175 types of healthy and pathological tissues
Authors: Sami Kilpinen, Reija Autio, Kalle Ojala, Kristiina Iljin, Elmar Bucher, Henri Sara, Tommi Pisto, Matti Saarela, Rolf I Skotheim, Mari Björkman, John-Patrick Mpindi, Saija Haapa-Paananen, Paula Vainio, Henrik Edgren, Maija Wolf, Jaakko Astola, Matthias Nees, Sampsa Hautaniemi, Olli Kallioniemi
Journal: Genome biology (2008)

Abstract Our knowledge on tissue- and disease-specific functions of human genes is rather limited and highly context-specific. Here, we have developed a method for the comparison of mRNA expression levels of most human genes across 9,783 Affymetrix gene expression array experiments representing 43 normal human tissue types, 68 cancer types, and 64 other diseases. This database of gene expression patterns in normal human tissues and pathological conditions covers 113 million datapoints and is available from the GeneSapiens website.
Maternal Lipids as Strong Determinants of Fetal Environment and Growth in Pregnancies With Gestational Diabetes Mellitus
Authors: Ute M. Schaefer-Graf, Kristof Graf, Irina Kulbacka, Siri L. Kjos, Joachim Dudenhausen, Klaus Vetter, Emilio Herrera
Journal: Diabetes Care (2008)

To determine the contribution of maternal glucose and lipids to intrauterine metabolic environment and fetal growth in pregnancies with gestational diabetes mellitus (GDM).In 150 pregnancies, serum triglycerides (TGs), cholesterol, free fatty acids (FFAs), glycerol, insulin, and glucose were determined in maternal serum and cord blood during the 3rd trimester. Maternal glucose values came from oral glucose tolerance testing and glucose profiles. Measurements of fetal abdominal circumference (AC) were performed simultaneously with maternal blood sampling and birth weight, and BMI and neonatal fat mass were obtained following delivery.Maternal TGs and FFAs correlated with fetal AC size (at 28 weeks: triglycerides, P = 0.001; FFAs, P = 0.02), and at delivery they correlated with all neonatal anthropometric measures (FFA: birth weight, P = 0.002; BMI, P = 0.001; fat mass, P = 0.01). After adjustment for confounding variables, maternal FFAs and TGs at delivery remained the only parameters independently related to newborns large for gestational age (LGA) (P = 0.008 and P = 0.04, respectively). Maternal FFA levels were higher in mothers with LGA newborns than in those with appropriate for gestational age (AGA) newborns (362.8 +/- 101.7 vs. 252.4 +/- 10.1, P = 0.002). Maternal levels of TGs, FFAs, and glycerol at delivery correlated with those in cord blood (P = 0.003, P = 0.004, and P = 0.005, respectively). Fetal triglyceride and cholesterol levels were negatively correlated with newborn birth weight (P = 0.001), BMI (P = 0.004), and fat mass (P = 0.001). TGs were significantly higher in small for gestational age (SGA) newborns compared with AGA or LGA newborns, while insulin-to-glucose ratio and FFAs were the highest in LGA newborns.In well-controlled GDM pregnancies, maternal lipids are strong predictors for fetal lipids and fetal growth. Infants with abnormal growth seem to be exposed to a distinct intrauterine environment compared with those with appropriate growth.
Spontaneous pneumomediastinum: is it a rare cause of chest pain?
Authors: A Yellin, M Gapany-Gapanavicius, Y Lieberman
Journal: Thorax (1983)

A policy of obtaining a routine chest radiograph in every young patient with unexplained chest pain or dyspnoea led to the diagnosis of 14 cases of spontaneous pneumomediastinum within four years, whereas only two cases from former years could be found retrospectively. One patient had recurrent spontaneous pneumomediastinum, the first case so far reported. Analysis of admission data suggested that this entity may be much more common than is generally believed, and may be second only to spontaneous pneumothorax as a cause of admission of young, healthy individuals experiencing sudden chest pain or shortness of breath. After reviewing the published reports we propose the following definition of spontaneous mediastinal emphysema: the non-traumatic presence of free air in the mediastinum in a patient with no known underlying lung disease. When it occurs without associated pneumothorax it is benign. The incidence of spontaneous pneumomediastinum for the four-year period under study was 1 per 12 850 admissions.
Prevalence, Severity, and Importance of Physical and Emotional Symptoms in Chronic Hemodialysis Patients
Authors: Steven D Weisbord, Linda F Fried, Robert M Arnold, Michael J Fine, David J Levenson, Rolf A Peterson, Galen E Switzer
Journal: Journal of the American Society of Nephrology (2005)

The prevalence, severity, and clinical significance of physical and emotional symptoms in patients who are on maintenance hemodialysis remain incompletely characterized. This study sought to assess symptoms and their relationship to quality of life and depression. The recently developed Dialysis Symptom Index was used to assess the presence and the severity of 30 symptoms. The Illness Effects Questionnaire and Beck Depression Inventory were used to evaluate quality of life and depression, respectively. Correlations among symptom burden, symptom severity, quality of life, and depression were assessed using Spearman correlation coefficient. A total of 162 patients from three dialysis units were enrolled. Mean age was 62 y, 48% were black, 62% were men, and 48% had diabetes. The median number of symptoms was 9.0 (interquartile range 6 to 13). Dry skin, fatigue, itching, and bone/joint pain each were reported by ≥50% of patients. Seven additional symptoms were reported by &gt;33% of patients. Sixteen individual symptoms were described as being more than “somewhat bothersome.” Overall symptom burden and severity each were correlated directly with impaired quality of life and depression. In multivariable analyses adjusting for demographic and clinical variables including depression, associations between symptoms and quality of life remained robust. Physical and emotional symptoms are prevalent, can be severe, and are correlated directly with impaired quality of life and depression in maintenance hemodialysis patients. Incorporating a standard assessment of symptoms into the care provided to maintenance hemodialysis patients may provide a means to improve quality of life in this patient population.
A Land of Lotus-Eaters?
Authors: GEORGE MORRISON CARSTAIRS
Journal: American Journal of Psychiatry (1969)

With the popularization of the psychotropic drugs, the author observes, a peculiar aberration has entered into public thinking: everyone nowadays expects to be happy. Pills have come to be regarded as a means to do away with the everyday anxieties and pain that have long served as spurs to human progress by leading to constructive action. This new view of unhappiness as a wholly negative and unnecessary emotion, the author suggests, is in need of reevaluation.
eEF-2 Kinase Dictates Cross-Talk between Autophagy and Apoptosis Induced by Akt Inhibition, Thereby Modulating Cytotoxicity of Novel Akt Inhibitor MK-2206
Authors: Yan Cheng, Xingcong Ren, Yi Zhang, Rajesh Patel, Arati Sharma, Hao Wu, Gavin P. Robertson, Li Yan, Eric Rubin, Jin-Ming Yang
Journal: Cancer Research (2011)

Inhibition of the survival kinase Akt can trigger apoptosis, and also has been found to activate autophagy, which may confound tumor attack. In this study, we investigated regulatory mechanisms through which apoptosis and autophagy were modulated in tumor cells subjected to Akt inhibition by MK-2206, the first allosteric small molecule inhibitor of Akt to enter clinical development. In human glioma cells, Akt inhibition by MK-2206 or siRNA-mediated attenuation strongly activated autophagy, whereas silencing of eukaryotic elongation factor-2 (eEF-2) kinase, a protein synthesis regulator, blunted this autophagic response. Suppression of MK-2206-induced autophagy by eEF-2 silencing was accompanied by a promotion of apoptotic cell death. Similarly, siRNA-mediated inhibition of eEF-2 kinase potentiated the efficacy of MK-2206 against glioma cells. Together, these results showed that blunting autophagy and augmenting apoptosis by inhibition of eEF-2 kinase could modulate the sensitivity of glioma cells to Akt inhibition. Our findings suggest that targeting eEF-2 kinase may reinforce the antitumor efficacy of Akt inhibitors such as MK-2206.
Urinary Protein Binding Does Not Affect Response to Furosemide in Patients with Nephrotic Syndrome
Authors: RAJIV AGARWAL, J. CHRISTOPHER GORSKI, KIMBERLY SUNDBLAD, D. CRAIG BRATER
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Response to loop diuretics in patients with nephrotic syndrome (NS) is subnormal. Studies in animal models of NS have suggested that binding of diuretic to urinary albumin is one of the mechanisms that may be operative in this diuretic resistance. To explore this hypothesis, 12 patients with NS were studied to determine whether displacement from urinary protein binding with sulfisoxazole would restore response to 120 mg of furosemide. The study was stopped after treating seven patients because it was clear that sulfizoxazole had no effect. Sodium excretion (mean ± SD) from furosemide alone was 239 ± 90 versus 240 ± 115 mEq/8 h with sulfisoxazole. Sulfisoxazole had modest effects on serum pharmacokinetics of furosemide but had no effect on either the time course of furosemide urinary excretion or overall amount excreted: 49 ± 15 mg versus 54 ± 12 mg for furosemide alone and furosemide plus sulfisoxazole, respectively. It is concluded that urinary protein binding of loop diuretics is not a major mechanism for the diuretic resistance of NS. In turn, strategies aimed at displacing such binding are unlikely to be clinically helpful.