tbuckley/cabot-search huggingface dataset:
Spontaneous heat shock protein synthesis by alveolar macrophages in interstitial lung disease associated with phagocytosis of eosinophils
Authors: BS Polla, S Kantengwa, GJ Gleich, M Kondo, CM Reimert, AF Junod
Journal: European Respiratory Journal (1993)

Synthesis of heat shock proteins (HSPs) is induced in all cells and tissues after exposure to elevated temperatures, or a variety of other types of injury, including oxidative injury. We have previously reported that stress proteins are induced in monocytes-macrophages during phagocytosis of red blood cells. Receptor-mediated phagocytosis is associated with activation of the respiratory burst, generation of the lipid mediators of inflammation, and increased production of cytokines. Similar activation events have been described in the alveolar macrophage (AM) during pulmonary fibrosis. We therefore analysed the pattern of proteins synthesized by human AMs recovered by bronchoalveolar lavage (BAL) in interstitial lung disease, both under basal conditions and after in vitro exposure to heat or hydrogen peroxide (H2O2). In two out of the 17 cases studied, we observed a high alveolar eosinophilia (10 and 24%, respectively) and phagocytosis, by the AMs, of eosinophilic material. Whereas exposure to heat or H2O2 induced in all AMs the synthesis of the classical HSPs, in these two cases, we found spontaneous synthesis of HSPs and of a 32 kD oxidation-specific stress protein, haeme oxygenase (HO). Exposure of AM to purified eosinophil-derived proteins, such as major basic protein (MBP), eosinophil peroxidase (EPO), eosinophil-derived neurotoxin (EDN), alone or in combination, did not induce stress protein synthesis, further suggesting that phagocytosis is involved in this induction. Stress protein synthesis by AMs may represent a new cellular marker of pulmonary injury and eosinophilic inflammation, and an autoprotective mechanism against oxidative stress.
Development of acute lung injury after the combination of intravenous bleomycin and exposure to hyperoxia in rats.
Authors: J G Hay, P L Haslam, A Dewar, B Addis, M Turner-Warwick, G J Laurent
Journal: Thorax (1987)

Pulmonary toxicity is an important adverse effect of bleomycin treatment. Very little is known of the mechanisms underlying the development of lung injury, especially after intravenous administration, or how it can be modulated. In this study acute lung injury induced by bleomycin has been examined in rats by assessment of alveolar lavage cell profiles, histological examination, and measurement of the total pulmonary extravascular albumin space. Intratracheal instillation of bleomycin 1.5 mg resulted in a severe pneumonitis with influx of inflammatory cells into the alveoli as assessed by alveolar lavage, oedema of the alveolar walls, and up to an eight fold increase in the total pulmonary extravascular albumin space, maximal at 72 hours. Intravenous bleomycin 0.15-5 mg produced no detectable injury when assessed in these ways. Exposure to hyperoxia (40-90%) after intravenous bleomycin, however, induced lung injury similar to that produced by intratracheal bleomycin. A much more severe injury followed administration of intravenous bleomycin after an exposure to hyperoxia, which itself resulted in lung injury; but lung injury was still detectable after bleomycin when the exposure to hyperoxia was insufficient to induce changes in control animals. Lung injury was not observed when the exposure to hyperoxia preceded bleomycin treatment. These results indicate the importance of oxygen in the pathways leading to acute lung injury following intravenous bleomycin. We conclude that exposure to oxygen might induce lung injury during and after bleomycin treatment, and suggest that in these circumstances oxygen therapy should be kept to a minimum.
Observations on the factors that control the generation of triiodothyronine from thyroxine in rat liver and the nature of the defect induced by fasting.
Authors: A Balsam, S H Ingbar
Journal: Journal of Clinical Investigation (1979)

Studies were performed to explore the mechanism underlying the impaired generation of 125-I-3,5,3'-triiodothyronine (T3) from 125I-thyroxine (T4) (T3-neogenesis)) in preparations of liver from rats fasted for 48 h and the prevention of this effect by the feeding of glucose. T3-neogenesis in livers from fasted animals and those fed chow or glucose was assessed in various mixtures of crude microsomal fractions with either buffer or cytosols. T3-neogenesis was mediated by an enzyme present in the microsomal fraction whose activity was enhanced by cytosolic cofactor(s). In livers from animals fasted for 48 h, the supporting activity of cytosol was decreased, whereas the activity of the enzyme was unaffected. Administration of glucose as the sole nutritional source prevented the decrease in the supporting activity of hepatic cytosol that was regularly observed in the case of animals totally deprived of food. The diminished supporting activity for T3-neogenesis provided by liver cytosol from fasted animals was restored to normal by enrichment with either NADPH or GSH, but the two cofactors appeared to act at different loci. GSH stimulated T3-neogenesis in microsomes incubated in the absence of cytosol, i.e., in buffer, whereas NADPH did not. The stimulatory effect of both agents was blocked by the sulfhydryl oxidant, diamide, which also inhibited T3-neogenesis in mixtures of microsomes with cytosols. Taken together, these observations suggest that GSH acts directly on the enzyme in the crude microsomal fraction, whereas NADPH acts within the cytosol, possibly by increasing the concentration of GSH through the action of the enzyme glutathione reductase, for which NADPH is a cofactor. In this light, the decreased supporting activity of hepatic cytosol from starved animals appears to reflect, at least partly, a decreased concentration of one or both cofactors. The direct stimulation of enzyme activity by GSH, and the apparent lack of inhibition of unstimulated activity by diamide, suggests that the 5'-monodeiodinase for thyroxine that mediates T3-neogenesis may be a GSH transhydrogenase.
Cardiovascular Effects of Thyroxine Treatment in Hypophysectomized Rats
Authors: MARGARET BEZNAK, A. Marcsan, T. Fournie
Journal: Circulation Research (1963)

Oxygen consumption, weight and rate of the heart, blood pressure, cardiac output and work are restored to normal if rats hypophysectomized two to three months previously are treated with thyroxine over a period of three to five weeks. Although under basal conditions the above parameters in these rats are the same as those in normal rats, the maximum output and work during loading by infusion of polyvinylpyrrolidone into the right side of the heart are less in hypophysectomized rats treated with thyroxine than they are in normal rats. Similarly, if a load is imposed on the heart by constriction of the aorta, cardiac output and work are well below the values measured in normal rats with aortic constriction. It is concluded that thyroxine treatment of hypophysectomized rats can restore to normal the performance of the cardiovascular system under basal conditions but that during loading (polyvinylpyrrolidone infusion, aortic constriction) the performance of the cardiovascular system is less than in normal rats.
Low-Frequency HIV-1 Drug Resistance Mutations and Risk of NNRTI-Based Antiretroviral Treatment Failure
Authors: Jonathan Z. Li
Journal: JAMA (2011)

Presence of low-frequency, or minority, human immunodeficiency virus type 1 (HIV-1) drug resistance mutations may adversely affect response to antiretroviral treatment (ART), but evidence regarding the effects of such mutations on the effectiveness of first-line ART is conflicting.
Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients
Authors: L. Boussemart, E. Routier, C. Mateus, K. Opletalova, G. Sebille, N. Kamsu-Kom, M. Thomas, S. Vagner, M. Favre, G. Tomasic, J. Wechsler, L. Lacroix, C. Robert
Journal: Annals of Oncology (2013)
Intraspecific Polymorphism, Interspecific Divergence, and the Origins of Function-Altering Mutations in Deer Mouse Hemoglobin
Authors: Chandrasekhar Natarajan, Federico G. Hoffmann, Hayley C. Lanier, Cole J. Wolf, Zachary A. Cheviron, Matthew L. Spangler, Roy E. Weber, Angela Fago, Jay F. Storz
Journal: Molecular Biology and Evolution (2015)

Major challenges for illuminating the genetic basis of phenotypic evolution are to identify causative mutations, to quantify their functional effects, to trace their origins as new or preexisting variants, and to assess the manner in which segregating variation is transduced into species differences. Here, we report an experimental analysis of genetic variation in hemoglobin (Hb) function within and among species of Peromyscus mice that are native to different elevations. A multilocus survey of sequence variation in the duplicated HBA and HBB genes in Peromyscus maniculatus revealed that function-altering amino acid variants are widely shared among geographically disparate populations from different elevations, and numerous amino acid polymorphisms are also shared with closely related species. Variation in Hb-O2 affinity within and among populations of P. maniculatus is attributable to numerous amino acid mutations that have individually small effects. One especially surprising feature of the Hb polymorphism in P. maniculatus is that an appreciable fraction of functional standing variation in the two transcriptionally active HBA paralogs is attributable to recurrent gene conversion from a tandemly linked HBA pseudogene. Moreover, transpecific polymorphism in the duplicated HBA genes is not solely attributable to incomplete lineage sorting or introgressive hybridization; instead, it is mainly attributable to recurrent interparalog gene conversion that has occurred independently in different species. Partly as a result of concerted evolution between tandemly duplicated globin genes, the same amino acid changes that contribute to variation in Hb function within P. maniculatus also contribute to divergence in Hb function among different species of Peromyscus. In the case of function-altering Hb mutations in Peromyscus, there is no qualitative or quantitative distinction between segregating variants within species and fixed differences between species.
Serum Fibrin/Fibrinogen Degradation Products Associated with Postoperative Pulmonary Embolus and Venous Thrombosis
Authors: C. V. Ruckley, P. C. Das, A. G. Leitch, A. A. Donaldson, W. A. Copland, A. T. Redpath, P. Scott, J. D. Cash
Journal: BMJ (1970)

A total of 76 "high-risk" surgical patients were studied for evidence of venous thromboembolic disease. Episodes of deep vein thrombosis and of pulmonary embolism were related to changes in blood levels of fibrin degradation products (F.D.P.). When diagnosed either by ordinary clinical means or by venography and isotope scanning significantly raised F.D.P. levels were found in all cases. Serum F.D.P. estimations are unlikely to help in detecting deep vein thrombosis, but may prove valuable in diagnosing pulmonary embolism.
Gonorrhea and Chlamydia in the United States among Persons 14 to 39 Years of Age, 1999 to 2002
Authors: S. Deblina Datta, Maya Sternberg, Robert E. Johnson, Stuart Berman, John R. Papp, Geraldine McQuillan, Hillard Weinstock
Journal: Annals of Internal Medicine (2007)

Nationally representative surveys of chlamydia and gonorrhea are an important measure of disease burden and progress of screening programs.To measure chlamydia and gonorrhea prevalence in the United States.Analysis of sexual history information and urine specimens collected in the National Health and Nutrition Examination Survey (NHANES), 1999-2002.U.S. civilian noninstitutionalized population as sampled by NHANES, 1999-2002.6632 NHANES respondents.Urine specimens were tested for chlamydia and gonorrhea. Results were weighted to represent the U.S. civilian, noninstitutionalized population between 14 and 39 years of age.Prevalence of gonorrheal infection was 0.24% (95% CI, 0.16% to 0.38%). Prevalence of gonorrheal infection was higher among non-Hispanic black persons (1.2% [CI, 0.7% to 1.9%]) than among non-Hispanic white persons (0.07% [CI, 0.02% to 0.24%]). Among those with gonorrheal infection, 46% also had chlamydial infection. Prevalence of chlamydial infection was 2.2% (CI, 1.8% to 2.8%) and was similar between males (2.0% [CI, 1.6% to 2.5%]) and females (2.5% [CI, 1.8% to 3.4%]). Among females, the highest prevalence was in those age 14 to 19 years, whereas among males, it was highest in those age 14 to 29 years. Prevalence was higher among non-Hispanic black persons (6.4% [CI, 5.4% to 7.5%]) than non-Hispanic white persons (1.5% [CI, 1.0% to 2.4%]). Among females with a history of gonorrhea or chlamydia in the previous 12 months, chlamydia prevalence was 16.7% (CI, 5.5% to 50.7%).The specificity of urine-based assays for chlamydia and gonorrhea is limited, and the possible misclassification of sexual experience status may have affected the accuracy of some estimates.The findings support current recommendations to screen sexually active females age 25 years or younger for chlamydia, to retest infected females for chlamydial infection, and to co-treat individuals with gonorrhea for chlamydia.
ESCMID guidelines for the management of the infection control measures to reduce transmission of multidrug-resistant Gram-negative bacteria in hospitalized patients
Authors: E. Tacconelli, M.A. Cataldo, S.J. Dancer, G. De Angelis, M. Falcone, U. Frank, G. Kahlmeter, A. Pan, N. Petrosillo, J. Rodríguez-Baño, N. Singh, M. Venditti, D.S. Yokoe, B. Cookson
Journal: Clinical Microbiology and Infection (2013)
WL-276, an Antagonist against Bcl-2 Proteins, Overcomes Drug Resistance and Suppresses Prostate Tumor Growth
Authors: Liangyou Wang, Daniel T. Sloper, Sadiya N. Addo, Defeng Tian, Joel W. Slaton, Chengguo Xing
Journal: Cancer Research (2008)

Abstract Patients with hormone-refractory prostate cancer (HRPC) have an estimated median survival of only 10 months because of acquired drug resistance, urging the need to develop therapies against the drug-resistant HRPC phenotype. Accumulating evidence suggests that overexpressing antiapoptotic Bcl-2 family proteins is at least partially responsible for the development of drug resistance among HRPC patients. Antagonizing the antiapoptotic Bcl-2 family proteins, therefore, is one potential approach to circumventing drug resistance in HRPC. WL-276 was developed as a small-molecule antagonist against antiapoptotic Bcl-2 family proteins, with binding potency comparable to (−)-gossypol. Overexpressing Bcl-2 or Bcl-XL failed to confer resistance to WL-276. WL-276 also effectively induced apoptosis in PC-3 cells. In addition, three PC-3 cell lines with acquired drug resistance against standard cancer chemotherapies were more sensitive to WL-276 than the parent PC-3 cell line. The increased cytotoxicity toward drug-resistant PC-3 cells shows the clinical potential of WL-276 against HRPC that is resistant to conventional therapies. The anticancer activity of WL-276 was manifested in its suppression of PC-3–induced prostate tumor growth in vivo. The selective toxicity of WL-276 against drug-resistant PC-3 cells and its in vivo suppression of PC-3 prostate tumor growth suggest that WL-276 is a promising lead candidate for the development of Bcl-2 antagonists against drug-resistant HRPC. [Cancer Res 2008;68(11):4377–83]
Combination of interferon and ribavirin in chronic hepatitis C: Re-treatment of nonresponders to interferon
Authors: A Di Bisceglie
Journal: Hepatology (2001)

Chronic infection with hepatitis C virus (HCV) may result in cirrhosis, liver failure, and hepatocellular carcinoma. A minority of patients have a sustained response to antiviral therapy, and nonresponders remain at risk of developing progressive liver disease. We conducted a randomized, controlled trial of therapy with the combination of interferon (IFN) and ribavirin in patients with chronic hepatitis C who had not responded to an initial course of therapy with IFN alone. A total of 124 patients were randomized to receive the combination of IFN and ribavirin for either 24 or 48 weeks and followed for an additional 24 weeks after stopping therapy. Thirty-eight treated patients (30.6%) achieved a sustained virologic response (undetectable HCV RNA at the 24-week follow-up point). This was associated with significant improvement in necroinflammatory activity noted on liver biopsy. Interestingly, there was not a statistically significant difference in response rates based on the duration of treatment; HCV genotype was the strongest predictor of a sustained response. Sustained responses were noted even in patients with poor predictive factors, including those with advanced hepatic fibrosis or cirrhosis, high levels of HCV RNA in serum, and those infected with HCV genotype 1. The study included 24 patients with normal serum alanine transaminase (ALT) values before therapy who had similar responses to those with initially elevated transaminase values. This study suggests that the combination of IFN and ribavirin is a useful modality of therapy in patients with chronic hepatitis C who did not respond to IFN alone.
Beneficial Effects of Fenofibrate to Improve Endothelial Dysfunction and Raise Adiponectin Levels in Patients With Primary Hypertriglyceridemia
Authors: Kwang Kon Koh, Seung Hwan Han, Michael J. Quon, Jeong Yeal Ahn, Eak Kyun Shin
Journal: Diabetes Care (2005)

OBJECTIVE—Improvement in endothelial function is predicted to improve insulin sensitivity, and this may be one mechanism by which fenofibrate decreases the incidence of coronary heart disease. We hypothesize fenofibrate improves endothelial function by enhancing insulin sensitivity. RESEARCH DESIGN AND METHODS—We administered placebo or fenofibrate 200 mg daily for 8 weeks to 46 patients with primary hypertriglyceridemia (24 had metabolic syndrome). This study was randomized, double blind, placebo controlled, and crossover in design. RESULTS—Compared with placebo, fenofibrate decreased total cholesterol, non-HDL cholesterol, apolipoprotein B, and triglycerides and increased HDL cholesterol and apolipoprotein A-I (all P &amp;lt; 0.001) while tending to decrease LDL cholesterol (P = 0.069). Fenofibrate significantly improved percent flow-mediated dilator response to hyperemia by 48 ± 5% (P &amp;lt; 0.001) and lowered plasma levels of high-sensitivity C-reactive protein (hsCRP) relative to baseline measurements from 0.80 to 0.70 mg/l (P = 0.001) and fibrinogen levels by 16 ± 3% (P &amp;lt; 0.001). Compared with placebo, fenofibrate therapy significantly increased plasma levels of adiponectin by 14 ± 5% (P = 0.008) and increased insulin sensitivity (assessed by quantitative insulin sensitivity check index [QUICKI]) by 6 ± 2% (P = 0.048). There were significant correlations between percent changes in adiponectin levels and percent changes in flow-mediated dilation (r = 0.401, P = 0.006), hsCRP (r = −0.443, P = 0.002), or QUICKI (r = 0.292, P = 0.049). Multivariate regression analysis showed that only changes in adiponectin levels persisted as an independent predictor of changes in flow-mediated dilation (r = 0.504, P = 0.013). Overall, we observed similar results in 24 patients with metabolic syndrome. CONCLUSIONS—Fenofibrate therapy significantly improved percent flow-mediated dilator response to hyperemia, reduced inflammation marker levels, increased adiponectin levels, and improved insulin sensitivity in hypertriglyceridemic or metabolic syndrome patients.
Blind and Confused
Authors: Vibhash D. Sharma, Patrick Malafronte, Nicole De Simone, Benjamin M. Greenberg
Journal: JAMA Neurology (2013)

A 62-year-old man developed confusion and was diagnosed as having encephalitis. The etiology was not identified. He continued to have cognitive impairment but remained clinically stable. Five months later, he woke with bilateral vision loss. On neurological examination, he had no light perception bilaterally. The remainder of the neurological examination results were normal. Magnetic resonance imaging of the brain revealed multiple brain lesions. He was treated with steroids and plasmapheresis, with mild improvement in vision. He was then transferred to a long-term care facility, where he developed increasing confusion and ultimately died. An autopsy was performed; the differential diagnosis, neuropathology, and final diagnosis are discussed here.
Intractable vomiting due to a brainstem lesion in the absence of neurological signs or raised intracranial pressure
Authors: S D Mann, B J Danesh, M A Kamm
Journal: Gut (1998)

The case of a 30 year old man who was believed to have a gastrointestinal motility disorder causing his chronic vomiting is reported. He had been well until 21 months previously when he had developed recurrent vomiting which would occur up to 10 times in a 24 hour period. Vomiting was not precipitated by eating and was not associated with any other symptoms. He had lost 25 kg in weight. A psychiatric assessment did not reveal a psychogenic cause for his vomiting. A brainstem magnetic resonance imaging scan revealed an area of low signal in the low midbrain just above the pons to the left of the midline. After gadolinium contrast injection the area enhanced. There was little or no mass effect, that is minimal displacement of normal structures, and minimal oedema. The appearance was that of a low grade or early brainstem tumour. There were no features of haemorrhage or infarct. The patient was managed with oral dexamethasone, resulting in prompt resolution of his symptoms. A search for a central neurological cause is recommended in a patient with unexplained persistent vomiting, even in the absence of other features to suggest a neurological problem. Autonomic function testing may provide additional information.
Antimyeloma Activity of a Multitargeted Kinase Inhibitor, AT9283, via Potent Aurora Kinase and STAT3 Inhibition Either Alone or in Combination with Lenalidomide
Authors: Loredana Santo, Teru Hideshima, Diana Cirstea, Madhavi Bandi, Erik A. Nelson, Gullu Gorgun, Scott Rodig, Sonia Vallet, Samantha Pozzi, Kishan Patel, Christine Unitt, Matt Squires, Yiguo Hu, Dharminder Chauhan, Anuj Mahindra, Nikhil C. Munshi, Kenneth C. Anderson, Noopur Raje
Journal: Clinical Cancer Research (2011)

Aurora kinases, whose expression is linked to genetic instability and cellular proliferation, are being investigated as novel therapeutic targets in multiple myeloma (MM). In this study, we investigated the preclinical activity of a small-molecule multitargeted kinase inhibitor, AT9283, with potent activity against Aurora kinase A, Aurora kinase B, and Janus kinase 2/3.We evaluated the in vitro antimyeloma activity of AT9283 alone and in combination with lenalidomide and the in vivo efficacy by using a xenograft mouse model of human MM.Our data showed that AT9283 induced cell-growth inhibition and apoptosis in MM. Studying the apoptosis mechanism of AT9283 in MM, we observed features consistent with both Aurora kinase A and Aurora kinase B inhibition, such as increase of cells with polyploid DNA content, decrease in phospho-histone H3, and decrease in phospho-Aurora A. Importantly, AT9283 also inhibited STAT3 tyrosine phosphorylation in MM cells. Genetic depletion of STAT3, Aurora kinase A, or Aurora kinase B showed growth inhibition of MM cells, suggesting a role of AT9283-induced inhibition of these molecules in the underlying mechanism of MM cell death. In vivo studies showed decreased MM cell growth and prolonged survival in AT9283-treated mice compared with controls. Importantly, combination studies of AT9283 with lenalidomide showed significant synergistic cytotoxicity in MM cells, even in the presence of bone marrow stromal cells. Enhanced cytotoxicity was associated with increased inhibition of phosphorylated STAT3 and phosphorylated extracellular signal-regulated kinase.Demonstration of in vitro and in vivo anti-MM activity of AT9283 provides the rationale for the clinical evaluation of AT9283 as monotherapy and in combination therapy for treating patients with MM.