tbuckley/cabot-search huggingface dataset:
Nitric oxide, an endothelial cell relaxation factor, inhibits neutrophil superoxide anion production via a direct action on the NADPH oxidase.
Authors: R M Clancy, J Leszczynska-Piziak, S B Abramson
Journal: Journal of Clinical Investigation (1992)

Nitric oxide provokes vasodilation and inhibits platelet aggregation. We examined the effect of nitric oxide on superoxide anion production by three sources: activated intact neutrophils, xanthine oxidase/hypoxanthine, and the NADPH oxidase. Nitric oxide significantly inhibited the generation of superoxide anion by neutrophils exposed to either FMLP (10(-7)M) or PMA (150 ng/ml) (IC50 = 30 microM). To determine whether the effect of nitric oxide on the respiratory burst was due to simple scavenging of O2+, kinetic studies that compared effects on neutrophils and the cell-free xanthine oxidase system were performed. Nitric oxide inhibited O2+ produced by xanthine oxidase only when added simultaneously with substrate, consistent with the short half-life of NO in oxygenated solution. In contrast, the addition of nitric oxide to neutrophils 20 min before FMLP resulted in the inhibition of O2+ production, which suggests formation of a stable intermediate. The effect of nitric oxide on the cell-free NADPH oxidase superoxide-generating system was also examined: The addition of NO before arachidonate activation (t = -6 min) significantly inhibited superoxide anion production. Nitric oxide did not inhibit O2+ when added at NADPH initiation (t = 0). Treatment of the membrane but not cytosolic component of the oxidase was sufficient to inhibit O2+ generation. The data suggest that nitric oxide inhibits neutrophil O2+ production via direct effects on membrane components of the NADPH oxidase. This action must occur before the assembly of the activated complex.
Improved regional left ventricular function after successful satellite cell grafting in rabbits with myocardial infarction
Authors: Alex Blatt, Dror Robinson, Gad Cotter, Shai Efrati, Yariv Simantov, Ilan Bar, Edo Kaluski, Ricardo Krakover, Stanislav Sidenko, Zoharia Evron, Lidia Lipa, Natalia Posternak, Zvi Nevo, Zvi Vered
Journal: European Journal of Heart Failure (2003)
Multicenter Phase II Trial of YM155, a Small-Molecule Suppressor of Survivin, in Patients With Advanced, Refractory, Non–Small-Cell Lung Cancer
Authors: Giuseppe Giaccone, Petr Zatloukal, Jaromir Roubec, Karijn Floor, Jaromir Musil, Milan Kuta, Rob J. van Klaveren, Subhash Chaudhary, Adrie Gunther, Setareh Shamsili
Journal: Journal of Clinical Oncology (2009)

Purpose To evaluate the antitumor activity and safety of YM155, a novel, small-molecule suppressor of survivin, as single-agent therapy in patients with previously treated, advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIb/IV NSCLC who had experienced treatment failure during one or two prior chemotherapy regimens (at least one of which was platinum based) received YM155 as a continuous intravenous infusion (4.8 mg/m 2 /d) over 168 hours followed by observation for 14 days in 21-day treatment cycles. The primary end point was objective tumor response rate (ORR). Secondary end points included duration of stable disease (SD), progression-free survival (PFS), overall survival (OS), safety and pharmacokinetic profiles, and pharmacodynamic evaluations. Results Thirty-seven patients received YM155. Two patients achieved a confirmed partial response, with an ORR of 5.4% (95% CI, 0.7% to 18.2%). An additional 14 patients (37.8%) achieved SD resulting in a disease control rate of 43.2% (95% CI, 27.1% to 60.5%). Median duration of PFS was 1.7 months (95% CI, 1.3 to 2.8 months). Median duration of OS was 6.6 months (95% CI, 4 to 12.2 months), with a 1-year survival rate of 35.1%. Treatment with YM155 was well tolerated with the majority of treatment discontinuations not treatment related. Conclusion YM155 exhibited modest single-agent activity in patients with refractory, advanced NSCLC. A favorable safety/tolerability profile was reported. Further evaluation of YM155 in combination with chemotherapy and other targeted agents may be warranted.
IFNγ-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice
Authors: Toshikatsu Hanada, Takashi Kobayashi, Takatoshi Chinen, Kazuko Saeki, Hiromi Takaki, Keiko Koga, Yasumasa Minoda, Takahito Sanada, Tomoko Yoshioka, Hiromitsu Mimata, Seiya Kato, Akihiko Yoshimura
Journal: The Journal of Experimental Medicine (2006)

Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-κB pathway was shown to play an essential role in promoting inflammation-associated cancer, but the role of the JAK/STAT pathway, another important signaling pathway of proinflammatory cytokines, remains to be investigated. Suppressor of cytokine signaling-1 (SOCS1) acts as an important physiological regulator of cytokine responses, and silencing of the SOCS1 gene by DNA methylation has been found in several human cancers. Here, we demonstrated that SOCS1-deficient mice (SOCS1−/−Tg mice), in which SOCS1 expression was restored in T and B cells on a SOCS1−/− background, spontaneously developed colorectal carcinomas carrying nuclear β-catenin accumulation and p53 mutations at 6 months of age. However, interferon (IFN)γ−/−SOCS1−/− mice and SOCS1−/−Tg mice treated with anti-IFNγ antibody did not develop such tumors. STAT3 and NF-κB activation was evident in SOCS1−/−Tg mice, but these were not sufficient for tumor development because these are also activated in IFNγ−/−SOCS1−/− mice. However, colons of SOCS1−/−Tg mice, but not IFNγ−/−SOCS1−/− mice, showed hyperactivation of STAT1, which resulted in the induction of carcinogenesis-related enzymes, cyclooxygenase-2 and inducible nitric oxide synthase. These data strongly suggest that SOCS1 is a unique antioncogene which prevents chronic inflammation-mediated carcinogenesis by regulation of the IFNγ/STAT1 pathways.
Histone deacetylase 3 (HDAC3) plays an important role in retinal ganglion cell death after acute optic nerve injury
Authors: Heather M Schmitt, Heather R Pelzel, Cassandra L Schlamp, Robert W Nickells
Journal: Molecular Neurodegeneration (2014)

Optic nerve damage initiates a series of early atrophic events in retinal ganglion cells (RGCs) that precede the BAX-dependent committed step of the intrinsic apoptotic program. Nuclear atrophy, including global histone deacetylation, heterochromatin formation, shrinkage and collapse of nuclear structure, and the silencing of normal gene expression, comprise an important obstacle to overcome in therapeutic approaches to preserve neuronal function. Several studies have implicated histone deacetylases (HDACs) in the early stages of neuronal cell death, including RGCs. Importantly, these neurons exhibit nuclear translocation of HDAC3 shortly after optic nerve damage. Additionally, HDAC3 activity has been reported to be selectively toxic to neurons.RGC-specific conditional knockout of Hdac3 was achieved by transducing the RGCs of Hdac3fl/fl mice with an adeno-associated virus serotype 2 carrying CRE recombinase and GFP (AAV2-Cre/GFP). Controls included similar viral transduction of Rosa26fl/fl reporter mice. Optic nerve crush (ONC) was then performed on eyes. The ablation of Hdac3 in RGCs resulted in significant amelioration of characteristics of ONC-induced nuclear atrophy such as H4 deacetylation, heterochromatin formation, and the loss of nuclear structure. RGC death was also significantly reduced. Interestingly, loss of Hdac3 expression did not lead to protection against RGC-specific gene silencing after ONC, although this effect was achieved using the broad spectrum inhibitor, Trichostatin A.Although other HDACs may be responsible for gene expression changes in RGCs, our results indicate a critical role for HDAC3 in nuclear atrophy in RGC apoptosis following axonal injury. This study provides a framework for studying the roles of other prevalent retinal HDACs in neuronal death as a result of axonal injury.
Gene Set Analysis of Lung Samples Provides Insight into Pathogenesis of Progressive, Fibrotic Pulmonary Sarcoidosis
Authors: Helen E. Lockstone, Sharon Sanderson, Nina Kulakova, Dilair Baban, Andrew Leonard, Wai Ling Kok, Simon McGowan, Andrew J. McMichael, Ling-Pei Ho
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Approximately 60 to 70% of patients with pulmonary sarcoidosis have disease that resolves spontaneously; the rest follow a chronic course with varying levels of fibrosis. It is unclear why some patients progress and if treatment affects outcome.Objectives: To determine differential gene expression profile in lungs of patients with self-limiting sarcoidosis compared to those with progressive-fibrotic disease, and to analyze the biological relevance of these differentially expressed genes.Methods: We examined microarray expression of 26,626 genes in transbronchial biopsies of granulomatous areas in lungs of patients with active but self-limiting (n = 8) versus those with active, progressive (± fibrotic) pulmonary disease (n = 7).Measurements and Main Results: Three hundred thirty-four genes were differentially expressed between the two groups (P < 0.01, Bayesian moderated t test). Gene Set Enrichment Analysis showed over-representation of gene-sets (defined by Gene Ontology) related to host immune activation, proliferation, and defense, among genes up-regulated in the progressive-fibrotic group (FDR q < 0.0001 for the top 43 gene sets), and a marked enrichment of, and similarity in gene expression profiles between, progressive-fibrotic sarcoidosis and hypersensitivity pneumonitis (HP), (q < 0.001), but not idiopathic pulmonary fibrosis (IPF).Conclusions: The findings suggest that patients with progressive/fibrotic pulmonary sarcoidosis have intense immune activity related to host defense in their lungs, with processes more similar to HP than IPF. The study also demonstrates that transbronchial lung biopsy samples can provide good-quality RNA for gene expression profiling, supporting its potential use as a prognostic classifier for pulmonary sarcoidosis.
Randomized Trial Comparing Bleomycin/Etoposide/Cisplatin With Alternating Cisplatin/Cyclophosphamide/Doxorubicin and Vinblastine/Bleomycin Regimens of Chemotherapy for Patients With Intermediate- and Poor-Risk Metastatic Nonseminomatous Germ Cell Tumors: Genito-Urinary Group of the French Federation of Cancer Centers Trial T93MP
Authors: Stéphane Culine, Andrew Kramar, Christine Théodore, Lionel Geoffrois, Christine Chevreau, Pierre Biron, Binh Bui Nguyen, Jean-François Héron, Pierre Kerbrat, Armelle Caty, Rémy Delva, Pierre Fargeot, Karim Fizazi, Jeannine Bouzy, Jean-Pierre Droz
Journal: Journal of Clinical Oncology (2008)

Purpose Two chemotherapy regimens for intermediate- and poor-risk metastatic nonseminomatous germ cell tumors were compared for efficacy and toxicity. Patients and Methods From February 1994 to February 2000, 190 patients were randomly assigned between either four cycles of BEP (bleomycin 30 mg d1, d8, d15; etoposide 100 mg/m 2 d1-5; cisplatin 20 mg/m 2 d1-5) or four to six alternating cycles of CISCA/VB (cyclophosphamide 400 mg/m 2 d1-2, doxorubicin 35 mg/m 2 d1-2, cisplatin 100 mg/m 2 d3/vinblastine 2.5 mg/m 2 d1-5, bleomycin 25 mg/m 2 d1-5). Risk was initially defined according to the Institut Gustave Roussy (Villejuif, France) prognostic model based on serum alpha-fetoprotein and human chorionic gonadotropin levels only. Patients were retrospectively assigned into the International Germ Cell Consensus Classification. Results Among 185 assessable patients, favorable responses did not differ statistically between the two arms: 49 in the CISCA/VB arm (56%; 95% CI, 45% to 66%), 57 in the BEP arm (65%; 95% CI, 55% to 75%). The CISCA/VB regimen induced more significant hematologic and mucous toxicities compared with the BEP arm. The 5-year event-free survival rates were 37% (95% CI, 27% to 47%) and 47% (95% CI, 37% to 57%) in CISCA/VB and BEP arms, respectively (hazard ratio [HR] = 0.76; 95% CI, 0.52 to 1.11; P = .15). With a median follow-up of 7.8 years, the 5-year overall survival rates were 59% (95% CI, 47% to 67%) and 69% (95% CI, 58% to 77%) in CISCA/VB and BEP arms, respectively (HR = 0.73; 95% CI, 0.46 to 1.18; P = .24). Conclusion Because of equivalent efficacy and lesser toxicity, the standard treatment for patients with intermediate- and poor-risk metastatic nonseminomatous germ cell tumors remains four cycles of BEP.
Phylogenetic Analysis of 47 Chloroplast Genomes Clarifies the Contribution of Wild Species to the Domesticated Apple Maternal Line
Authors: Svetlana V. Nikiforova, Duccio Cavalieri, Riccardo Velasco, Vadim Goremykin
Journal: Molecular Biology and Evolution (2013)

Both the origin of domesticated apple and the overall phylogeny of the genus Malus are still not completely resolved. Having this as a target, we built a 134,553-position-long alignment including two previously published chloroplast DNAs (cpDNAs) and 45 de novo sequenced, fully colinear chloroplast genomes from cultivated apple varieties and wild apple species. The data produced are free from compositional heterogeneity and from substitutional saturation, which can adversely affect phylogeny reconstruction. Phylogenetic analyses based on this alignment recovered a branch, having the maximum bootstrap support, subtending a large group of the cultivated apple sorts together with all analyzed European wild apple (Malus sylvestris) accessions. One apple cultivar was embedded in a monophylum comprising wild M. sieversii accessions and other Asian apple species. The data demonstrate that M. sylvestris has contributed chloroplast genome to a substantial fraction of domesticated apple varieties, supporting the conclusion that different wild species should have contributed the organelle and nuclear genomes to the domesticated apple.
MURDER WITHOUT APPARENT MOTIVE: A STUDY IN PERSONALITY DISORGANIZATION
Authors: JOSEPH SATTEN, KARL MENNINGER, IRWIN ROSEN, MARTIN MAYMAN
Journal: American Journal of Psychiatry (1960)

In this paper we have described a number of common characteristics found in individuals who have committed impulsive senseless murders. These characteristics were: severe weakness of impulse control; blurring of the boundaries between fantasy and reality, with periods of altered states of consciousness; blunted and shallow emotional reactions; and a violent and primitive fantasy life. This constellation seems to have grown out of a history characterized by extreme parental violence and early severe emotional deprivation. In these cases, there appeared an ego weakness which allowed the periodic breakthrough of intense aggressive impulses, sometimes of homicidal proportion. When such apparently senseless murders occur, they are seen to be an end result of a period of increasing tension and disorganization in the murderer starting before the contact with the victim who, by fitting into the unconscious conflicts of the murderer, unwittingly serves to set into motion his homicidal potential. It remains a task of future research to: 1. Differentiate these individuals from other murderers as well as from others with similar disturbances but who do not kill; 2. Weigh the significance of the individual factors described; 3. Devise measures for identifying and effectively controlling these individuals before they commit murder.
Importance of Mitral Valve Second-Order Chordae for Left Ventricular Geometry, Wall Thickening Mechanics, and Global Systolic Function
Authors: Filiberto Rodriguez, Frank Langer, Katherine B. Harrington, Frederick A. Tibayan, Mary K. Zasio, Allen Cheng, David Liang, George T. Daughters, James W. Covell, John C. Criscione, Neil B. Ingels, D. Craig Miller
Journal: Circulation (2004)

Mitral valvular-ventricular continuity is important for left ventricular (LV) systolic function, but the specific contributions of the anterior leaflet second-order "strut" chordae are unknown.Eight sheep had radiopaque markers implanted to silhouette the LV, annulus, and papillary muscles (PMs); 3 transmural bead columns were inserted into the mid-lateral wall between the PMs. The strut chordae were encircled with exteriorized wire snares. Three-dimensional marker images and hemodynamic data were acquired before and after chordal cutting. Preload recruitable stroke work (PRSW) and end-systolic elastance (E(es)) were calculated to assess global LV systolic function (n=7). Transmural strains were measured from bead displacements (n=4). Chordal cutting caused global LV dysfunction: E(es) (1.48+/-1.12 versus 0.98+/-1.30 mm Hg/mL, P=0.04) and PRSW (69+/-16 versus 60+/-15 mm Hg, P=0.03) decreased. Although heart rate and time from ED to ES were unchanged, time of mid-ejection was delayed (125+/-18 versus 136+/-19 ms, P=0.01). Globally, the LV apex and posterior PM tip were displaced away from the fibrous annulus and LV base-apex length increased at end-diastole and end-systole (all +1 mm, P<0.05). Locally, subendocardial end-diastolic strains occurred: Longitudinal strain (E22) 0.030+/-0.013 and radial thickening (E33) 0.081+/-0.041 (both P<0.05 versus zero). Subendocardial systolic shear strains were also perturbed: Circumferential-longitudinal "micro-torsion" (E12) (0.099+/-0.035 versus 0.075+/-0.025) and circumferential radial shear (E13) (0.084+/-0.023 versus 0.039+/-0.008, both P<0.05).Cutting second-order chords altered LV geometry, remodeled the myocardium between the PMs, perturbed local systolic strain patterns affecting micro-torsion and wall-thickening, and caused global systolic dysfunction, demonstrating the importance of these chordae for LV structure and function.
Differential Effect of Swallowed Inhaled Corticosteroids on Eosinophilic Infiltration of the Proximal vs the Distal Esophagus in Eosinophilic Esophagitis
Authors: J.T. Stribling, C. Uram-Tuculescu, M. Abu-Shukair, A.M. Irani
Journal: Journal of Allergy and Clinical Immunology (2011)
Use of the flexible fibreoptic bronchoscope in diagnosis of sputum-negative pulmonary tuberculosis.
Authors: P A Willcox, S R Benatar, P D Potgieter
Journal: Thorax (1982)

In four years' use of the flexible fibreoptic bronchoscope in diagnosing sputum-negative pulmonary tuberculosis, of 275 patients with tuberculosis suspected from chest radiographic appearances, 89 (32.4%) were shown to have active disease. In 60 (67.4%) of these patients the diagnosis was made from samples obtained through the fibreoptic bronchoscope (56 from bronchial brushings, four from transbronchial biopsy samples). Of the 56 positive bronchial brushings, 35 were positive on direct smear and 21 only on culture. Transbronchial biopsy exclusively accounted for only four of the 60 positive diagnoses. In the remaining 29 patients, the diagnosis was made from further sputum or biopsy specimens in 15, from the response to treatment in 12, and at necropsy in two. In six of 10 patients with military tuberculosis, bronchial brushings were positive on direct smear.
Management of Crush-Related Injuries after Disasters
Authors: Mehmet Sukru Sever, Raymond Vanholder, Norbert Lameire
Journal: New England Journal of Medicine (2006)

Acute renal failure after massive disasters such as earthquakes is one of the few life-threatening complications of crush injuries that can be reversed. This article considers lifesaving aspects of medical care that can be related to both global and local coordination of the treatment of such complications and that are based on the experiences of the authors during disasters such as the earthquakes in Marmara, Turkey, and Bam, Iran.
Electrophoretic and functional variants of NADH-methemoglobin reductase in hereditary methemoglobinemia
Authors: Hsin-Soon Hsieh, Ernst R. Jaffé
Journal: Journal of Clinical Investigation (1971)

The electrophoretic mobility and activity of NADH-methemoglobin reductase in erythrocytes of patients with hereditary methemoglobinemia, obligatory heterozygotes, and normal subjects were examined. Six distinct electrophoretic variants were found in studies of erythrocytes from members of ten different families. Five variants (Boston Slow, Duarte, Princeton, Puerto Rico, and California) were associated with significant methemoglobinemia and moderate to marked decreases in enzymic activity. Precise correlations between levels of NADH-methemoglobin reductase activity, electrophoretic mobility, and clinical severity of methemoglobinemia, however, could not be drawn. One variant (Boston Fast) was associated with almost normal activity and very minimal methemoglobinemia. Nine members from three generations of two Italian families were found to have two bands with NADH-methemoglobin reductase activity in their erythrocytes, one with normal mobility and one with a mobility identical with that of Boston Fast. No functional or clinical impairment could be attributed to this abnormality. The observations made in this investigation were consistent with an autosomal recessive mode of inheritance of multiple alleles for NADH-methemoglobin reductase. As has been shown to be true for hemoglobin and glucose-6-phosphate dehydrogenase, multiple aberrations in the NADH-methemoglobin reductase of human erythrocytes apparently exist, some with and some without functional consequences. Two bands with NADPH-methemoglobin reductase activity with electrophoretic mobilities distinct from those of the NADH-methemoglobin reductase were found in human erythrocytes. These bands were normal in hemolysates of erythrocytes from patients with hereditary methemoglobinemia, but were absent from the hemolysate of erythrocytes deficient in NADPH-methemoglobin reductase activity. These latter erythrocytes, however, contained normal concentrations of methemoglobin and had a normal ability to reduce methemoglobin in vitro. These observations were most consistent with the thesis that the NADH-methemoglobin reductase, distinct from any NADPH-methemoglobin reductase, was the major system responsible for the reduction of methemoglobin to hemoglobin in human erythrocytes.
Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells
Authors: Ramon C Sun, Philip G Board, Anneke C Blackburn
Journal: Molecular Cancer (2011)

Cancer cells have a different metabolic profile compared to normal cells. The Warburg effect (increased aerobic glycolysis) and glutaminolysis (increased mitochondrial activity from glutamine catabolism) are well known hallmarks of cancer and are accompanied by increased lactate production, hyperpolarized mitochondrial membrane and increased production of reactive oxygen species.In this study we target the Warburg effect with dichloroacetate (DCA) and the increased mitochondrial activity of glutaminolysis with arsenic trioxide (ATO) in breast cancer cells, measuring cell proliferation, cell death and mitochondrial characteristics.The combination of DCA and ATO was more effective at inhibiting cell proliferation and inducing cell death than either drug alone. We examined the effect of these treatments on mitochondrial membrane potential, reactive oxygen species production and ATP levels and have identified new molecular mechanisms within the mitochondria for both ATO and DCA: ATO reduces mitochondrial function through the inhibition of cytochrome C oxidase (complex IV of the electron transport chain) while DCA up-regulates ATP synthase β subunit expression. The potentiation of ATO cytotoxicity by DCA is correlated with strong suppression of the expression of c-Myc and HIF-1α, and decreased expression of the survival protein Bcl-2.This study is the first to demonstrate that targeting two key metabolic hallmarks of cancer is an effective anti-cancer strategy with therapeutic potential.