tbuckley/cabot-search huggingface dataset:
The NADH Oxidase ENOX1, a Critical Mediator of Endothelial Cell Radiosensitization, Is Crucial for Vascular Development
Authors: Amudhan Venkateswaran, Konjeti R. Sekhar, Daniel S. Levic, David B. Melville, Travis A. Clark, Witold M. Rybski, Alexandra J. Walsh, Melissa C. Skala, Peter A. Crooks, Ela W. Knapik, Michael L. Freeman
Journal: Cancer Research (2013)

ENOX1 is a highly conserved NADH oxidase that helps to regulate intracellular nicotinamide adenine dinucleotide levels in many cell types, including endothelial cells. Pharmacologic and RNA interference (RNAi)-mediated suppression of ENOX1 impairs surrogate markers of tumor angiogenesis/vasculogenesis, providing support for the concept that ENOX1 represents an antiangiogenic druggable target. However, direct genetic evidence that demonstrates a role for ENOX1 in vascular development is lacking. In this study, we exploited a zebrafish embryonic model of development to address this question. Whole-mount in situ hybridization coupled with immunofluorescence performed on zebrafish embryos demonstrate that enox1 message and translated protein are expressed in most tissues, and its expression is enriched in blood vessels and heart. Morpholino-mediated suppression of Enox1 in Tg(fli1-eGFP) and Tg(flk1-eGFP) zebrafish embryos significantly impairs the development of vasculature and blood circulation. Using in vivo multiphoton microscopy, we show that morpholino-mediated knockdown of enox1 increases NADH levels, consistent with loss of enzyme. VJ115 is a small-molecule inhibitor of Enox1's oxidase activity shown to increase intracellular NADH in endothelial cells; we used VJ115 to determine if the oxidase activity was crucial for vascular development. We found that VJ115 suppressed vasculogenesis in Tg(fli1-eGFP) embryos and impaired circulation. Previously, it was shown that suppression of ENOX1 radiosensitizes proliferating tumor vasculature, a consequence of enhanced endothelial cell apoptosis. Thus, our current findings, coupled with previous research, support the hypothesis that ENOX1 represents a potential cancer therapy target, one that combines molecular targeting with cytotoxic sensitization.
Combined Chemoradiotherapy Regimens of Paclitaxel and Carboplatin for Locally Advanced Non–Small-Cell Lung Cancer: A Randomized Phase II Locally Advanced Multi-Modality Protocol
Authors: Chandra P. Belani, Hak Choy, Phil Bonomi, Charles Scott, Patrick Travis, John Haluschak, Walter J. Curran
Journal: Journal of Clinical Oncology (2005)

This phase II noncomparative randomized trial was conducted to determine the optimal sequencing and integration of paclitaxel/carboplatin with standard daily thoracic radiation therapy (TRT), in patients with locally advanced unresected stage III non-small-cell lung cancer (NSCLC). Survival data were compared with historical standard sequential chemoradiotherapy data from the Radiation Therapy Oncology Group.Patients with unresected stages IIIA and IIIB NSCLC, with Karnofsky performance status > or = 70% and weight loss < or = 10%, received two cycles of induction paclitaxel (200 mg/m2)/carboplatin (area under the plasma concentration time curve [AUC] = 6) followed by TRT 63.0 Gy (arm 1, sequential) or two cycles of induction paclitaxel (200 mg/m2)/carboplatin (AUC = 6) followed by weekly paclitaxel (45 mg/m2)/carboplatin (AUC = 2) with concurrent TRT 63.0 Gy (arm 2, induction/concurrent), or weekly paclitaxel (45 mg/m2)/carboplatin (AUC = 2)/TRT (63.0 Gy) followed by two cycles of paclitaxel (200 mg/m2)/carboplatin (AUC = 6; arm 3, concurrent/consolidation).With a median follow-up time of 39.6 months, median overall survival was 13.0, 12.7, and 16.3 months for arms 1, 2, and 3, respectively. During induction chemotherapy, grade 3/4 granulocytopenia occurred in 32% and 38% of patients on study arms 1 and 2, respectively. The most common locoregional grade 3/4 toxicity during and after TRT was esophagitis, which was more pronounced with the administration of concurrent chemoradiotherapy on study arms 2 and 3 (19% and 28%, respectively).Concurrent weekly paclitaxel, carboplatin, and TRT followed by consolidation seems to be associated with the best outcome, although this schedule was associated with greater toxicity.
PLAQUE RUPTURE IS ASSOCIATED WITH WORSE REPERFUSION OUTCOMES AFTER PERCUTANEOUS CORONARY INTERVENTION IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION
Authors: Takumi Higuma, Naoki Abe, Shunta Tateyama, Shuji Shibutani, Kenji Hanada, Hiroaki Yokoyama, Masahiro Yamada, Tomohiro Osanai, Ken Okumura
Journal: Journal of the American College of Cardiology (2014)
Noninvasive Analysis of the Sputum Transcriptome Discriminates Clinical Phenotypes of Asthma
Authors: Xiting Yan, Jen-Hwa Chu, Jose Gomez, Maria Koenigs, Carole Holm, Xiaoxuan He, Mario F. Perez, Hongyu Zhao, Shrikant Mane, Fernando D. Martinez, Carole Ober, Dan L. Nicolae, Kathleen C. Barnes, Stephanie J. London, Frank Gilliland, Scott T. Weiss, Benjamin A. Raby, Lauren Cohn, Geoffrey L. Chupp
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

The airway transcriptome includes genes that contribute to the pathophysiologic heterogeneity seen in individuals with asthma.We analyzed sputum gene expression for transcriptomic endotypes of asthma (TEA), gene signatures that discriminate phenotypes of disease.Gene expression in the sputum and blood of patients with asthma was measured using Affymetrix microarrays. Unsupervised clustering analysis based on pathways from the Kyoto Encyclopedia of Genes and Genomes was used to identify TEA clusters. Logistic regression analysis of matched blood samples defined an expression profile in the circulation to determine the TEA cluster assignment in a cohort of children with asthma to replicate clinical phenotypes.Three TEA clusters were identified. TEA cluster 1 had the most subjects with a history of intubation (P = 0.05), a lower prebronchodilator FEV1 (P = 0.006), a higher bronchodilator response (P = 0.03), and higher exhaled nitric oxide levels (P = 0.04) compared with the other TEA clusters. TEA cluster 2, the smallest cluster, had the most subjects that were hospitalized for asthma (P = 0.04). TEA cluster 3, the largest cluster, had normal lung function, low exhaled nitric oxide levels, and lower inhaled steroid requirements. Evaluation of TEA clusters in children confirmed that TEA clusters 1 and 2 are associated with a history of intubation (P = 5.58 × 10(-6)) and hospitalization (P = 0.01), respectively.There are common patterns of gene expression in the sputum and blood of children and adults that are associated with near-fatal, severe, and milder asthma.
Tissue Engineering Therapy for Cardiovascular Disease
Authors: Helen M. Nugent, Elazer R. Edelman
Journal: Circulation Research (2003)

The present treatments for the loss or failure of cardiovascular function include organ transplantation, surgical reconstruction, mechanical or synthetic devices, or the administration of metabolic products. Although routinely used, these treatments are not without constraints and complications. The emerging and interdisciplinary field of tissue engineering has evolved to provide solutions to tissue creation and repair. Tissue engineering applies the principles of engineering, material science, and biology toward the development of biological substitutes that restore, maintain, or improve tissue function. Progress has been made in engineering the various components of the cardiovascular system, including blood vessels, heart valves, and cardiac muscle. Many pivotal studies have been performed in recent years that may support the move toward the widespread application of tissue-engineered therapy for cardiovascular diseases. The studies discussed include endothelial cell seeding of vascular grafts, tissue-engineered vascular conduits, generation of heart valve leaflets, cardiomyoplasty, genetic manipulation, and in vitro conditions for optimizing tissue-engineered cardiovascular constructs.
Number of particles in exhaled air is decreased by broncho-constriction
Authors: Anna-Carin Olin, Emilia Viklund, Per Larsson, Ann-Charlotte Almstrand, Anna Bredberg, Ekaterina Mirgorodskaya, Björn Bake
Journal: European Respiratory Journal (2013)

Background : Particles in exhaled air (PEx) are formed from the lining fluid in small airways, and is suggested a new method to monitor respiratory disease affecting small airways. To interpret PEx results it is important to know effects of potential influential factors like bronchoconstriction.   Aim : To examine the effect of bronchomotor tone and pollen season on PEx.   Method : 13 subjects with pollen-asthma and 12 healthy non-atopic subjects were examined before and after bronchodilation during and after pollen season. The subjects performed spirometry and sampling of PEx in 60 L of exhaled air, by an in-house developed instrument, using a breathing maneuvers allowing for airway closure and re-opening   Results : The subjects with asthma had mild symptoms and low reversibility also during pollen-season (ΔFEV 1  = 6.1 % predicted normal). They had lower PEx concentrations during pollen season compared to out of pollen season (3.46 v s 4.32, p=0.01). Controls showed non-significant differences between seasons, and exhaled significanly higher contentration of particles than subjects with asthma, but only during pollenseason.  PEx concentrations increased after bronchodilatation in subjects with asthma (median 4.05*10 3  to 4.92*10 3 , p=0.02), but not in controls. The change in PEx concentration (%) was associated with the change in FVC (%) (r p = 0.51, p=0.001) and FEV 1  (r p = 0.46, p=0.003) among subjects with asthma whereas there were no significant correlations among controls.   Conclusion : During pollen season airway opening is reduced despite unaffected spirometry among pollen sensitized subjects with asthma. Bronchodilatation presumably increases airway opening resulting in an increased number of exhaled particles.
Fas and activation-induced Fas ligand mediate apoptosis of T cell hybridomas: inhibition of Fas ligand expression by retinoic acid and glucocorticoids.
Authors: Y Yang, M Merćep, C F Ware, J D Ashwell
Journal: The Journal of Experimental Medicine (1995)

Activation of T cell hybridomas induces a G1/S cell cycle block and apoptosis. We isolated a variant of the 2B4.11 T cell hybridoma that, when activated via the TCR, produced IL-2 and underwent growth inhibition but did not die. Analysis of a variety of cell surface molecules revealed that the variant cell line, termed VD1, expressed very low levels of Fas compared to the wild type cells. Unlike 2B4.11 cells, VD1 cells were not killed by Fas ligand (FasL)-bearing effector cells. To determine if Fas is involved in activation-induced apoptosis, two different reagents that specifically bind Fas without killing the T cell hybridomas, a monoclonal antibody and a soluble Fas:Fc chimeric molecule, were added to activated T cell hybridomas. Both treatments prevented activation-induced apoptosis in a dose-dependent manner, but had no effect on IL-2 production or growth inhibition. Northern blot analysis revealed that unactivated 2B4.11 cells expressed negligible levels of FasL mRNA, but transcripts were detectable as early as 2 h after activation and continued to increase up to 4-6 h after activation. Anti-TCR induced activation of 2B4.11 cells in the presence of a TCR- 2B4.11 variant resulted in death of the unactivated "bystander" cells, which was inhibited by anti-Fas antibodies. Finally, treatment of T hybridoma cells with 9-cis retinoic acid or glucocorticoids, which are known to prevent activation-induced T cell apoptosis, inhibited the up-regulation of FasL. We conclude that up-regulated expression of FasL and its subsequent interaction with Fas accounts for the apoptotic response of T cell hybridomas to activation, and that retinoic acid and corticosteroids inhibit activation-induced apoptosis by preventing up-regulation of FasL.
Clinical Efficacy of Lenalidomide in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of a Phase II Study
Authors: Asher Chanan-Khan, Kena C. Miller, Laurie Musial, David Lawrence, Swaminathan Padmanabhan, Kenichi Takeshita, Carl W. Porter, David W. Goodrich, Zale P. Bernstein, Paul Wallace, David Spaner, Alice Mohr, Catriona Byrne, Francisco Hernandez-Ilizaliturri, Cynthia Chrystal, Petr Starostik, Myron S. Czuczman
Journal: Journal of Clinical Oncology (2006)

Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) have profound immune defects and limited treatment options. Given the dramatic activity of lenalidomide in other B-cell malignancies and its pleotropic immunomodulatory effects, we conducted a phase II trial of this agent in CLL.Patients with relapsed or refractory B-cell CLL (B-CLL) were eligible if they required treatment as per the National Cancer Institute Working Group 1996 guidelines. Lenalidomide was administered orally at 25 mg on days 1 through 21 of a 28-day cycle. Response was assessed after each cycle. Patients were to continue treatment until disease progression, unacceptable toxicity, or complete remission. Rituximab was added to lenalidomide on disease progression.Forty-five patients were enrolled, with a median age of 64 years. Sixty-four percent of the patients had Rai stage III or IV disease, and 51% were refractory to fludarabine. The overall response rate was 47%, with 9% of the patients attaining a complete remission. Fatigue, thrombocytopenia, and neutropenia were the most common adverse effects noted in 83%, 78%, and 78% of the patients, respectively.Lenalidomide is clinically active in patients with relapsed or refractory B-CLL. These findings are encouraging and warrant further investigation of this agent in the treatment of this disorder.
Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis
Authors: Agostinho Carvalho, Gloria Giovannini, Antonella De Luca, Carmen D'Angelo, Andrea Casagrande, Rossana G Iannitti, Giovanni Ricci, Cristina Cunha, Luigina Romani
Journal: Cellular and Molecular Immunology (2012)
Respiratory microbiota: addressing clinical questions, informing clinical practice
Authors: Geraint B Rogers, Dominick Shaw, Robyn L Marsh, Mary P Carroll, David J Serisier, Kenneth D Bruce
Journal: Thorax (2014)

Over the last decade, technological advances have revolutionised efforts to understand the role played by microbes in airways disease. With the application of ever more sophisticated techniques, the literature has become increasingly inaccessible to the non-specialist reader, potentially hampering the translation of these gains into improvements in patient care. In this article, we set out the key principles underpinning microbiota research in respiratory contexts and provide practical guidance on how best such studies can be designed, executed and interpreted. We examine how an understanding of the respiratory microbiota both challenges fundamental assumptions and provides novel clinical insights into lung disease, and we set out a number of important targets for ongoing research.
Immune responses during pregnancy. Evidence of suppressor cells for splenic antibody response.
Authors: K Suzuki, T B Tomasi
Journal: The Journal of Experimental Medicine (1979)

The primary IgM antibody response to sheep erythrocytes in vivo as well as in vitro is markedly decreased in the spleen cells of pregnant mice, compared to age-matched female controls. Decreased antibody synthesis appears to be mediated by nonspecific suppressor cells, because the addition of pregnant spleen cells to the normal spleen cell cultures causes a significant suppression of plaque-forming-cell responses of the normal spleen cells. Suppressor cell activity was not observed in lymph nodes of pregnant mice. At least two populations of pregnant spleen cells were shown to exert a suppressor cell activity; one is T lymphocytes and the other a nylon-adherent cell present in the B-cell-enriched macrophage-depleted fraction. Pregnant spleen cells cultured in vitro were shown to secrete a soluble suppressive factor(s) into the supernatant medium.
TORSION OF THE GREAT OMENTUM: A CASE CLINICALLY RESEMBLING OVARIAN CYST WITH TWISTED PEDICLE
Authors: J. P. Hedley
Journal: BMJ (1911)

To'o.sioN of tlhe great otnientunis is a rarc colnlitioln, alnd tlle -reported cases are still less tlhani one hundred in number.I ai!m recordinig this case partly oni account of its rarity anid ziartly because tlle signls anld syniptomns very closely resellibled those produLced by the twvisting of the pedicle vf an ovarialn cyst.I never sus)ected that I was (dealinlg witlh alnyvtlhing btut an vrdlinary ovarianl cyst wvithl a tw isted pedicle uilntil I examiined the patienit niuider the alnaestlhetic before operatinig.Then it wA-as clear that there wNvas Ino large cyst, bLit ani irregutlar
Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels
Authors: Holger Pflicke, Michael Sixt
Journal: The Journal of Experimental Medicine (2009)

Although both processes occur at similar rates, leukocyte extravasation from the blood circulation is well investigated, whereas intravasation into lymphatic vessels has hardly been studied. In contrast to a common assumption—that intra- and extravasation follow similar molecular principles—we previously showed that lymphatic entry of dendritic cells (DCs) does not require integrin-mediated adhesive interactions. In this study, we demonstrate that DC-entry is also independent of pericellular proteolysis, raising the question of whether lymphatic vessels offer preexisting entry routes. We find that the perilymphatic basement membrane of initial lymphatic vessels is discontinuous and therefore leaves gaps for entering cells. Using a newly developed in situ live cell imaging approach that allows us to dynamically visualize the cells and their extracellular environment, we demonstrate that DCs enter through these discontinuities, which are transiently mechanically dilated by the passaging cells. We further show that penetration of the underlying lymphatic endothelial layer occurs through flap valves lacking continuous intercellular junctions. Together, we demonstrate free cellular communication between interstitium and lymphatic lumen.
Free Fatty Acid Metabolism of Leg Muscles during Exercise in Patients with Obliterative Iliac and Femoral Artery Disease before and after Reconstructive Surgery
Authors: L. Hagenfeldt, J. Wahren, B. Pernow, R. Cronestrand, S. Ekeström
Journal: Journal of Clinical Investigation (1972)

The free fatty acid (FFA) uptake and oxidation and the carbohydrate substrate exchange of leg muscles were studied during exercise in 14 patients with occlusive disease of the iliac or femoral arteries before and 3-6 months after reconstructive vascular surgery and in 5 healthy subjects. (14)C-labeled oleic acid was infused continuously at rest and during exercise at work loads of 150-400 kg-m/min. The arterial concentration of FFA was similar both at rest and during exercise in patients and controls. The patients showed a smaller increase in the fractional turnover of FFA during exercise. Leg uptake and release of FFA in terms of micromoles per liter plasma did not differ significantly either at rest or during exercise between patients and controls. FFA oxidation could not be measured at rest but exercise data showed a lower fractional oxidation of FFA (P < 0.001) in the patient group (53+/-6%) compared with the controls (84+/-2%). For the entire material, fractional oxidation of FFA showed a significant negative regression on the lactate/pyruvate ratio in femoral venous blood. The ventilatory respiratory quotient (RQ) and the leg muscle exchange of glucose and lactate in the patients exceeded that of the controls. When six patients were studied after reconstructive surgery, fractional oxidation of FFA had risen from a preoperative value of 47+/-8 to 90+/-10%, other data for leg muscle FFA metabolism being unchanged. IT IS CONCLUDED: (a) that substrate catabolism by the leg muscles during exercise in these patients proceeds in excess of the simultaneous capacity to oxidize acetyl-CoA in the tricarboxylic acid cycle, and (b) oxidation of FFA by contracting muscle is related to the muscle cell redox state.
Transient ischaemic colitis following an aeroplane flight
Authors: I E Koutroubakis
Journal: Gut (2003)

Caution with the use of cyclosporin in pregnancyWe read the article by Alstead and Nelson-Piercy with great interest. 1 We report a case (submitted for publication) of a woman with fulminant ulcerative colitis in the 29th week of pregnancy.Her disease was refractory to steroids, but she refused to have cyclosporin whilst pregnant.She therefore underwent an emergency Caesarean section and was given intravenous cyclosporin post-operatively.After 48 hours of treatment she developed severe hypertension with hypertensive encephalopathy and seizures.Although cyclosporin has been considered to be safe for both mother and foetus, we would like to highlight concerns that it is associated with potentially life threatening side effects.As a result, patients must be counselled thoroughly about the potential morbidity associated with this treatment and monitored closely.We agree with Dr Alstead in that cyclosporin should be used with extreme caution in pregnancy and the postnatal period.
Definition of Ubiquitination Modulator COP1 as a Novel Therapeutic Target in Human Hepatocellular Carcinoma
Authors: Yun-Han Lee, Jesper B. Andersen, Ho-Taek Song, Adam D. Judge, Daekwan Seo, Tsuyoshi Ishikawa, Jens U. Marquardt, Mitsuteru Kitade, Marian E. Durkin, Chiara Raggi, Hyun Goo Woo, Elizabeth A. Conner, Itzhak Avital, Ian MacLachlan, Valentina M. Factor, Snorri S. Thorgeirsson
Journal: Cancer Research (2010)

Abstract The development of targeted therapeutics for hepatocellular carcinoma (HCC) remains a major challenge. The ubiquitination modulator COP1 regulates p53 activity by ubiquitination and it is frequently overexpressed in human HCC. In this study, we tested the hypothesis that COP1 blockade by short interfering RNA (siRNA)–mediated inhibition could affect the course of HCC progression. The COP1 isoform COP1-1 was selected as the most effective target for siRNAs in terms of growth inhibition and apoptotic induction in several HCC cell lines. Growth inhibition occurred in HCC cells that retained wild-type p53 or expressed mutant p53 (Y220C or R249S), whereas p53-null Hep3B cells were resistant. Microarray expression analysis revealed that the antiproliferative effects of COP1 blockade were driven by a common subset of molecular alterations including a p53-associated functional network. In an orthotopic mouse xenograft model of HCC, systemic delivery of a modified COP1 siRNA by stable nucleic acid–lipid particles suppressed neoplastic growth in liver without unwanted immune responses. Our findings offer a first proof of principle that COP1 can be a promising target for systemic therapy of HCC. Cancer Res; 70(21); 8264–9. ©2010 AACR.