tbuckley/cabot-search huggingface dataset:
Carbonic Anhydrase IX in Early-Stage Non–Small Cell Lung Cancer
Authors: Seok Jin Kim, Zahid N. Rabbani, Robin T. Vollmer, Ernst-Gilbert Schreiber, Egbert Oosterwijk, Mark W. Dewhirst, Zeljko Vujaskovic, Michael J. Kelley
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Tumor hypoxia is associated with poor prognosis and increased tumor aggressiveness. Carbonic anhydrase (CA) IX, an endogenous marker for tumor hypoxia, catalyzes the hydration of carbon dioxide into carbonic acid and contributes to the pH regulation of tumor cells. Therefore, CA IX might allow tumors to acclimate to a hypoxic microenvironment, promoting tumor cell proliferation. We hypothesized that CA IX expression is related to tumor cell proliferation and poor disease-free survival in patients with early-stage non–small-cell lung cancer (NSCLC). Experimental Design: CA IX expression was measured in 75 resected NSCLC tumors to assess prognostic implications for disease-free survival. The relationship of CA IX expression with microvessel density (MVD) and proliferation (Ki-67) index was assessed via colocalization analysis. Results: All patients had operable NSCLC (stage I, 58; stage II, 17). CA IX expression was present in 54 (72%) of 75 patients and was associated with tumor necrosis (P &amp;lt; 0.05). CA IX-positive tumor areas showed greater cell proliferation as measured by Ki-67 index (P &amp;lt; 0.05) and less MVD (P &amp;lt; 0.05) than did CA IX-negative areas in colocalization analysis. The percentage of CA IX-positive tumor cells was significantly related to postoperative recurrence and poor disease-free survival (P &amp;lt; 0.05). Ki-67 index and pathologic stage were also independent prognostic factors for worse disease-free survival (P &amp;lt; 0.05). Conclusions: CA IX expression of tumor cells may be an indicator for poor disease-free survival in early-stage NSCLC.
Government's antimicrobial resistance strategy will have real impact, UK ministers promise
Authors: A. O'Dowd
Journal: BMJ (2014)

The UK government’s strategy on tackling antimicrobial resistance is already making strong progress and will have a real impact in years to come, MPs have been told.

Plans are also afoot for a publicity campaign later this year that will encourage patients to stop putting pressure on their GPs to prescribe antibiotics during consultations.

MPs on the House of Commons science and technology committee quizzed government ministers and officials on 12 March as part of their inquiry into antimicrobial resistance.

During the evidence session MPs asked Jane Ellison, the public health minister, whether the government’s latest five year strategy,1 published in September last year, would be fully implemented—given that around 20 of the recommendations of …
The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects
Authors: PL Harbinson, D MacLeod, R Hawksworth, S O'Toole, PJ Sullivan, P Heath, S Kilfeather, CP Page, J Costello, ST Holgate, TH Lee
Journal: European Respiratory Journal (1997)

Recent studies have suggested that theophylline, a nonspecific phospho-diesterase inhibitor, has useful anti-inflammatory actions in asthma. Phosphodiesterase 4 (PDE4) represents the predominant PDE isoenzyme present in inflammatory cells. PDE4 inhibitors might, therefore, have beneficial effects in asthma. Side-effects, specifically nausea, have limited the use of existing agents. CDP840 is an orally active, potent and selective PDE4 inhibitor. We have examined the effect of CDP840 on the allergen-induced asthmatic response, its possible modes of action, and its tolerability at therapeutic doses. A total of 54 patients were recruited to three double-blind, placebo-controlled studies. The first study examined the effect of CDP840 (15 mg b.i.d. for 9.5 days) on the allergen-induced asthmatic response in patients with known dual response to allergen. A second study examined the effect of CDP840 (15 mg b.i.d. for 9.5 days) on airway responsiveness to histamine. A third study examined whether single dose CDP840 (15 and 30 mg) had significant bronchodilatory effects. In all studies, CDP840 was well-tolerated, with no patients reporting nausea. CDP840 did not lead to changes in baseline forced expiratory volume in one second (FEV1) as compared to placebo. The late asthmatic response (LAR) to allergen, expressed as area under the curve at 3-8 h (AUC3-8h), was inhibited by 30% (p=0.016), an effect which persisted to the end of the observation period. The early asthmatic response (EAR) was unaffected, and there was no bronchodilatory effect at the doses used. Treatment with CDP840 did not affect bronchial hyperresponsiveness to histamine. In conclusion, CDP840 significantly attenuated the late asthmatic response to allergen challenge in the absence of any bronchodilatory or histamine antagonist effect. This suggests that CDP840 may exert its effects via an anti-inflammatory mechanism.
Detection of linezolid in endotracheal tube biofilm of ventilated pigs with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia
Authors: Laia Fernández-Barat, Miquel Ferrer, Laura Guerrero, Dolors Soy, Jordi Vila, Gianluigi Li Bassi, Josep Maria Sierra, Lina María Saucedo, Pilar Martínez-Olondris, Montserrat Rigol, Mariano Esperatti, Néstor Luque, Joan Daniel Martí, Antoni Torres
Journal: European Respiratory Journal (2011)

Introduction: Linezolid presents good penetration into respiratory secretions; we hypothesized that secretions could transport linezolid into ETT and limit burden of MRSA in biofilm.

Aim: To determine linezolid concentration in biofilm inside the ETT using High-performance liquid chromatography (HPLC).

Methods: We analyzed 16 samples of ETT from pigs with MRSA pneumonia, ventilated up to 96 hours and treated with linezolid (10 mg/kg every 12h IV). To determine linezolid concentration by HPLC we disrupted the biofilm matrix with several sonications, enzymes and perchloric acid. We also assessed MRSA count in each ETT sample.

Results: We retrieved from the ETT samples 63±54 mg of biofilm. In 4 (25%) samples linezolid was inferior to the sensitiveness of the technique (1.56 μg/mL). In the remaining 12 samples the concentration of linezolid was 38 (11-83) μg/mL of biofilm (median (IQR)). Hence, linezolid concentration in biofilm was 19 (5-41) times above the MRSA MIC for linezolid (2 μg/mL). The concentration of MRSA in the biofilm of pigs treated with linezolid was 1.98±0.84 Log CFU/mL. No significant correlation was found between biofilm concentration of linezolid and MRSA burden (r=0.48, p=0.11).

Conclusion: Despite the high concentration of linezolid above the MIC in biofilm inside the ETT, MRSA was found in most samples of pigs treated with this antibiotic, without significant correlation between linezolid levels and MRSA burden.

Funded: FIS 05/0620, 070419, 016077 and 050136, SEPAR 2005, Fundaciόn Lilly, Ciberes (CB06/06/0028), 2009-SGR-911, IDIBAPS, FUCAP 2010.
Impaired Quality of Life in Child Asthmatics in Tokyo, Japan
Authors: N. Kojima, Y. Ohya, M. Futamura, M. Akashi, K. Akiyama, K. Takahashi, T. Nakagawa, F. Kobayashi, A. Eboshida, H. Nakamura, H. Odajima, Y. Adachi, A. Akasawa
Journal: Journal of Allergy and Clinical Immunology (2006)
Anorectal necrosis after paracetamol abuse
Authors: E. Streit, P. Gholam, E. Hadaschik, W. Hartschuh
Journal: British Journal of Dermatology (2013)

Journal Article Anorectal necrosis after paracetamol abuse Get access E. Streit, E. Streit Department of Dermatology University of Heidelberg Im Neuenheimer Feld 440 69120 Heidelberg Germany Search for other works by this author on: Oxford Academic Google Scholar P. Gholam, P. Gholam Department of Dermatology University of Heidelberg Im Neuenheimer Feld 440 69120 Heidelberg Germany Search for other works by this author on: Oxford Academic Google Scholar E. Hadaschik, E. Hadaschik Department of Dermatology University of Heidelberg Im Neuenheimer Feld 440 69120 Heidelberg Germany Search for other works by this author on: Oxford Academic Google Scholar W. Hartschuh W. Hartschuh Department of Dermatology University of Heidelberg Im Neuenheimer Feld 440 69120 Heidelberg Germany Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 170, Issue 1, 1 January 2014, Pages 217–218, https://doi.org/10.1111/bjd.12595 Published: 01 January 2014
Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes
Authors: William B. White, Christopher P. Cannon, Simon R. Heller, Steven E. Nissen, Richard M. Bergenstal, George L. Bakris, Alfonso T. Perez, Penny R. Fleck, Cyrus R. Mehta, Stuart Kupfer, Craig Wilson, William C. Cushman, Faiez Zannad
Journal: New England Journal of Medicine (2013)

To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome.We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo.Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.).
Physiological Basis for Potassium ( <sup>39</sup> K) Magnetic Resonance Imaging of the Heart
Authors: David S. Fieno, Raymond J. Kim, Wolfgang G. Rehwald, Robert M. Judd
Journal: Circulation Research (1999)

Abstract —The potassium cation (K + ) is fundamentally involved in myocyte metabolism. To explore the potential utility of direct MRI of the most abundant natural isotope of potassium, 39 K, we compared 39 K magnetic resonance (MR) image intensity with regional myocardial K + concentrations after irreversible injury. Rabbits were subjected either to 40 minutes of in situ coronary artery occlusion and 1 hour of reperfusion (n=26) or to 24 hours of permanent occlusion (n=4). The hearts were then isolated and imaged by 39 K MRI (n=10), or tissue samples were analyzed for regional 39 K content by MR spectroscopy (n=9), K + and Na + concentrations by atomic emission spectroscopy (inductively coupled plasma atomic emission spectroscopy; n=5), or intracellular K + content by electron probe x-ray microanalysis (n=6). Three-dimensional 39 K MR images of the isolated hearts were acquired in 44 minutes with 3×3×3–mm resolution. 39 K MR image intensity was reduced in infarcted regions (51.7±4.8% of remote; P &lt;0.001). The circumferential extent and location of regions of reduced 39 K image intensity were correlated with those of infarcted regions defined histologically ( r =0.97 and r =0.98, respectively). Compared with remote regions, tissue analysis revealed that infarcted regions had reduced 39 K concentration (by MR spectroscopy, 40.5±9.3% of remote; P &lt;0.001), reduced potassium-to-sodium ratio (by inductively coupled plasma atomic emission spectroscopy, 20.7±2.1% of remote; P &lt;0.01), and reduced intracellular potassium (by electron probe x-ray microanalysis, K + peak-to-background ratio 0.95±0.32 versus 2.86±1.10, respectively; P &lt;0.01). We acquired the first 39 K MR images of hearts subjected to infarction. In the pathophysiologies examined, potassium ( 39 K) MR image intensity primarily reflects regional intracellular K + concentrations.
Deficiency of MMP17/MT4-MMP Proteolytic Activity Predisposes to Aortic Aneurysm in Mice
Authors: Mara Martín-Alonso, Ana B. García-Redondo, Dongchuan Guo, Emilio Camafeita, Fernando Martínez, Arántzazu Alfranca, Nerea Méndez-Barbero, Ángela Pollán, Cristina Sánchez-Camacho, David T. Denhardt, Motoharu Seiki, Jesús Vázquez, Mercedes Salaices, Juan Miguel Redondo, Dianna Milewicz, Alicia G. Arroyo
Journal: Circulation Research (2015)

Rationale: Aortic dissection or rupture resulting from aneurysm causes 1% to 2% of deaths in developed countries. These disorders are associated with mutations in genes that affect vascular smooth muscle cell differentiation and contractility or extracellular matrix composition and assembly. However, as many as 75% of patients with a family history of aortic aneurysms do not have an identified genetic syndrome. Objective: To determine the role of the protease MMP17/MT4-MMP in the arterial wall and its possible relevance in human aortic pathology. Methods and Results: Screening of patients with inherited thoracic aortic aneurysms and dissections identified a missense mutation (R373H) in the MMP17 gene that prevented the expression of the protease in human transfected cells. Using a loss-of-function genetic mouse model, we demonstrated that the lack of Mmp17 resulted in the presence of dysfunctional vascular smooth muscle cells and altered extracellular matrix in the vessel wall; and it led to increased susceptibility to angiotensin-II–induced thoracic aortic aneurysm. We also showed that Mmp17-mediated osteopontin cleavage regulated vascular smooth muscle cell maturation via c-Jun N-terminal kinase signaling during aorta wall development. Some features of the arterial phenotype were prevented by re-expression of catalytically active Mmp17 or the N-terminal osteopontin fragment in Mmp17-null neonates. Conclusions: Mmp17 proteolytic activity regulates vascular smooth muscle cell phenotype in the arterial vessel wall, and its absence predisposes to thoracic aortic aneurysm in mice. The rescue of part of the vessel-wall phenotype by a lentiviral strategy opens avenues for therapeutic intervention in these life-threatening disorders.
<scp>R</scp>educed occurrence of tumor flare with flavopiridol followed by combined flavopiridol and lenalidomide in patients with relapsed chronic lymphocytic leukemia (CLL)
Authors: Kami Maddocks, Lai Wei, Darlene Rozewski, Yao Jiang, Yuan Zhao, Mikhil Adusumilli, William E. Pierceall, Camille Doykin, Michael H. Cardone, Jeffrey A. Jones, Joseph Flynn, Leslie A. Andritsos, Michael R. Grever, John C. Byrd, Amy J. Johnson, Mitch A. Phelps, Kristie A Blum
Journal: American Journal of Hematology (2015)

Flavopiridol and lenalidomide have activity in refractory CLL without immunosuppression or opportunistic infections seen with other therapies. We hypothesized that flavopiridol treatment could adequately de-bulk disease prior to lenalidomide therapy, decreasing the incidence of tumor flare with higher doses of lenalidomide. In this Phase I study, the maximum tolerated dose was not reached with treatment consisting of flavopiridol 30 mg m(-2) intravenous bolus (IVB) + 30 mg m(-2) continuous intravenous infusion (CIVI) cycle (C) 1 day (D) 1 and 30 mg m(-2) IVB + 50 mg m(-2) CIVI C1 D8,15 and C2-8 D3,10,17 with lenalidomide 15 mg orally daily C2-8 D1-21. There was no unexpected toxicity seen, including no increased tumor lysis, tumor flare (even at higher doses of lenalidomide) or opportunistic infection. Significant clinical activity was demonstrated, with a 51% response rate in this group of heavily pretreated patients. Biomarker testing confirmed association of mitochondrial priming of the BH3 only peptide Puma with response.
Mechanisms of anti-tumor action of Corynebacterium parvum. I. Potentiated tumor-specific immunity and its therapeutic limitations.
Authors: E S Dye, R J North, C D Mills
Journal: The Journal of Experimental Medicine (1981)

The anti-tumor mechanism in mice induced by a subcutaneous injection of syngeneic tumor cells admixed with Corynebacterium parvum was investigated. When mice were implanted in a hind footpad with x 2 1096) tumor cells admixed with 100 microgram C. parvum, the tumor that emerged grew progressively for about 9 d and then underwent progressive and complete regression. It was found that this C. parvum-induced regression was associated with the acquisition of a systemic, T cell-mediated mechanism of immunity to tumor-specific transplantation antigens, which enabled the host to cause the regression of an untreated test tumor growing simultaneously at a distant site. The generation of a C. parvum-potentiated anti-tumor response was dependent on the presence of tumor cells in close association with C. parvum, tumor immunogenicity, and the quantity of tumor antigen in the admixture. The anti-tumor immunity was specific for the tumor in the therapeutic admixture and could be adoptively transferred to normal recipients with Thy-1.2-positive lymphocytes, but not with serum. Complete regression of a distant test tumor by the C. parvum-tumor admixture was limited to tumors below a certain critical size.
Role of the HER2 [Ile655Val] genetic polymorphism in tumorogenesis and in the risk of trastuzumab-related cardiotoxicity
Authors: S Beauclair, P Formento, J.L. Fischel, W Lescaut, R Largillier, E Chamorey, P Hofman, J.M. Ferrero, G Pagès, G Milano
Journal: Annals of Oncology (2007)
Estrogen Receptor α Binds to Peroxisome Proliferator–Activated Receptor Response Element and Negatively Interferes with Peroxisome Proliferator–Activated Receptor γ Signaling in Breast Cancer Cells
Authors: Daniela Bonofiglio, Sabrina Gabriele, Saveria Aquila, Stefania Catalano, Mariaelena Gentile, Emilia Middea, Francesca Giordano, Sebastiano Andò
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The molecular mechanisms involved in the repressive effects exerted by estrogen receptors (ER) on peroxisome proliferator–activated receptor (PPAR) γ–mediated transcriptional activity remain to be elucidated. The aim of the present study was to provide new insight into the crosstalk between ERα and PPARγ pathways in breast cancer cells. Experimental Design: Using MCF7 and HeLa cells as model systems, we did transient transfections and electrophoretic mobility shift assay and chromatin immunoprecipitation studies to evaluate the ability of ERα to influence PPAR response element–mediated transcription. A possible direct interaction between ERα and PPARγ was ascertained by coimmunoprecipitation assay, whereas their modulatory role in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway was evaluated by determining PI3K activity and AKT phosphorylation. As a biological counterpart, we investigated the growth response to the cognate ligands of both receptors in hormone-dependent MCF7 breast cancer cells. Results: Our data show for the first time that ERα binds to PPAR response element and represses its transactivation. Moreover, we have documented the physical and functional interactions of ERα and PPARγ, which also involve the p85 regulatory subunit of PI3K. Interestingly, ERα and PPARγ pathways have an opposite effect on the regulation of the PI3K/AKT transduction cascade, explaining, at least in part, the divergent response exerted by the cognate ligands 17β-estradiol and BRL49653 on MCF7 cell proliferation. Conclusion: ERα physically associates with PPARγ and functionally interferes with PPARγ signaling. This crosstalk could be taken into account in setting new pharmacologic strategies for breast cancer disease.
A20 Inhibits Cytokine-Induced Apoptosis and Nuclear Factor κB–Dependent Gene Activation in Islets
Authors: Shane T. Grey, Maria B. Arvelo, Wendy Hasenkamp, Fritz H. Bach, Christiane Ferran
Journal: The Journal of Experimental Medicine (1999)

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease resulting from apoptotic destruction of β cells in the islets of Langerhans. Low expression of antioxidants and a predilection to produce nitric oxide (NO) have been shown to underscore β cell apoptosis. With this perspective in mind, we questioned whether β cells could mount an induced protective response to inflammation. Here we show that human and rat islets can be induced to rapidly express the antiapoptotic gene A20 after interleukin (IL)-1β activation. Overexpression of A20 by means of adenovirus-mediated gene transfer protects islets from IL-1β and interferon γ–induced apoptosis. The cytoprotective effect of A20 against apoptosis correlates with and is dependent on the abrogation of cytokine-induced NO production. The inhibitory effect of A20 on cytokine-stimulated NO production is due to transcriptional blockade of inducible NO synthase (iNOS) induction; A20 inhibits the activation of the transcription factor nuclear factor κB at a level upstream of IκBα degradation. These data demonstrate a dual antiapoptotic and antiinflammatory function for A20 in β cells. This qualifies A20 as part of the physiological cytoprotective response of islets. We propose that A20 may have therapeutic potential as a gene therapy candidate to achieve successful islet transplantation and the cure of IDDM.
High burden of rapidly growing non-tuberculosis mycobacteria in patients with respiratory disease undergoing elective bronchoscopy
Authors: Neranjan Dissanayake, Dushantha Madegedara, Dhammika MaganaArachchi, Udani Karunarathna, Duminda Yasaratne, Chathuranga De Silva, Chandana Kulathunga, Samadara Nakandala, Prasanne Wijerathne, Chathura Wirasinghe
Journal: European Respiratory Journal (2011)

Background:  Pathogenecity of pulmonary non-tuberculous Mycobacteria (NTM) is less well understood than that of M. tuberculosis (MTB) complex. Both will show identical results on acid-fast staining (AFS), but culture characteristics are commonly used for differentiation in the local setting.   Objective:  To assess the pattern of mycobacterial culture among patients with respiratory illness and negative sputum for AFS, in a pulmonary tuberculosis (PTB) prevalent environment.   Method:  Bronchoalveolar lavage samples from 120 patients were inoculated onto solid media (Lowenstein-Jensen and Middlebrook 7H-10) at 280C and 370C, in both light and dark conditions. All patients were negative for sputum AFS. Indications for bronchoscopy were bronchiectasis, cavitatory lung disease and smear negative PTB.   Results:  67 patients yielded positive colonies within 8 weeks. 37 colonies were positive for AFS, of which 31 were rapidly growing Mycobacteria (RGM;  7 days). Rapid colony growth strongly favours towards NTM. PCR based restriction fragment length polymorphism analyses on NTM are in progress. Concomitant sterile water, instrument cleanser fluid and saline samples did not yield culture growth.   Conclusion:  We observed a high prevalence (>25%) of RGM in the study population. This raises major concerns on possible over-diagnosis of PTB leading to inappropriate therapy and false categorization of patients, in limited resource settings where sputum AFS results play a central role in managing PTB in clinical practice.