tbuckley/cabot-search huggingface dataset:
P107 Functional significance of the nitric oxide-asymmetric dimethylarginine-dimethylarginine dimethylaminohydrolase (NO-ADMA-DDAH) axis in TGF-β mediated epithelial-mesenchymal transition
Authors: HK Lota, JM Leiper
Journal: Thorax (2015)

<h3>Background</h3> Transforming growth factor (TGF)-β is a key mediator of epithelial-mesenchymal transition (EMT), a pathogenetic mechanism in idiopathic pulmonary fibrosis (IPF). Nitric oxide (NO) may potentiate TGF-β/Smad-signalling and increased levels of NO and one isoform of its generating enzyme, inducible nitric oxide synthetase (iNOS), are observed in experimental models of IPF. Asymmetric dimethylarginine (ADMA) competitively inhibits iNOS, and is hydrolysed by dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2. Our prior data suggests that regulation of NO production via inhibitory methylarginines may play a role in IPF. The role of NOS inhibition on the NO-ADMA-DDAH axis in TGF-β mediated EMT is unknown. <h3>Methods</h3> Human type II alveolar epithelial cells (A549) were serum starved for 24 hrs before stimulation with 5 ng/ml TGF-β (control); co-treatment with TGF-β 5 ng/ml and 100 uM/ml 1400 W (highly selective iNOS inhibitor); and 1400 W treatment alone. A separate experiment was performed with 100 uM/ml exogenous ADMA (pan-NOS inhibitor). A profile indicating transformation from an epithelial to mesenchymal phenotype (E-cadherin, a-SMA), and expression and protein levels of DDAH isoforms and NOS enzymes was assessed by qRT-PCR and Western blotting. <h3>Results</h3> TGF-β mediated EMT was confirmed by significant changes in protein levels in both 1400 W and ADMA experiments respectively: decreased E-cadherin (p = 0.0002, p = 0.0005) and increased a-SMA (p = 0.009, p = 0.003). Protein levels of DDAH2 (p = 0.01, p = 0.0024) and iNOS (p = 0.01, p = 0.0083) were increased. In the presence of either TGF-β and 1400 W or TGF-β and ADMA co-treatments; the mesenchymal pattern of changes in E-cadherin and α-SMA, and the elevation in DDAH2 and iNOS levels, were not attenuated. Treatment with either 1400 W or ADMA alone resulted in significantly elevated E-cadherin levels compared to TGF-β control or co-treatments (Figure 1). Pan-NOS inhibition with ADMA alone resulted in a several fold increase in E-cadherin levels compared to no treatment (p = 0.0005) (Figure 1b). <h3>Conclusion</h3> TGF-β mediated transition towards a mesenchymal phenotype is not attenuated by NOS inhibition. However, our results suggest that regulation of NO production by ADMA promotes E-cadherin expression via an iNOS independent mechanism and may play a role in the maintenance of an epithelial phenotype in IPF.
Case 21-1992
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, C.M. Norris, Max L. Goodman
Journal: New England Journal of Medicine (1992)

Presentation of CaseA 65-year-old man was admitted to the hospital because of a large mass that invaded the base of the right side of the skull.The patient was well until 18 months earlier, when he experienced painless horizontal diplopia. He consulted an ophthalmologist, who found right hypertropia. On a random determination the blood glucose level was reported to be normal. The diplopia resolved spontaneously after four days, and the patient failed to return for a planned visual-field examination. He then became lost to follow-up examination until nine months before entry, when painless horizontal diplopia recurred. He returned to . . .
Sequential Atrioventricular Pacing in Heart Block Complicating Acute Myocardial Infarction
Authors: D. A. Chamberlain, R. C. Leinbach, C. E. Vassaux, J. A. Kastor, R. W. DeSanctis, C. A. Sanders
Journal: New England Journal of Medicine (1970)

The hemodynamic effects of ventricular pacing and of sequential atrioventricular pacing were compared in nine patients with second-degree or third-degree heart block complicating acute myocardial infarction. The restoration of normal atrioventricular relations resulted in an increase in cardiac output in each case (average values of 2.9 to 3.6 liters per minute, or 24 per cent — p less than 0.001). Significant rises in arterial pressure and falls in venous pressure were also obtained. Because of the small number of cases and the short study period, the overall clinical effect of sequential pacing could not be assessed, nor could an opinion be formed concerning its effect on prognosis.
P193 How safe is domiciliary change of tracheostomy tube in ventilator dependent patients?
Authors: JM Palmer
Journal: Thorax (2015)

<h3>Introduction</h3> Tracheostomy ventilation (T-HMV) is indicated in a small group of patients with chronic ventilatory failure. These patients often reside outside of formal health-care environments. Tracheostomy tubes generally need to be changed monthly. Our unit undertakes the majority of tube changes in the patient’s home. There are little data evaluating the safety of this procedure outside of the hospital. <h3>Method</h3> We conducted a retrospective review of domiciliary tracheostomy tube changes on ventilator dependent patients. Concurrently all HMV-UK network centres were sent a basic electronic survey. Data collection took place during December 2014. <h3>Results</h3> E-Surveys were sent to 37 centres. Responses were received from 12 (32%). 75% (n = 9) of those responding undertake the majority of tracheostomy changes in the community, 1 centre brings patients into hospital. 2 others do not routinely manage T-HMV patients. Tube changes undertaken at home, are frequently but not exclusively completed by trained professionals including care support workers. 5 areas reported that family members undertake some domiciliary tube changes. The notes of 11 ventilator dependent T-HMV patients were reviewed. Each patient had a mean 9.2 domiciliary tube changes undertaken by the respiratory outreach team. 72% (n = 66) of changes took place without complication or incident. Of the 26 changes which had documented complications, 69% related to minor bleeding only, 3 described moderate bleeding. 5 changes were associated with incidents. 3 of these related to difficulty inserting a new tube with 1 patient requiring a smaller diameter replacement tube. 1 patient, erroneously, had a wrong diameter tube inserted, this was not replaced as the patient found it more comfortable and continued to ventilate effectively. 1 change was associated with loss of speech for 24-hours post procedure. Nobody was admitted or harmed as a direct result of a tube changed at home. The notes of a further patient were reviewed. Approximately 50 domiciliary tube changes were undertaken by her brother without supervision or involvement of health care workers. There were no documented complications or admissions as a result of these changes. <h3>Conclusion</h3> Domiciliary tracheostomy tube change by trained personnel on ventilator dependent patients is safe and effective.
Endogenous Transmembrane TNF-Alpha Protects Against Premature Senescence in Endothelial Colony Forming Cells
Authors: Linden A. Green, Victor Njoku, Julie Mund, Jaime Case, Mervin Yoder, Michael P. Murphy, Matthias Clauss
Journal: Circulation Research (2016)

Rationale: Transmembrane tumor necrosis factor-α (tmTNF-α) is the prime ligand for TNF receptor 2, which has been shown to mediate angiogenic and blood vessel repair activities in mice. We have previously reported that the angiogenic potential of highly proliferative endothelial colony–forming cells (ECFCs) can be explained by the absence of senescent cells, which in mature endothelial cells occupy &gt;30% of the population, and that exposure to a chronic inflammatory environment induced premature, telomere-independent senescence in ECFCs. Objective: The goal of this study was to determine the role of tmTNF-α in the proliferation of ECFCs. Methods and Results: Here, we show that tmTNF-α expression on ECFCs selects for higher proliferative potential and when removed from the cell surface promotes ECFC senescence. Moreover, the induction of premature senescence by chronic inflammatory conditions is blocked by inhibition of tmTNF-α cleavage. Indeed, the mechanism of chronic inflammation–induced premature senescence involves an abrogation of tmTNF/TNF receptor 2 signaling. This process is mediated by activation of the tmTNF cleavage metalloprotease TNF-α–converting enzyme via p38 MAP kinase activation and its concurrent export to the cell surface by means of increased iRhom2 expression. Conclusions: Thus, we conclude that tmTNF-α on the surface of highly proliferative ECFCs plays an important role in the regulation of their proliferative capacity.
Large Bowel Adenocarcinoma Metastases Presenting as Appendicitis
Authors: Barbara Heller, John Kane, Remedios Penetrante, Tom Weber, Miguel Rodriguez-Bigas, Nicholas Petrelli
Journal: Journal of Clinical Oncology (1999)

Article Tools DIAGNOSIS IN ONCOLOGY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1999.17.8.2623 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10561330 Large Bowel Adenocarcinoma Metastases Presenting as Appendicitis Barbara HellerxBarbara HellerSearch for articles by this author , John KanexJohn KaneSearch for articles by this author , Remedios PenetrantexRemedios PenetranteSearch for articles by this author , Tom WeberxTom WeberSearch for articles by this author , Miguel Rodriguez-BigasxMiguel Rodriguez-BigasSearch for articles by this author , Nicholas PetrellixNicholas PetrelliSearch for articles by this author Show More Departments of Surgical Oncology and Pathology, Roswell Park Cancer Institute and State University of New York at Buffalo, Buffalo, NY https://doi.org/10.1200/JCO.1999.17.8.2623 Full Text PDF Figures and Tables "Large Bowel Adenocarcinoma Metastases Presenting as Appendicitis." Journal of Clinical Oncology, 17(8), p. 2623© 1999 by American Society of Clinical Oncology
An open label phase I study of ABR-215050 in patients with prostate cancer refractory to hormone therapy and with rising PSA for determination of MTD and long-term tolerability and safety
Authors: J. Damber, O. Bratt, G. Ahlgren, M. Häggman, A. Björk, S. Kilany, K. Hannander
Journal: Journal of Clinical Oncology (2007)

15510 Background: Preclinical studies have demonstrated that ABR-215050, an orally active 3-quinoline-carboxamide derivative with anti-angiogenic abilities, consistently inhibits growth of established prostate cancer in rodent and human xenografts model systems. Tumor vessel density was inhibited by 44–65% consistent with the 41–78% inhibition in tumor weights. The anti-angiogenic response was correlated with an increase in both tumor hypoxic and apoptotic fraction. Based upon these results, ABR-215050 is now tested in the clinical setting. Methods: Cohorts of 6 patients (pts) with hormone refractory prostate cancer and rising PSA were to receive escalating doses of ABR- 215050 (0.5, 1.0, 2.0 and 3.0 mg daily) for 28 days in addition to the androgen ablative therapy. Pts showing stable disease at day 28 were offered to enter a one year extension period at the MTD level to assess long-term tolerability and safety. The primary endpoint in the 28-day study was determination of MTD. Secondary endpoints included changes in PSA levels. Results: Two DLTs (sinus tachycardia and amylase, G3) occurred in the 1.0 mg cohort. The MTD was therefore set to 0.5 mg. Additional 11 pts were enrolled at the MTD level. A total of 17 pts received 0.5 mg and 7 pts 1.0 mg of ABR-215050 once daily. The most frequently related AEs reported during the first 28 days were muscle or joint pain, nausea and fatigue, all of which being mild and transient. Laboratory changes were also seen, such as a transient increase in CRP and amylase. Fifteen out of 17 pts continued into the extension period. Fourteen out of 15 pts remained on treatment = 4 months. The AE profile in the extension period was similar to that reported during the first 28 days of treatment. Nine out of 14 pts had a &gt;50% decrease in PSA velocity at 4 months compared to the pre-treatment period. Six of these pts exhibited a decrease in PSA from baseline, ranging from 8% to 58% (mean 29%). Conclusions: ABR-215050 0.5 mg is well tolerated with manageable side effects. In addition available PSA results suggest stabilization/lowering of the PSA levels. No significant financial relationships to disclose.
Relation between Activated Smooth-Muscle Cells in Coronary-Artery Lesions and Restenosis after Atherectomy
Authors: Michael Simons, Guy Leclerc, Robert D. Safian, Jeffrey M. Isner, Lawrence Weir, Donald S. Baim
Journal: New England Journal of Medicine (1993)

Neointimal proliferation leading to restenosis frequently develops after coronary angioplasty. This process is associated with a change in vascular smooth-muscle cells from a contractile (quiescent) phenotype to a synthetic or proliferating (activated) one. We investigated whether the presence of activated smooth-muscle cells in coronary lesions at the time of coronary atherectomy predisposes patients to subsequent restenosis.
IL-1β limits the extent of human 6-sulfo LacNAc dendritic cell (slanDC)-mediated NK cell activation and regulates CD95-induced apoptosis
Authors: Dejene Milkessa Tufa, Fareed Ahmad, Debanjana Chatterjee, Gerrit Ahrenstorf, Reinhold Ernst Schmidt, Roland Jacobs
Journal: Cellular and Molecular Immunology (2016)
Abstract LB-104: Excited electrons in melanin induce cyclobutane dimers in the dark
Authors: Sanjay Premi, Silvia Wallisch, Camila Mano, Adam Weiner, Antonella Bacchiocchi, Kazumasa Wakamatsu, Etelvino Bechara, Ruth Halaban, Thierry Douki, Douglas E. Brash
Journal: Cancer Research (2015)

Abstract Sunlight-induced melanomas contain UV-signature mutations, which are caused by cyclobutane pyrimidine dimers (CPD). These photoproducts are typically created picoseconds after a UV photon is absorbed at adjacent thymines or cytosines. However, using immunohistochemistry, mass spectrometry, and RNAi, we find that melanocytes generate CPD for &amp;gt;3 hours after exposure to UVA or UVB, wavelengths found in sunlight and in tanning beds; these “dark CPD” constitute the majority of CPD induced. Using pharmacologic inhibitors, single-photon counting, and specific energy acceptors, we elucidated the mechanism. The process begins when UV-induced superoxide and nitric oxide combine to form peroxynitrite, one of the few biological molecules capable of exciting an electron. Excitation creates a quantum triplet state in the skin pigment melanin that has the energy of a UV photon but induces CPD by transferring its energy to DNA in a radiation-independent manner. Melanin is evidently carcinogenic as well as protective. These findings may underlie the dependence of UV-induced and spontaneous skin cancers on melanin type. The results also validate the long-standing suggestion that chemical generation of excited electronic states - the source of bioluminescence in lower organisms - is important in mammalian biology. Citation Format: Sanjay Premi, Silvia Wallisch, Camila Mano, Adam Weiner, Antonella Bacchiocchi, Kazumasa Wakamatsu, Etelvino Bechara, Ruth Halaban, Thierry Douki, Douglas E. Brash. Excited electrons in melanin induce cyclobutane dimers in the dark. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-104. doi:10.1158/1538-7445.AM2015-LB-104
Endovascular treatment versus medical care alone for ischaemic stroke: systematic review and meta-analysis
Authors: Filipe Brogueira Rodrigues, Joana Briosa Neves, Daniel Caldeira, José M Ferro, Joaquim J Ferreira, João Costa
Journal: BMJ (2016)

<b>Objectives</b>&nbsp;To evaluate the efficacy and safety of endovascular treatment, particularly adjunctive intra-arterial mechanical thrombectomy, in patients with ischaemic stroke. <b>Design</b>&nbsp;Systematic review and meta-analysis. <b>Data sources</b>&nbsp;Medline, Embase, Cochrane Central Register of Controlled Trials, Web of Science, SciELO, LILACS, and clinical trial registries from inception to December 2015. Reference lists were crosschecked. <b>Eligibility criteria for selecting studies</b>&nbsp;Randomised controlled trials in adults aged 18 or more with ischaemic stroke comparing endovascular treatment, including thrombectomy, with medical care alone, including intravenous recombinant tissue plasminogen activator (rt-PA). Trial endpoints were functional outcome (modified Rankin scale scores of ≤2) and mortality at 90 days after onset of symptoms. No language or time restrictions applied. <b>Results</b>&nbsp;10 randomised controlled trials (n=2925) were included. In pooled analysis endovascular treatment, including thrombectomy, was associated with a higher proportion of patients experiencing good (modified Rankin scale scores ≤2) and excellent (scores ≤1) outcomes 90 days after stroke, without differences in mortality or rates for symptomatic intracranial haemorrhage, compared with patients randomised to medical care alone, including intravenous rt-PA. Heterogeneity was high among studies. The more recent studies (seven randomised controlled trials, published or presented in 2015) proved better suited to evaluate the effect of adjunctive intra-arterial mechanical thrombectomy on its index disease owing to more accurate patient selection, intravenous rt-PA being administered at a higher rate and earlier, and the use of more efficient thrombectomy devices. In most of these studies, more than 86% of the patients were treated with stent retrievers, and rates of recanalisation were higher (&gt;58%) than previously reported. Subgroup analysis of these seven studies yielded a risk ratio of 1.56 (95% confidence interval 1.38 to 1.75) for good functional outcomes and 0.86 (0.69 to 1.06) for mortality, without heterogeneity among the results of the studies. All trials were open label. Risk of bias was moderate across studies. The full results of two trials are yet to be published. <b>Conclusions</b>&nbsp;Moderate to high quality evidence suggests that compared with medical care alone in a selected group of patients endovascular thrombectomy as add-on to intravenous thrombolysis performed within six to eight hours after large vessel ischaemic stroke in the anterior circulation provides beneficial functional outcomes, without increased detrimental effects. <b>Systematic review registration</b>&nbsp;PROSPERO CRD42015019340.
EZH2 Inhibitor DZNep Induces Apoptosis In Adult T-Cell Leukemia/Lymphoma Cells By BCL2 Suppression Via Regulation Of Mir-181a
Authors: Sasaki Daisuke, Hasegawa Hiroo, Taniguchi Hiroaki, Yoshitaka Imaizumi, Uno Naoki, Morinaga Yoshitomo, Yasushi Miyazaki, Yanagihara Katsunori
Journal: Blood (2013)
Rationale and design of the European Polyp Surveillance (EPoS) trials
Authors: Rodrigo Jover, Michael Bretthauer, Evelien Dekker, Øyvind Holme, Michal Kaminski, Magnus Løberg, Ann Zauber, Miguel Hernán, Iris Lansdorp-Vogelaar, Annike Sunde, Eleanor McFadden, Antoni Castells, Jaroslaw Regula, Enrique Quintero, Maria Pellisé, Carlo Senore, Mette Kalager, Mario Dinis-Ribeiro, Louise Emilsson, David Ransohoff, Geir Hoff, Hans-Olov Adami
Journal: Endoscopy (2016)

<b>Background:</b> Current guidelines recommend surveillance colonoscopies after polyp removal depending on the number and characteristics of polyps, but there is a lack of evidence supporting the recommendations. This report outlines the rationale and design of two randomized trials and one observational study investigating evidence-based surveillance strategies following polyp removal. <b>Study design and endpoints:</b> The EPoS studies started to recruit patients in April 2015. EPoS study I randomizes 13 746 patients with low-risk adenomas (1 – 2 tubular adenomas size < 10 mm, low-grade dysplasia) to surveillance after 5 and 10 years, or 10 years only. EPoS study II randomizes 13 704 patients with high-risk adenomas (3 – 10 adenomas or adenoma ≥ 10 mm in diameter, or adenoma with high-grade dysplasia, or > 25 % villous features) to surveillance after 3, 5, and 10 years, or 5 and 10 years only. EPoS study III offers surveillance after 5 and 10 years to patients with serrated polyps ≥ 10 mm in diameter at any location, or serrated polyps ≥ 5 mm in diameter proximal to the splenic flexure. All polyps are removed before patients enter the trials. The primary end point is colorectal cancer incidence after 10 years. We assume a colorectal cancer risk of 1 % for patients in EPoS I, and 2 % for patients in EPoS II. Using a noninferiority hypothesis with an equivalence interval of 0.5 % for EPoS I and 0.7 % for EPoS II, the trials are 90 % powered to uncover differences larger than the equivalence intervals. For EPoS III, no power analyses have been performed. <b>Conclusions:</b> The present trials aim to develop evidence-based strategies for polyp surveillance, thereby maximizing effectiveness and minimizing resources. Trial registration: ClinicalTrials.gov (NCT02319928).
Phase II trial of autophagy inhibition using hydroxychloroquine (HCQ) with FOLFOX/bevacizumab in the first-line treatment of advanced colorectal cancer.
Authors: Arturo Loaiza-Bonilla, Mark H. O'Hara, Maryann Redlinger, Nevena Damjanov, Ursina R. Teitelbaum, Irina Vasilevskaya, Mark Alan Rosen, Daniel F Heitjan, Ravi K. Amaravadi, Peter J. O'Dwyer
Journal: Journal of Clinical Oncology (2015)

3614 Background: We have shown that autophagy, the regulated dissolution of cellular elements to maintain survival in adverse environmental conditions, is a determinant of resistance to chemotherapy in colorectal cancer models, and is reversed by chloroquine (Selvakumaran M, et al. Clin Cancer Res, 2013). A Phase I run-in demonstrated that full doses of mFOLFOX6/bevacizumab were tolerated with HCQ 600mg PO twice daily. Methods: We report a Phase II trial in previously-untreated patients with metastatic colorectal cancer. Patients were treated every two weeks with 5-FU (400mg/m2 bolus, then 2400 mg/m2 over 46h) together with leucovorin 200mg/m2, oxaliplatin 85mg/m2, bevacizumab 5mg/kg, all IV, repeated every two weeks, with HCQ as above. After 12 cycles, oxaliplatin was omitted and patients were continued on 5-FU, bevacizumab, and HCQ. Imaging was performed every 8 weeks. Results: Twenty-four patients (pts) have been accrued, of whom 23 are eligible: 10 female/13 Male; 19 Caucasian/3 Black/1 East-Asian. Toxicity has been generally tolerable. Grade 3 effects included neutropenia 9/23), diarrhea (1/23), and anorexia (1/23). There were two episodes of myocardial infarction, one fatal, one of atrial arrhythmia, and two of pulmonary embolism in the course of the trial. 20/23 patients were able to maintain full dose of HCQ. Patients evaluable for response include 19 (4 pts too early). There were 1 complete response (5%), 9 partial responses (47%), and 7 stable disease (37%). Four patients went off study for resection of metastatic disease after 3-25 months. Median progression-free and overall survival have not been reached. Autophagy biomarkers in peripheral mononuclear cells show autophagy inhibition in the majority of patients. Six of thirteen patients with genomic testing available had a TP53 mutation. Four of these six patients had a major response (1CR, 3 PR). Conclusions: The combination of FOLFOX/bevacizumab with HCQ is an active regimen in unselected patients with colorectal cancer. A randomized Phase II trial of the combination is in development. Clinical trial information: NCT01206530.