tbuckley/cabot-search huggingface dataset:
Autophagic flux determines cell death and survival in response to Apo2L/TRAIL (dulanermin)
Authors: Kamini Singh, Arishya Sharma, Maria C Mir, Judith A Drazba, Warren D Heston, Cristina Magi-Galluzzi, Donna Hansel, Brian P Rubin, Eric A Klein, Alexandru Almasan
Journal: Molecular Cancer (2014)

Macroautophagy is a catabolic process that can mediate cell death or survival. Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment (TR) is known to induce autophagy. Here we investigated whether SQSTM1/p62 (p62) overexpression, as a marker of autophagic flux, was related to aggressiveness of human prostate cancer (PCa) and whether autophagy regulated the treatment response in sensitive but not resistant PCa cell lines. Immunostaining and immunoblotting analyses of the autophagic markers p62 [in PCa tissue microarrays (TMAs) and PCa cell lines] and LC3 (in PCa cell lines), transmission electron microscopy, and GFP-mCherry-LC3 were used to study autophagy induction and flux. The effect of autophagy inhibition using pharmacologic (3-methyladenine and chloroquine) and genetic [(short hairpin (sh)-mediated knock-down of ATG7 and LAMP2) and small interfering (si)RNA-mediated BECN1 knock-down] approaches on TR-induced cell death was assessed by clonogenic survival, sub-G1 DNA content, and annexinV/PI staining by flow cytometry. Caspase-8 activation was determined by immunoblotting. We found that increased cytoplasmic expression of p62 was associated with high-grade PCa, indicating that autophagy signaling might be important for survival in high-grade tumors. TR-resistant cells exhibited high autophagic flux, with more efficient clearance of p62-aggregates in four TR-resistant PCa cell lines: C4-2, LNCaP, DU145, and CWRv22.1. In contrast, autophagic flux was low in TR-sensitive PC3 cells, leading to accumulation of p62-aggregates. Pharmacologic (chloroquine or 3-methyladenine) and genetic (shATG7 or shLAMP2) inhibition of autophagy led to cell death in TR-resistant C4-2 cells. shATG7-expressing PC3 cells, were less sensitive to TR-induced cell death whereas those shLAMP2-expressing were as sensitive as shControl-expressing PC3 cells. Inhibition of autophagic flux using chloroquine prevented clearance of p62 aggregates, leading to caspase-8 activation and cell death in C4-2 cells. In PC3 cells, inhibition of autophagy induction prevented p62 accumulation and hence caspase-8 activation. We show that p62 overexpression correlates with advanced stage human PCa. Pharmacologic and genetic inhibition of autophagy in PCa cell lines indicate that autophagic flux can determine the cellular response to TR by regulating caspase-8 activation. Thus, combining various autophagic inhibitors may have a differential impact on TR-induced cell death.
CHROMIUM AS A SUPPLEMENT
Authors: Henry C. Lukaski
Journal: Annual Review of Nutrition (1999)

▪ Abstract Chromium (Cr) is an essential mineral element that has received considerable public attention. The suggestion that Cr intake is generally low has generated interest regarding the purported beneficial effects of Cr supplementation on biological function and health of animals and humans. This review briefly describes key aspects of Cr nutritional status and evaluates the effects of Cr supplementation on various components of biological function, body composition, and health. A novel biological role of Cr in regulation of insulin function is described. Although promising results of Cr supplementation are presented, the considerable challenge of developing methods for routine assessment of Cr nutriture in humans remains.
Molecular characterisation and cetuximab-based treatment in a patient with refractory small bowel adenocarcinoma
Authors: S. De Dosso, F. Molinari, V. Martin, M. Frattini, P. Saletti
Journal: Gut (2010)

Small bowel adenocarcinoma (SBA) is an uncommon, aggressive neoplasm and limited data are available to guide systemic therapeutic decisions. Only two prospective studies have evaluated the role of chemotherapy in advanced disease, whilst most of the data are generated from retrospective analyses of single institutions. By analogy with metastatic colorectal cancer (mCRC), fluoropyrimidine-based regimens are commonly used.

The role of biologicals in this disease is as yet unexplored; nonetheless we read with interest the article by Tsang et al on the use of bevacizumab in advanced SBA.1

Cetuximab is a monoclonal antibody (mAb) directed against the epidermal growth factor receptor (EGFR), approved for the treatment of irinotecan-refractory mCRC. In addition, in mCRC it has been shown to improve efficacy in …
Interaction of neuropeptide Y and the sympathetic nervous system in vascular control in man.
Authors: J Clarke, N Benjamin, S Larkin, D Webb, A Maseri, G Davies
Journal: Circulation (1991)

There is increasing evidence that neuropeptide Y (NPY) contributes to the autonomic control of the circulation. NPY coexists with noradrenaline in perivascular nerve terminals, may be released during sympathetic stimulation, and is a potent constrictor of the human coronary circulation and other vascular beds. In vitro studies show that NPY can act either directly on vascular smooth muscle or indirectly by modulation of the presynaptic release or the postsynaptic actions of noradrenaline. It is unclear to what extent these mechanisms operate in vivo.The effect on forearm blood flow of intra-arterial NPY was studied in six volunteers during coinfusion of noradrenaline and during reflex sympathetic stimulation induced by lower-body negative pressure. NPY alone induced a dose-dependent reduction of forearm blood flow in all subjects studied, to a maximum of 49 +/- 6.1%. The reduction of flow during infusion of noradrenaline alone was 42 +/- 8%. The response to noradrenaline was unaffected by coinfusion of a threshold constrictor dose of NPY (50 pmol/min). Furthermore, the reflex sympathetic vasoconstrictor response to 20 cm H2O of lower-body negative pressure was similar in both the infused and control arms during the infusion of 50 pmol/min NPY. The response to noradrenaline was abolished by alpha-blockade with phentolamine, but the flow reduction induced by NPY was unaffected by alpha-blockade.NPY is a potent constrictor of human forearm resistance vessels and has a direct effect independent of alpha-receptors. NPY has no detectable modulating effect in vivo on the action of endogenous or infused noradrenaline.
Is Physostigmine Effective for Cardiac Toxicity of Tricyclic Antidepressant Drugs?
Authors: J. Thomas Bigger
Journal: JAMA (1977)

To the Editor.—  Tobis and Das (235: 1474, 1976) report, for the first time, successful use of physostigmine salicylate in the treatment of malignant ventricular arrhythmias and conduction defects caused by tricyclic antidepressant (TCA) poisoning in a 22-year-old woman admitted two hours after ingesting about 1,000 mg amitriptyline hydrochloride. Among other measures, large doses of physostigmine were given and, after 48 hours, ventricular conduction abnormalities and arrhythmias abated. Improvement in cardiac toxicity was attributed to physostigmine therapy. If this conclusion were correct, physostigmine might be an important addition to the therapy of TCA cardiotoxicity. However, we are doubtful that improvement in cardiac status was caused by this drug.  Physostigmine (6 mg) was given to the patient immediately on arrival, but the ECG did not change. Shortly afterward, a rhythm interpreted as ventricular tachycardia developed, and the patient was given lidocaine hydrochloride and physostigmine. By the following morning, the QRS complex
Thrombotic thrombocytopenic purpura in a human immunodeficiency virus (HIV)‐seropositive homosexual man
Authors: Janet Jokela, Thomas Flynn, Keith Henry
Journal: American Journal of Hematology (1987)

Abstract A case of thrombotic thrombocytopenic purpura (TTP) in a human immunodeficiency virus (HIV)‐seropositive homosexual man is reported. The patient improved after corticosteroid and plasma exchange therapy was instituted. The case demonstrated most of the classic features of TTP, including histologic evidence of fibrin thrombi in small blood vessels. Atypical features included reduced number of megakaryocytes in the bone marrow and only partial resolution of thrombocytopenia after therapy was begun. An autoimmune thrombocytopenia has been well‐characterized in HIV ‐antibody‐seropositive homosexual men. Physicians caring for HIV‐seropositive persons should also be aware of a possible association with TTP.
Platelet Protease Nexin-1, a Serpin That Strongly Influences Fibrinolysis and Thrombolysis
Authors: Yacine Boulaftali, Benoit Ho-Tin-Noe, Ana Pena, Stéphane Loyau, Laurence Venisse, Déborah François, Benjamin Richard, Véronique Arocas, Jean-Philippe Collet, Martine Jandrot-Perrus, Marie-Christine Bouton
Journal: Circulation (2011)

Protease nexin-1 (PN-1) is a serpin that inhibits plasminogen activators, plasmin, and thrombin. PN-1 is barely detectable in plasma, but we have shown recently that PN-1 is present within the α-granules of platelets.In this study, the role of platelet PN-1 in fibrinolysis was investigated with the use of human platelets incubated with a blocking antibody and platelets from PN-1-deficient mice. We showed by using fibrin-agar zymography and fibrin matrix that platelet PN-1 inhibited both the generation of plasmin by fibrin-bound tissue plasminogen activator and the activity of fibrin-bound plasmin itself. Rotational thromboelastometry and laser scanning confocal microscopy were used to demonstrate that PN-1 blockade or deficiency resulted in increased clot lysis and in an acceleration of the lysis front. Protease nexin-1 is thus a major determinant of the lysis resistance of platelet-rich clots. Moreover, in an original murine model in which thrombolysis induced by tissue plasminogen activator can be measured directly in situ, we observed that vascular recanalization was significantly increased in PN-1-deficient mice. Surprisingly, general physical health, after tissue plasminogen activator-induced thrombolysis, was much better in PN-1-deficient than in wild-type mice.Our results reveal that platelet PN-1 can be considered as a new important regulator of thrombolysis in vivo. Inhibition of PN-1 is thus predicted to promote endogenous and exogenous tissue plasminogen activator-mediated fibrinolysis and may enhance the therapeutic efficacy of thrombolytic agents.
Evaluation of pulmonary disease using static lung volumes in primary ciliary dyskinesia
Authors: Massimo Pifferi, Andrew Bush, Giovanni Pioggia, Davide Caramella, Gennaro Tartarisco, Maria Di Cicco, Marta Zangani, Iolanda Chinellato, Fabrizio Maggi, Giovanna Tezza, Pierantonio Macchia, Attilio Boner
Journal: Thorax (2012)

<h3>Background</h3> In primary ciliary dyskinesia (PCD) lung damage is usually evaluated by high-resolution CT (HRCT). <h3>Objective</h3> To evaluate whether HRCT abnormalities and <i>Pseudomonas aeruginosa</i> infection were better predicted by spirometry or plethysmography. <h3>Methods</h3> A cross-sectional study performed in consecutive patients with PCD who underwent sputum culture, spirometry, plethysmography and HRCT within 48 h. Principal component analysis and soft computing were used for data evaluation. <h3>Results</h3> Fifty patients (26 children) were studied. <i>P aeruginosa</i> infection was found in 40% of the patients and bronchiectasis in 88%. There was a correlation between infection with <i>P aeruginosa</i> and extent of bronchiectasis (p=0.009; r =0.367) and air-trapping (p=0.03; r =0.315). Moreover, there was an association between infection with <i>P aeruginosa</i> and residual volume (RV) values &gt;150% (p=0.04) and RV/total lung capacity (TLC) ratio &gt;140% (p=0.001), but not between infection with <i>P aeruginosa</i> and forced expiratory volume in 1 s (FEV<sub>1</sub>)&lt;80%, or forced expiratory flow between 25% and 75% of forced vital capacity (FVC) (FEF<sub>25–75%</sub>)&lt;70% or FEV<sub>1</sub>/FVC&lt;70% (&lt;80% in children). Severity of the total lung impairment on chest HRCT directly correlated with RV when expressed as per cent predicted (p=0.003; r =0.423), and RV/TLC (p&lt;0.001; r =0.513) or when expressed as z scores (p=0.002, r =0.451 and p&lt;0.001, r =0.536 respectively). Principal component analysis on plethysmographic but not on spirometry data allowed recognition of different severities of focal air trapping, atelectasis and extent of bronchiectasis. <h3>Conclusions</h3> Plethysmography better predicts HRCT abnormalities than spirometry. Whether it might be a useful test to define populations of patients with PCD who should or should not have HRCT scans requires further longitudinal studies.
Training volume as a risk factor for the development of jumper's knee? data from the patellar tendinopathy cohort 2006-2010
Authors: H Visnes, R Bahr
Journal: British Journal of Sports Medicine (2011)

Background Previous studies on players with jumper's knee (cross-sectional studies and case-control studies) have found that symptomatic athletes were training more strength and more workouts per week compared with healthy asymptomatic players. Registration of training volume as risk factor for the development of jumper's knee is to our knowledge not previously done. Aim Study training volume as a risk factor for the developing jumper's knee. Design Cohort study. Participants Elite volleyball players at junior high school (Top Volley Norway) at Sand, Norway. Method Registration of training volume through weekly training diary on the internet, and interviews with the player and the coach. The jumper's knee diagnosis was based on a standardised clinical examination. Results A total of 140 symptom-free students were included (69 boys and 71 girls), with an mean observation time of 1.8 years. Of these, 28 developed jumper (22 boys and 6 girls). The jumper's knee group trained 20.1 ± 6.9 (SD) h per week, compared with the asymptomatic athletes 16.9 ± 6.9 h (p&lt;0.001). The difference in the training workload was primarily related to indoor volleyball training, where the jumper's knee group trained 15.0 ± 3.0 h and the asymptomatic players 11.9 ± 3.8 h (p&lt;0.001). The volume for other forms of training (volleyball, strength training, flexibility training and other training) were similar. For further analysis, the total training exposure (average hours per week) were divided into four groups. The training group 4 (21–28 h per week) have a significantly increased risk of developing jumper's knee. χ 2 test=8.57 gives p=0.01. Conclusion We find that athletes who developed jumper's knee significantly trained more than athletes who remain asymptomatic. High training loads in the form of indoor volleyball training will therefore be an important risk factor for the developing jumper's knee.
Randomised controlled trial of acute mental health care by a crisis resolution team: the north Islington crisis study
Authors: Sonia Johnson, Fiona Nolan, Stephen Pilling, Andrew Sandor, John Hoult, Nigel McKenzie, Ian R White, Marie Thompson, Paul Bebbington
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To evaluate the effectiveness of a crisis resolution team. <b>Design</b> Randomised controlled trial. <b>Participants</b> 260 residents of the inner London Borough of Islington who were experiencing crises severe enough for hospital admission to be considered. <b>Interventions</b> Acute care including a 24 hour crisis resolution team (experimental group), compared with standard care from inpatient services and community mental health teams (control group). <b>Main outcome measures</b> Hospital admission and patients9 satisfaction. <b>Results</b> Patients in the experimental group were less likely to be admitted to hospital in the eight weeks after the crisis (odds ratio 0.19, 95% confidence interval 0.11 to 0.32), though compulsory admission was not significantly reduced. A difference of 1.6 points in the mean score on the client satisfaction questionnaire (CSQ-8) was not quite significant (P = 0.07), although it became so after adjustment for baseline characteristics (P = 0.002). <b>Conclusion</b> Crisis resolution teams can reduce hospital admissions in mental health crises. They may also increase satisfaction in patients, but this was an equivocal finding.
Genomic medicine: considerations for health professionals and the public
Authors: Denise Avard, Bartha Knoppers
Journal: Genome Medicine (2009)

Advances in human genomics are ushering in a new era of predictive, preventative and personalized approaches to medicine. However, as the integration of genomic medicine progresses, the health community has a responsibility to communicate to the public the risks and challenges of genetic information. A possible knowledge transfer framework is outlined as a means to bridge the practical uses of genetics within various ethical, social and economic contexts. Tools and resources are needed to help clinicians understand genetic risks and help them inform the public appropriately and effectively.
Preparation of functional smooth muscle cells from the rabbit aorta.
Authors: H E Ives, G S Schultz, R E Galardy, J D Jamieson
Journal: The Journal of Experimental Medicine (1978)

A procedure for dissociating the rabbit aorta into single, functional smooth muscle cells is described. After removal of adventitia and intima, slices of media were incubated with purified collagenase, elastase, and soybean trypsin inhibitor in a Krebs-Ringer buffer modified with Hepes, amino acids, and a [Ca2+] of 0.2 mM. After enzymatic digestion and mechanical shear, the yield of dispersed cells was approximately 25% based on DNA recovered. Greater than 95% of the cells excluded trypan blue and approximately 80-90% adhered to tissue culture dishes. By phase contrast microscopy, most of the cells were elongate and approximately 10 micron X 30 micron in size. The remainder were either spherical or highly crenated and contracted. Electron microscopy of the cells showed that immediately after dissociation greater than 95% could be identified as smooth muscle, though most had undergone some degree of structural change compared to cells in situ. Depending on the preparation, from 5 to 50% of these cells contracted in response to agonists. Cells shortened by 10-15% and developed numerous evaginations when stimulated by angiotensin II norepinephrine, or carbamylcholine. Cells relaxed after washout of agonists and could subsequently be restimulated. Specific inhibitors of each of the agonists blocked the contractile response. Dispersed cells cultured for 1-5 days contracted in even higher numbers than the freshly prepared cells, suggesting restoration of hormone binding and/or contractile function in culture. This preparation provides a system in which the physiology of individual vascular smooth muscle cells may be studied.
Producing Nature’s Gene-Chips: The Generation of Peptides for Display by MHC Class I Molecules
Authors: Nilabh Shastri, Susan Schwab, Thomas Serwold
Journal: Annual Review of Immunology (2002)

Gene-chips contain thousands of nucleotide sequences that allow simultaneous analysis of the complex mixture of RNAs transcribed in cells. Like these gene-chips, major histocompatibility complex (MHC) class I molecules display a large array of peptides on the cell surface for probing by the CD8 + T cell repertoire. The peptide mixture represents fragments of most, if not all, intracellular proteins. The antigen processing machinery accomplishes the daunting task of sampling these proteins and cleaving them into the precise set of peptides displayed by MHC I molecules. It has long been believed that antigenic peptides arose as by-products of normal protein turnover. Recent evidence, however, suggests that the primary source of peptides is newly synthesized proteins that arise from conventional as well as cryptic translational reading frames. It is increasingly clear that for many peptides the C-terminus is generated in the cytoplasm, and N-terminal trimming occurs in the endoplasmic reticulum in an MHC I–dependent manner. Nature's gene-chips are thus both parsimonious and elegant.
METHEMOGLOBIN FORMATION BY STERILE CULTURE FILTRATES OF PNEUMOCOCCUS
Authors: Hugh J. Morgan, James M. Neill
Journal: The Journal of Experimental Medicine (1924)

1. Sterile filtrates of aerobic cultures of pneumococcus which contain hydrogen peroxide are capable of converting catalase-free solutions of crystalline oxyhemoglobin into methemoglobin. This action is dependent upon the hydrogen peroxide in the filtrates and occurs only in the absence of blood catalase. 2. In catalase-containing solutions of hemoglobin from laked corpuscles, the actual methemoglobin-forming system of Pneumococcus involves a labile constituent of the bacterial cell. This intracellular substance is itself susceptible to oxidizing agents and may be rendered inactive, if exposed to peroxide or similar substances previous to its introduction into oxyhemoglobin solutions. The activity of this function in the case of sterile filtrates of pneumococcus cultures depends, therefore, upon the liberation of cell constituents into the medium and upon the protection of these cellular substances from the oxidizing agents which are formed when pneumococcus cultures are freely exposed to air. When these cultural conditions are fulfilled sterile culture filtrates of Pneumococcus convert oxyhemoglobin into methemoglobin independent of the presence of blood catalase.
Heart rate variability in patients with mild to moderate heart failure: Effects of neurohormonal modulation by digoxin and ibopamine
Authors: Jan Brouwer, Dirk J. Van Veldhuisen, Arie J. Man In 't Veld, Peter H.J.M. Dunselman, Frans Boomsma, Jaap Haaksma, K.I. Lie
Journal: Journal of the American College of Cardiology (1995)
Urinary cadmium levels predict lower lung function in current and former smokers: data from the Third National Health and Nutrition Examination Survey
Authors: D M Mannino
Journal: Thorax (2004)

<b>Background:</b> A study was undertaken to determine the relation between urinary cadmium levels and lung function in a nationally representative cohort of current, former, and never smokers in the US. Urinary cadmium levels reflect the total body burden of cadmium. <b>Methods:</b> The following data from the Third National Health and Nutrition Examination Survey were analysed: urinary cadmium (adjusted for urinary creatinine), lung function, sex, race/ethnicity, age, education level, job category, body mass index, serum cotinine level, and smoking history. Linear regression models were developed to predict lung function using urinary cadmium as the main predictor, adjusting for other covariates and stratified by smoking status. <b>Results:</b> Data were available on 16 024 adults. Current smokers had higher mean (SE) urinary cadmium/creatinine levels (0.46 (0.01) μg/g) than former (0.32 (0.01) μg/g) or never smokers (0.23 (0.01) μg/g). Higher levels of urinary cadmium were associated with significantly lower forced expiratory volumes in 1 second (FEV<sub>1</sub>) in current (−2.06%, 95% confidence interval (CI) –2.86 to −1.26 per 1 log increase in urinary cadmium) and former smokers (−1.95%, 95% CI –2.87 to −1.03) but not in never smokers (−0.18%, 95% CI –0.60 to 0.24). Similar results were obtained for forced vital capacity (FVC) and FEV<sub>1</sub>/FVC. <b>Conclusions:</b> Cadmium, which is known to cause emphysema in occupational settings, may also be important in the development of tobacco related lung disease.