tbuckley/cabot-search huggingface dataset:
Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer
Authors: Jens U Marquardt, Luis Gomez-Quiroz, Lucrecia O Arreguin Camacho, Federico Pinna, Yun-Han Lee, Mitsuteru Kitade, Mayrel Palestino Domínguez, Darko Castven, Kai Breuhahn, Elizabeth A Conner, Peter R Galle, Jesper B Andersen, Valentina M Factor, Snorri S Thorgeirsson
Journal: Journal of Hepatology (2015)
Possible role of death receptor-mediated apoptosis by the E3 ubiquitin ligases Siah2 and POSH
Authors: Perry A Christian, Michael V Fiandalo, Steven R Schwarze
Journal: Molecular Cancer (2011)

Abstract Background A functioning ubiquitin proteasome system (UPS) is essential for a number of diverse cellular processes and maintenance of overall cellular homeostasis. The ability of proteasome inhibitors, such as Velcade, to promote extrinsic apoptotic effects illustrates the importance of the ubiquitin proteasome system in the regulation of death receptor signaling. Here, we set out to define the UPS machinery, particularly the E3 ubiquitin ligases, that repress apoptosis through the extrinsic pathway. A cell-based genome-wide E3 ligase siRNA screen was established to monitor caspase-8 activity following the addition of TRAIL. Results Data from the high-throughput screen revealed that targeting the RING-finger containing E3 ligase Siah2 as well as the signaling platform molecule POSH (SH3RF1) conferred robust caspase-8 activation in response to TRAIL stimulus. Silencing Siah2 or POSH in prostate cancer cells led to increased caspase activity and apoptosis in response to both TRAIL and Fas ligand. The E3 activity of Siah2 was responsible for mediating apoptosis resistance; while POSH protein levels were critical for maintaining viability. Further characterization of Siah2 revealed it to function downstream of early death receptor events in the apoptotic pathway. The observed apoptosis resistance provides one biological explanation for the induction of Siah2 and POSH reported in lung and prostate cancer, respectively. Expanding on an initial yeast-two-hybrid screen we have confirmed a physical interaction between E3 ligases Siah2 and POSH. Utilizing a yeast-two-hybrid mapping approach we have defined the spacer region of POSH, more specifically the RPxAxVxP motif encompassing amino acids 601-607, to be the site of Siah2 binding. Conclusions The data presented here define POSH and Siah2 as important mediators of death receptor mediated apoptosis and suggest targeting the interaction of these two E3 ligases is a promising novel cancer therapeutic strategy.
Supplemental oxygen and exercise ability in chronic obstructive airways disease.
Authors: A C Davidson, R Leach, R J George, D M Geddes
Journal: Thorax (1988)

The influence of supplemental oxygen on exercise performance was assessed in 17 patients with severe airflow obstruction. Exercise capacity was measured by the six minute walking distance, by an endurance walking test, and by an endurance cycling test and comparison was made with performance when the patient was breathing air. In addition, the relation between the flow rate of supplemental oxygen and cycling endurance time was studied. Portable oxygen (41 min-1) carried by the patient increased the mean endurance walking time by 59% and the six minute walking distance by 17%. The endurance time for cycling at a constant work load was increased by 51% with oxygen at a flow rate of 21 min-1, by 88% at 41 min-1, and by 80% at 61 min-1. Supplemental oxygen prolonged the length of time that the patients were able to walk at a fixed speed. It also increased the mean speed achieved during a six minute walk but this was variable and did not occur in all the subjects. The benefit from supplemental oxygen was not cancelled by the effort of carrying the portable cylinder.
Stimulation of Endothelial Cell Prostacyclin Production by Thrombin, Trypsin, and the Ionophore A 23187
Authors: Babette B. Weksler, Christopher W. Ley, Eric A. Jaffe
Journal: Journal of Clinical Investigation (1978)

Prostacyclin (PGI2) is an unstable prostaglandin which inhibits platelet aggregation and serotonin release and causes vasodilation. The PGI2 activity produced by monolayers of cultured human endothelial cells and fibroblasts was measured by the ability of their supernates to inhibit platelet aggregation in platelet-rich plasma, or to inhibit thrombin-induced [14C]serotonin release from aspirin-treated, washed platelet suspensions. Monolayers of cultured human endothelial cells, stimulated with sodium arachidonate, thrombin, the ionophore A 23187, or trypsin, secreted PGI2 into the supernatant medium. Monolayers of fibroblasts produced PGI2 activity only when stimulated by arachidonate. “Resting,” intact monolayers did not produce detectable PGI2, nor did monolayers treated with ADP or epinephrine. Production of PGI2 activity was abolished by treatment of the monolayers with indomethacin, tranylcypromine, or 15-hydroperoxy arachidonic acid. The PGI2 activity of the supernates was destroyed by boiling or acidification. Inhibition of thrombin with diisopropylfluoro-phosphate, and of trypsin with soybean trypsin inhibitor, abolished the stimulation of PGI2 production by these enzymes. Production of thrombin at a site of vascular injury could, by stimulating PGI2 synthesis by endothelial cells adjacent to the injured area, limit the number of platelets involved in the primary hemostatic response and help to localize thrombus formation.
Meiotic and mitotic nondisjunction: lessons from preimplantation genetic diagnosis
Authors: Anver Kuliev, Yury Verlinsky
Journal: Human Reproduction Update (2004)

Direct testing of the outcome of the first and second meiotic divisions has become possible with the introduction of preimplantation genetic diagnosis (PGD) for aneuploidies. Testing of oocytes by fluorescent in situ hybridization (FISH) analysis of the first and second polar bodies showed that more than half of oocytes from the IVF patients aged 35 years and older had chromosomal abnormalities, which originated from errors in meiosis I or meiosis II, or both: 41.9% of oocytes were aneuploid after meiosis I and 37.3% aneuploid after meiosis II, with 29.1% of these oocytes having both meiosis I and meiosis II errors. As a result, one third of oocytes detected as normal after meiosis I contained the meiosis II errors, and two thirds of those with meiosis II errors were already abnormal following meiosis I. Although the rates of chromosomal abnormalities deriving from meiosis I and II were comparable, meiosis I errors predominantly resulted in extra chromosome (chromatid) material in oocytes, in contrast to a random distribution of extra and missing chromatids after meiosis II. The majority of meiosis I abnormalities were represented by chromatid errors, which seem to be the major source of chromosomal abnormalities in the resulting embryos. Approximately one third of aneuploid oocytes deriving from sequential errors in the first and second meiotic divisions resulted in a balanced karyotype, representing a possible phenomenon of "aneuploidy rescue" during the second meiotic division. However, the majority of the embryos resulting from such oocytes appeared to be abnormal for the same or different chromosome(s), or were mosaic, suggesting a possible predisposition of the resulting embryos to further mitotic errors. Although the origin of a high frequency of mosaicism at the cleavage stage is not sufficiently understood, the mosaic embryos may originate from the chromosomally abnormal oocytes, as a result of a "trisomy rescue" mechanism during the first mitotic divisions, which renders polar body FISH analysis to have important clinical value for reliable pre-selection of aneuploidy-free embryos for transfer.
Treatment of genetically obese mice with the iminosugar N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin reduces body weight by decreasing food intake and increasing fat oxidation
Authors: Mirjam Langeveld, Sjoerd A.A. van den Berg, Nora Bijl, Silvia Bijland, Cindy P. van Roomen, Judith H. Houben-Weerts, Roelof Ottenhoff, Sander M. Houten, Ko Willems van Dijk, Johannes A. Romijn, Albert K. Groen, Johannes M. Aerts, Peter J. Voshol
Journal: Metabolism (2011)
Attributable Mortality of Ventilator-Associated Pneumonia
Authors: Maarten Bekaert, Jean-Francois Timsit, Stijn Vansteelandt, Pieter Depuydt, Aurélien Vésin, Maité Garrouste-Orgeas, Johan Decruyenaere, Christophe Clec'h, Elie Azoulay, Dominique Benoit
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Rationale: Measuring the attributable mortality of ventilator-associated pneumonia (VAP) is challenging and prone to different forms of bias. Studies addressing this issue have produced variable and controversial results.Objectives: We estimate the attributable mortality of VAP in a large multicenter cohort using statistical methods from the field of causal inference.Methods: Patients (n = 4,479) from the longitudinal prospective (1997–2008) French multicenter Outcomerea database were included if they stayed in the intensive care unit (ICU) for at least 2 days and received mechanical ventilation (MV) within 48 hours after ICU admission. A competing risk survival analysis, treating ICU discharge as a competing risk for ICU mortality, was conducted using a marginal structural modeling approach to adjust for time-varying confounding by disease severity.Measurements and Main Results: Six hundred eighty-five (15.3%) patients acquired at least one episode of VAP. We estimated that 4.4% (95% confidence interval, 1.6–7.0%) of the deaths in the ICU on Day 30 and 5.9% (95% confidence interval, 2.5–9.1%) on Day 60 are attributable to VAP. With an observed ICU mortality of 23.3% on Day 30 and 25.6% on Day 60, this corresponds to an ICU mortality attributable to VAP of about 1% on Day 30 and 1.5% on Day 60.Conclusions: Our study on the attributable mortality of VAP is the first that simultaneously accounts for the time of acquiring VAP, informative loss to follow-up after ICU discharge, and the existence of complex feedback relations between VAP and the evolution of disease severity. In contrast to the majority of previous reports, we detected a relatively limited attributable ICU mortality of VAP.
EXPERIMENTAL BONE MARROW REACTIONS
Authors: Gulli Lindh Muller
Journal: The Journal of Experimental Medicine (1926)

1. The effect produced by the intravenous administration of collargol on the bone marrow of rabbits varies directly with the amount of collargol injected, and three fairly well defined stages could be recognized. (a) An initial stage after comparatively few and small doses, with erythrocytic and endothelial hyperplasia in the bone marrow and with evidences of this stimulation in the peripheral blood in the form of young erythrocytes and normoblasts. (b) An intermediary stage which followed the injection of larger amounts of collargol, and which was characterized by a predominant myeloid hyperplasia. (c) A final stage with marked bone marrow aplasia and with colloidal silver deposited in endothelial cells, as well as in clasmatocytes. This was associated with a high grade anemia with low color index, resembling aplastic anemia in its main features. This stage terminated fatally. 2. There was no evidence of injury to blood cells in the peripheral circulation. The erythrocytic bone marrow aplasia was present before any appreciable decrease of red blood cells was found in the peripheral blood. 3. The results were less clear-cut in a series of rats, but anemia of a similar type was produced in all animals when sufficiently large doses were injected. 4. Splenectomy did not alter the course in rats materially. 5. It is fair to conclude that the cause of the anemia produced may be sought in the deviation of the parental endothelial cell toward clasmatocyte formation at the expense of the development of erythrocytes. 6. It is suggested that the results may be offered in support of the theory of the endothelial origin of both clasmatocytes and red blood cells.
Surgery for non-small cell lung cancer: systematic review and meta-analysis of randomised controlled trials
Authors: G Wright
Journal: Thorax (2006)

<b>Background:</b> Surgery is considered the treatment of choice for patients with resectable stage I and II (and some patients with stage IIIA) non-small cell lung cancer (NSCLC), but there have been no previously published systematic reviews. <b>Methods:</b> A systematic review and meta-analysis of randomised controlled trials was conducted to determine whether surgical resection improves disease specific mortality in patients with stages I–IIIA NSCLC compared with non-surgical treatment, and to compare the efficacy of different surgical approaches. <b>Results:</b> Eleven trials were included. No studies had untreated control groups. In a pooled analysis of three trials, 4 year survival was superior in patients undergoing resection with stage I–IIIA NSCLC who had complete mediastinal lymph node dissection compared with lymph node sampling (hazard ratio estimated at 0.78 (95% CI 0.65 to 0.93)). Another trial reported an increased rate of local recurrence in patients with stage I NSCLC treated with limited resection compared with lobectomy. One small study reported a survival advantage among patients with stage IIIA NSCLC treated with chemotherapy followed by surgery compared with chemotherapy followed by radiotherapy. No other trials reported significant improvements in survival after surgery compared with non-surgical treatment. <b>Conclusion:</b> It is difficult to draw conclusions about the efficacy of surgery for locoregional NSCLC because of the small number of participants studied and methodological weaknesses of the trials. However, current evidence suggests that complete mediastinal lymph node dissection is associated with improved survival compared with node sampling in patients with stage I–IIIA NSCLC undergoing resection.
Cardiac Arrest or Bradycardia Following Venipuncture
Authors: R. Brian Smith
Journal: JAMA (1979)

To the Editor.—  The correspondence on cardiac arrest or severe bradycardia (236:1846, 1976; 239:403, 1978; 241:134, 1979) following routine venipuncture describes a frequent and potentially lethal problem. For treatment, one author describes intravenous administration of atropine sulfate and another, cardiopulmonary resuscitation 1 with epinephrine and steroids. Prevention of syncope with the concomitant bradycardia from venipuncture in patients in whom this develops has not been mentioned except for having the patient lie horizontally.  Anesthesiologists frequently observe patients with bradycardia and severe hypotension following venipuncture, even when the patients are lying horizontally on the operating table. Most of these patients have been premedicated with atropine and a sedative (narcotic, barbiturates, or tranquilizer). I prefer to treat these cases with intravenous ephedrine titrated in 10-mg aliquots, providing some cardiac output is present. This is chosen over atropine because of the inotropic and vasoconstriction properties of ephedrine, in addition to the chronotropic effect. The results
A novel liver-specific zona pellucida domain containing protein that is expressed rarely in hepatocellular carcinoma
Authors: Zhi-Gang Xu, Jian-Jun Du, Xin Zhang, Zhi-Hong Cheng, Zhen-Zhong Ma, Hua-Sheng Xiao, Li Yu, Zhi-Qin Wang, Yu-Yang Li, Ke-Ke Huo, Ze-Guang Han
Journal: Hepatology (2003)

We currently identified a liver–specific gene that encodes a novel zona pellucida (ZP) domain–containing protein named liver–specific ZP domain–containing protein (LZP). The full–length complementary DNA (cDNA) of human LZP has 2,255 bp with a complete open reading frame (ORF) of 1,635 bp. The gene is localized on chromosome 10q21.3 and spans 40 kb with 9 encoding exons and 8 introns. The deduced protein sequence has 545 amino acid residues, with an N –terminal signal peptide followed by 3 epidermal growth factor (EGF)–like domains and a ZP domain in C–terminal section. Interestingly, human LZP is expressed specifically in liver out of 23 tissues examined, and its mouse counterpart was detected at very early stage during embryo development. Moreover, LZP can be secreted into blood, albeit the protein was localized mainly on the nuclear envelop of hepatocytes. Most importantly, LZP is down–regulated in hepatocellular carcinoma (HCC) and HCC cell lines; meanwhile, the decreased level of hLZP messenger RNA (mRNA) could, at least in some HCC samples, be related to the methylation status of the putative LZP promoter. However, overexpression of hLZP in HCC cell line SMMC–7721 and human liver cell line L02 by stable cell transfection did not inhibit cell growth, implying that the down–regulation of hLZP in HCC might be a consequence of the dedifferentiation involved in hepatocarcinogenesis. In conclusion, these data suggest that LZP is a liver–specific protein involved possibly in hepatocellular function and development, and the protein could be used as potential negative biomarker for HCC pathologic diagnosis.
Phase I Combining a P-Glycoprotein Inhibitor, MS209, in Combination with Docetaxel in Patients with Advanced Malignancies
Authors: Véronique Diéras, Jacques Bonneterre, Valérie Laurence, Marian Degardin, Jean-Yves Pierga, Marie-Edith Bonneterre, Sandrine Marreaud, Denis Lacombe, Pierre Fumoleau
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The purpose of this study was to investigate the safety and tolerability of MS209, a potent inhibitor of P-glycoprotein, when given in combination with docetaxel and to determine whether MS209 affects docetaxel pharmacokinetics. Experimental design: Patients with advanced solid malignancies were eligible for this phase I trial. Docetaxel as 1-hour infusion was given alone during the first cycle. MS209 was introduced as of cycle 2 and given orally 30 minutes after docetaxel infusion. The dose escalation scheme followed a modified Fibonacci model with six steps (docetaxel, 60-100 mg/m2 and MS209, 300-1,200 mg per body). Results: A total of 30 patients were treated at five dose levels. Dose-limiting toxicities were febrile neutropenia, infection, stomatitis, dysphagia, and fatigue. The maximum tolerated dose was reached at level 5 (docetaxel, 80-MS: 1,200). Pharmacokinetic analysis failed to show a strong pharmacokinetic interaction between the two compounds, but at the highest dose levels, there is a trend to an increase of docetaxel AUC when this agent is given in combination with MS209. Conclusion: MS209 can be given in combination with docetaxel, with limited effect on docetaxel toxicity or pharmacokinetics.
Outcomes of lung transplantation for cystic fibrosis in a large UK cohort
Authors: G Meachery, A De Soyza, A Nicholson, G Parry, A Hasan, K Tocewicz, T Pillay, S Clark, J L Lordan, S Schueler, A J Fisher, J H Dark, F K Gould, P A Corris
Journal: Thorax (2008)

<h3>Background:</h3> Lung transplantation is an important option to treat patients with advanced cystic fibrosis (CF) lung disease. The outcomes of a large UK cohort of CF lung transplantation recipients is reported. <h3>Methods:</h3> Retrospective review of case notes and transplantation databases. <h3>Results:</h3> 176 patients with CF underwent lung transplantation at our centre. The majority (168) had bilateral sequential lung transplantation. Median age at transplantation was 26 years. Diabetes was common pretransplantation (40%). Polymicrobial infection was common in individual recipients. A diverse range of pathogens were encountered, including the <i>Burkholderia cepacia</i> complex (BCC). The bronchial anastomotic complication rate was 2%. Pulmonary function (forced expiratory volume in 1 s % predicted) improved from a pretransplantation median of 0.8 l (21% predicted) to 2.95 l (78% predicted) at 1 year following transplantation. We noted an acute rejection rate of 41% within the first month. Our survival values were 82% survival at 1 year, 70% at 3 years, 62% at 5 years and 51% at 10 years. Patients with BCC infection had poorer outcomes and represented the majority of those who had a septic death. Data are presented on those free from these infections. Bronchiolitis obliterans syndrome (BOS) and sepsis were common causes of death. Freedom from BOS was 74% at 5 years and 38% at 10 years. Biochemical evidence of renal dysfunction was common although renal replacement was infrequently required (&lt;5%). <h3>Conclusion:</h3> Lung transplantation is an important therapeutic option in patients with CF even in those with more complex microbiology. Good functional outcomes are noted although transplantation associated morbidities accrue with time.
Long-Term Cardiovascular Risk in Type 2 Diabetic Compared With Nondiabetic First Acute Myocardial Infarction Patients
Authors: J. Francisco Cano, Jose M. Baena-Diez, Josep Franch, Joan Vila, Susana Tello, Joan Sala, Roberto Elosua, Jaume Marrugat
Journal: Diabetes Care (2010)

OBJECTIVE The aim of this study was to determine whether long-term cardiovascular risk differs in type 2 diabetic patients compared with first acute myocardial infarction patients in a Mediterranean region, considering therapy, diabetes duration, and glycemic control. RESEARCH DESIGN AND METHODS A prospective population-based cohort study with 10-year follow-up was performed in 4,410 patients aged 30–74 years: 2,260 with type 2 diabetes without coronary heart disease recruited in 53 primary health care centers and 2,150 with first acute myocardial infarction without diabetes recruited in 10 hospitals. We compared coronary heart disease incidence and cardiovascular mortality rates in myocardial infarction patients and diabetic patients, including subgroups by diabetes treatment, duration, and A1C. RESULTS The adjusted hazard ratios (HRs) for 10-year coronary heart disease incidence and for cardiovascular mortality were significantly lower in men and women with diabetes than in myocardial infarction patients: HR 0.54 (95% CI 0.45–0.66) and 0.28 (0.21–0.37) and 0.26 (0.19–0.36) and 0.16 (0.10–0.26), respectively. All diabetic patient subgroups had significantly fewer events than myocardial infarction patients: the HR of cardiovascular mortality ranged from 0.15 (0.09–0.26) to 0.36 (0.24–0.54) and that of coronary heart disease incidence ranged from 0.34 (0.26–0.46) to 0.56 (0.43–0.72). CONCLUSIONS Lower long-term cardiovascular risk was found in type 2 diabetic and all subgroups analyzed compared with myocardial infarction patients. These results do not support equivalence in coronary disease risk for diabetic and myocardial infarction patients.
Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: A report from the SHOCK trial registry
Authors: Rupert Fincke, Judith S. Hochman, April M. Lowe, Venu Menon, James N. Slater, John G. Webb, Thierry H. LeJemtel, Gad Cotter
Journal: Journal of the American College of Cardiology (2004)