tbuckley/cabot-search huggingface dataset:
Abstract 18938: Prognostically Important Myocardial Infarctions are Markedly Underreported in Patients Undergoing Percutaneous Coronary Intervention: Insights from CHAMPION PHOENIX
Authors: Kenneth W Mahaffey, Deepak L Bhatt, Gregg W Stone, C. Michael Gibson, P. Gabriel Steg, Christian W Hamm, Matthew D Wilson, Stacey Mangum, Sergio Leonardi, Matthew J Price, Tiepu Liu, Simona Skerjanec, Jayne Prats, Harvey D White, Robert A Harrington
Journal: Circulation (2014)

Objectives: In the CHAMPION PHOENIX trial, cangrelor was shown to reduce the primary composite endpoint of death, myocardial infarction (MI), ischemia driven revascularization, or stent thrombosis at 48 hours. We explored the effect of cangrelor on MI including different types of MI and the impact of event adjudication. Methods: A central clinical events committee (CEC) systematically identified and adjudicated MI events using pre-defined MI criteria. 30-day death was modeled using baseline characteristics including PCI related MIs. Results: Overall, 10,942 patients were included in the primary analyses; 462 patients had at least one MI at 48 hours reported by the CEC (207 [3.8 %] cangrelor; 255 [4.7 %] clopidogrel; OR 0.80; 95% CI [0.67, 0.97]; P = 0.022), and 143 patients had at least one MI at 48 hours reported by the site investigators (60 [1.1%] cangrelor; 83 [1.5%] clopidogrel; OR 0.72; 95% CI [0.52, 1.01]; P = 0.053). The Table shows the MI types reported by the CEC, the site investigator reported MIs and treatment comparisons. Of the 462 MIs reported by the CEC, 92 (19.9%) were also reported by site investigators, and 370 (80.1%) were not (170 in cangrelor group, 200 in clopidogrel group). Of the 143 MI events reported by the Site Investigators, CEC reported an MI in 92 (64.3%). CEC reported MI events were independently predictive of 30 day mortality OR 3.48; 95% CI (2.00 - 6.03). Conclusions: In patients with ACS undergoing PCI, CEC procedures identified three times as many MIs as the site investigators reported. Site investigators under-report MIs related to percutaneous coronary intervention. MIs reported by the CEC were independently associated with worse 30-day death. The overall efficacy of cangrelor was similar on MIs reported by the site investigators or the CEC.
Abstract 3484: High Plasma Levels of Endogenous Free Dopamine Predict an Adverse Outcome in Patients with Heart Disease and Chronic Kidney Disease
Authors: Keita Sano, Yasushi Kodama, Mitsumasa Hirano, Isao Takishima, Aritaka Makino, Takamitsu Nakamura, Yoshinobu Kitta, Kennichi Kawabata, Junei Obata, Kiyotaka Kugiyama
Journal: Circulation (2008)

Sympathetic activity is heightened in chronic kidney disease (CKD). The increased sympathetic activity is a risk of future cardiovascular disease (CVD) events. Dopamine, a precursor of norepinephrine biosynthesis, is metabolized in the kidney and excreted into urine, and its plasma levels are increased in renal dysfunction. Thus, we examined whether plasma levels of endogenous dopamine may be related to future CVD events in patients with CKD. A total of 840 patients in stable condition with chronic heart disease (622 patients with ischemic heart disease and 218 with non-ischemic heart disease) (586 patients with GFR ≥ 60 ml/min/1.73 m 2 [normal/mild CKD]; 153 patients with 60 &gt; GFR ≥ 30 [moderate CKD]; 101 patients with 30 &gt; GRF [advanced CKD]) were prospectively followed-up for 5 years or until one of the following CVD events: cardiac death, non-fatal myocardial infarction, unstable angina pectoris requiring unplanned revascularization, worsening heart failure requiring hospitalization, or stroke. Plasma levels of endogenous free dopamine at entry were measured by high-performance liquid chromatography. Patients with a higher stage of CKD had higher dopamine levels than patients with a lower stage (63.0 ± 5.5, 45.0 ± 5.1, and 26 ± 1.2 pg/mL, respectively, ρ = 0.54, p &lt; 0.0001 Spearman rank correlation test). During the follow-up period, 233 patients had CVD events (cardiac death in 54, myocardial infarction in 18, others events in 161) (113 events [19%] in normal/mild CKD, 64 [42%] in moderate CKD, and 56 [55%] in advanced CKD). In patients with moderate CKD and advanced CKD, higher dopamine levels (≥ 40 pg/mL, defined by ROC analysis) were the strongest predictor of CVD events (HR 2.1 and 3.3, 95% CI 1.2 – 3.7 and 1.5 – 7.2, p = 0.006 and 0.003, respectively) in a multivariate Cox hazards analysis using plasma norepinephrine and BNP levels, hypertension, and hyperlipidemia as covariates. In contrast, dopamine levels did not have predictive value in normal/mild CKD (HR 1.2, 95% CI 0.7 – 2.0, p = 0.5). High plasma levels of endogenous free dopamine are a risk factor for future CVD in patients with CKD independently of norepinephrine levels. Increases in plasma endogenous free dopamine levels may serve as a mechanistic link between CKD and CVD.
Abstract 12393: Effects of Continuous Triiodothyronine Infusion on Citric Acid Cycle in the Normal Immature Swine Heart under Extracorporeal Membrane Oxygenation in vivo
Authors: Masaki Kajimoto, Colleen M O'Kelly Priddy, Dolena R Ledee, Chun Xu, Nancy Isern, Aaron K Olson, Michael A Portman
Journal: Circulation (2013)

Background: Extracorporeal membrane oxygenation (ECMO) is frequently used in infants with postoperative cardiopulmonary failure. ECMO also suppresses circulating triiodothyronine (T3) levels and mo...
Comprehensive Cardiovascular Risk Factor Control Improves Survival
Authors: Vera Bittner, Marnie Bertolet, Rafael Barraza Felix, Michael E. Farkouh, Suzanne Goldberg, Kodangudi B. Ramanathan, J. Bruce Redmon, Laurence Sperling, Martin K. Rutter
Journal: Journal of the American College of Cardiology (2015)
Combination is still widely used
Authors: R W R Farrell
Journal: BMJ (1995)

EDITOR,--The use of cocaine and adrenaline paste is a controversial issue among otolaryngologists.1 In 1991 the British Association of Otolaryngologists—Head and Neck Surgeons surveyed all consultant surgeons who were members and found that 63.5% used cocaine without adrenaline, 19.5% used cocaine and adrenaline, and 17% used cocaine with and without adrenaline.2 Of the 312 who used cocaine, …
Serious asthma exacerbations in a hospital setting
Authors: Teresa Martín, Fernando Meneses, Margarida Castanho, Helena Grumete, Jorge Roldão Vieira
Journal: European Respiratory Journal (2014)

Serious asthma exacerbations (SAE), defined as at least 1 hospitalization, ICU stay or mechanical ventilation in the previous year, are part of the definition of uncontrolled asthma. The aim of this study was to characterize patients (pts) with SAE admitted in a tertiary general hospital as well as readmissions in the 1 st  year after discharge.   Methods : The authors reviewed the clinical records of all pts admitted with SAE in 2012 dividing them in 2 groups: with or without inhaled corticosteroid (ICS) treatment before admission.   Results:  From a total of 38 pts, mean age 53,5y (17-93), 13 were male (34,2%) and 6 were smokers (13.35%). Both groups had 19 pts - ICS group, mean 57,8y (26-93); non ICS group, mean 49,1y (17-80).  In the non ICS group the duration of lack of asthma control before admission was longer. In the ICS group there was a higher proportion of respiratory tract infections (52,6% vs 15,8%) and a longer hospitalization.  There were no differences in the need of mechanical ventilation between the 2 groups (4 pts per group – 21%). There was 1 fatal exacerbation in the ICS group. In the ICS group there was a lower rate of emergency room visits and hospitalizations than in the non ICS group (26% vs 47%; 5,2% vs 21%).   Conclusion:  Despite being a small series of pts, our study recognized the importance of SAE as a major risk factor in asthma, confirmed by the high number of ventilated pts. ICS as a maintenance therapy did not prevent exacerbations suggesting a more severe disease. ICS were associated with respiratory tract infections, confirming the need of vaccination in this population. The higher rate of emergency room visits and hospitalizations in pts without previous ICS is possibly due to a poorer compliance.
Abstract 3560: Use of Hyperpolarized Magnetic Resonance for Non-Invasive Observation of Metabolic Regulation
Authors: Marie A Schroeder, Lisa C Heather, Helen J Atherton, Kieran Clarke, George K Radda, Damian J Tyler
Journal: Circulation (2008)

Hyperpolarized magnetic resonance (HP MR) has enabled real time visualization of in vivo metabolism. In this study, we postulated that HP MR could also non-invasively provide a measure of metabolic regulation. We focused on regulation of pyruvate dehydrogenase (PDH), a highly controlled enzyme that catalyzes the oxidation of pyruvate to acetyl CoA and CO2/HCO3-. We compared PDH flux in conditions of normal and attenuated enzyme activity, and in the presence of normal and augmented Krebs cycle flux, to determine the contributions of PDH activity and end product inhibition to enzyme regulation. Six rats were examined in the fed and fasted states (to modulate PDH activity), with 40 μmol HP 13C1-pyruvate alone and 40 μmol HP pyruvate co-infused with 40 μmol malate (to manipulate Krebs cycle flux/acetyl CoA uptake). HP tracer was infused into the rats in an MR scanner and cardiac spectra were acquired every second for 1 min. Conversion of pyruvate to 13HCO3-was monitored and the 13HCO3-/pyruvate ratio was used as a marker of PDH flux. Infusion of malate increased PDH flux by 31% compared with pyruvate alone, indicating that removal of acetyl CoA by incorporation into the Krebs cycle increased PDH flux. PDH flux was 57% lower in fasted rats injected with pyruvate alone compared with fed rats, and did not change with malate co-infusion. Here, low PDH activity prevented additional enzyme flux. These results suggest that end product inhibition limits fed state PDH flux, whereas PDH activity regulates pyruvate oxidation in the fasted state. In conclusion, this study has provided evidence that HP MR may be useful to obtain details of metabolic regulation, rather than just reflecting metabolic state. Figure 1 Bicarbonate/pyruvate ratio in fed and fasted rats, following an injection of pyruate or pyruate plus malate. In fed rats, co-infusion of malate increased PDH flux by 31% compared with injection of pyruvate alone (*p=0.02). Fasting reduced PDH flux by 57% (**p=0.002) following injection of pyruvate alone. Co-infusion with malate did not affect PDH flux in fasted rats.
LO6 : A two-stage genome-wide association study identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis
Authors: S. Buch, F. Stickel, E. Trépo, M. Way, A. Herrmann, H.D. Nischalke, M. Brosch, J. Rosendahl, T. Berg, J. Fischer, M. Ridinger, M. Rietschel, A. McQuillin, J. Frank, F. Kiefer, S. Schreiber, W. Lieb, M. Soyka, C. Datz, R. Schmelz, S. Brückner, N. Wodarz, J. Deviére, N. Clumeck, C. Sarrazin, F. Lammert, T. Gustot, P. Deltenre, H. Völtzke, M.M. Lerch, J. Mayerle, F. Eyer, C. Schafmayer, S. Cichon, M.M. Nöthen, M. Nothnagel, D. Ellinghaus, A. Franke, S. Zopf, C. Hellerbrand, C. Moreno, D. Franchimont, M.Y. Morgan, J. Hampe
Journal: Journal of Hepatology (2015)
Inactivated tumor infiltrating CD8+ T cells in primary and metastatic osteosarcoma
Authors: Dipyaman Ganguly, Austin Raymond, Dafydd Thomas, David Lucas, Kenneth Lee, Dennis Hughes
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

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Introduction:

Tumor infiltrating lymphocytes (TILs) have been documented in different types of tumors both in humans and mouse models. Many studies have found TILs to be favorable prognostic factors in patients with different tumors. Tumor cells may evade immune surveillance by different immunoregulatory strategies. Osteosarcoma, comprising 45% of all bone sarcomas, is a common solid tumor in adolescents and children. In the present study we determined the extent of TIL-infiltration in the tumor stroma in both primary osteosarcomas and metastatic osteosarcomas in lung using archival sections of metastatic lung osteosarcoma and a tissue microarray (TMA) generated from primary tumors.

Methods:

We performed immunohistochemical analysis of archival FFPE sections from patient-derived pulmonary metastatic osteosarcoma nodules (N=15) and a TMA of primary osteosarcomas (N=27) to assess the infiltration of CD8+ T cells and their activational status based on Granzyme-B positivity. We also assessed infiltration of FoxP3+ regulatory T cells (T-regs) in tumor stroma in the same specimens. The data obtained from immunohistochemical analysis were correlated with the clinical outcomes and histological grades for individual patients.

Results:

12 of 15 specimens (80%) of metastatic lung osteosarcoma showed infiltration by CD8+ T cells in the tumor stroma; while in only one sample (8.3%) did these cells express Granzyme-B. CD8+ T cells present in adjacent lung tissue expressed Granzyme-B, indicating functional responsiveness and serving as an internal positive control for each sample. In a tissue microarray of primary jaw osteosarcomas only 2 of 27 specimens (7.4%) showed intratumor CD8+ T cell infiltration; none were positive for Granzyme B. Of the 11 metastatic specimens showing inactivation of infiltrating CTLs, only 3 (27%) showed infiltrating FoxP3+ T-regs in tumor stroma. Thus concomitant infiltration of T-regs did not account for the CTL inactivation in all specimens.

Discussion:

Our data show that osteosarcoma evades immune response by specifically anergizing TILs by T-reg dependent and independent mechanisms. There have been multiple clinical trials attempting eradication of osteosarcomas by activating anti-tumor immune response, e.g. GM-CSF inhalation therapy and use of muramyl tripeptide-phosphatidylethanolamine (MTP-PE) for lung metastases of osteosarcoma. We envisage that these treatments may work by circumventing immunoregulatory strategies taken up by tumor cells. Elucidation of these mechanisms might thus prove to be extremely important in designing rational immunotherapeutic strategies.
Binding of mTOR (Mammalian Target of Rapamycin) to the Raptor-eIF4E-4EBP1 complex changes during myogenic differentiation.
Authors: Lili Shu, Peter Houghton
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2027 

The mammalian target of rapamycin, (mTOR), controls cell growth and proliferation via regulating ribosomal S6K1 and 4EBP1, the suppressor of eukaryotic initiation factor 4E (eIF4E, the mRNA cap-binding protein). Rapamycin, a very specific inhibitor of mTOR signaling inhibits myogenic differentiation in C2C12 myoblasts. However, exactly why mTOR signaling is essential in myogenic differentiation remains obscure. In cells mTOR is thought to exist in a large complex (> 1 megaDa) with several proteins including Raptor and GβL, and possibly other proteins. Previous studies reported that Raptor binds to mTOR though HEAT regions and binds to 4EBP1 through C terminal TOS motif of 4EBP1 to regulate the mTOR pathway. However, it is unknown whether mTOR complexes are regulated during myogenic differentiation. In this study we have analyzed complexes associated with eIF4E under conditions of growth (growth medium, GM) or differentiation (differentiation medium, DM). Under both conditions eIF4E binds to 7-methyl-GTP-sepharose-4B resin, and can be readily isolated. Using this ‘pull-down’ technique we have analyzed proteins bound to eIF4E under GM and DM. When C2C12 cells were cultured in GM, 4EBP1 and Raptor were associated with eIF4E, but mTOR was not detected in the complex. When C2C12 cells were cultured in DM for 24 hrs, mTOR was strongly detected in the eIF4E complex. These results suggest a conformational change during early differentiation that yields tight binding of mTOR to Raptor. Under nutrient restriction (low amino acids) Raptor binds more tightly to mTOR and inhibits mTOR-dependent signaling (Kim et al. Cell 110:163, 2002 ). To determine whether the mTOR-Raptor complex induced under DM also inhibited signaling, we examined the phosphorylation of two downstream targets of mTOR, p70S6K (Thr389) and 4EBP1 (Thr37). In contrast to the effect of amino acid deficiency, mTOR signaling is not inhibited in differentiating myoblasts. These results suggest that the affinity of mTOR-Raptor interactions increases during myogenic differentiation, and may be essential for terminal differentiation. The effect of rapamycin on the eIF4E-4EBP1-Raptor-mTOR complex in differentiating myoblasts will be presented. Supported by PHS grant CA77776
Subclonal Driver Mutations Predict Shorter Progression Free Survival in Chronic Lymphocytic Leukemia Following First-Line Chemo(immuno)Therapy: Results from the CLL8 Trial
Authors: Dan A. Landau, Eugen Tausch, Amaro N Taylor-Weiner, Sebastian Bottcher, Jasmin Bahlo, Chip Stewart, Jennifer Edelmann, Sandra Kluth, Daniel Mertens, Michael Kneba, Sabrina Kless, Carrie Sougnez, Kirsten Fischer, Matthias Ritgen, Stacey Gabriel, Eric Lander, Hartmut Dohner, Michael Hallek, Gad Getz, Donna Neuberg, Stephan Stilgenbauer, Catherine J. Wu
Journal: Blood (2014)
Tubal subfertility
Authors: Y. Khalaf
Journal: BMJ (2003)

Patent fallopian tubes are a prerequisite for normal human fertility. However, patency alone is not enough—normal function is crucial. Although patients often view them as either open or “blocked,” the fallopian tubes are highly specialised organs. They have a critical role in picking up eggs and transporting eggs, sperm, and the embryo. The fallopian tubes are also needed for sperm capacitation and egg fertilisation. Because the egg is fertilised in the fallopian tubes and the first stages of development of the embryo occur during its four day journey to the uterine cavity, the tubes are also important in nutrition and development. The fallopian tubes are vulnerable to infection and surgical damage, which may impair function by affecting the delicate fimbriae or the highly specialised endosalpinx. A fallopian tube obstruction occurs in 12% to 33% of infertile couples,1 and so tubal patency should be investigated early.
Abstract 5037: Immunotherapy meets epigenetics: GP96-Ig cellular vaccine genetic signature is modulated by the inhibition of histone modifications
Authors: George J. Fromm, Neal Schilling, Taylor H. Schreiber
Journal: Cancer Research (2015)

Abstract A number of novel cancer treatment strategies have been identified and developed over the last decade with hopes of eradicating a diverse range of cancers, however the molecular mechanisms behind patient immune responses and tumor microenvironment signaling are complex, and have often hindered the translation of these ideas into successful patient treatments. Two modalities at the forefront of these potential blockbuster strategies are combinatorial immunotherapy and epigenetic manipulation. These approaches are supported by compelling clinical data, but have been encumbered by a number of factors including: adverse event profiles, complicated manufacturing and regulatory issues, toxicity due to non-specific small molecule interactions, limited overlap in patient/therapy antigen presentation, and exorbitant cost of biological treatments. To circumvent a number of these limitations, we have taken a novel approach by engineering allogeneic cellular vaccines tailored to specific cancers, that secrete heat-shock protein gp96-Ig and achieve high-frequency polyclonal CD8+ T cell responses to femto-molar concentrations of tumor antigens through antigen cross-priming in vivo. Using genomics (RNA-sequencing) we identified differential mRNA expression levels genome-wide between normal bladder tissue, our proprietary bladder cancer cellular vaccine Vesigenurtacel-L or HS410, and patient bladder tumor biopsy samples, to generate a genomic signature of Bladder Cancer Altered Genes, or BCAGs. Next, we examined a number of small molecule inhibitors of epigenetic modifications (i.e. histone deacetylases or HDACs), and determined their effect on BCAG expression and antigen secretion in HS410 cells. We find that the inhibition of certain HDACs results in decreased proliferation, dampened secretion of gp96-Ig, and attenuated expression of tumor specific genes. Together our work has defined the pattern of gene dysregulation genome-wide in bladder cancer and shown that epigenetic modifiers are capable of modulating the expression of many of these genes, which may be important for the efficacy of our cancer vaccine strategy. Therefore, epigenetic manipulation may present an attractive means to fine-tune gene expression programs and maximize antigen secretion thereby increasing vaccine potency and the ability of a single vaccine to target a variety of cancer types. Citation Format: George J. Fromm, Neal Schilling, Taylor H. Schreiber. Immunotherapy meets epigenetics: GP96-Ig cellular vaccine genetic signature is modulated by the inhibition of histone modifications. [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 5037. doi:10.1158/1538-7445.AM2015-5037
Management for Doctors: The importance of quality: sharing responsibility for improving patient care
Authors: F. Moss, P. Garside
Journal: BMJ (1995)

tional needs should be taken up, and the development of a continuing medical education industry based on uncertain evidence of effectiveness, as has occurred in other countries, should be avoided.Linking audit and peer review to continuing medical education would allow anxieties about the effectiveness of continuing medical education to be addressed, would permit local ownership, and would allow doctors to choose learning methods that both meet their own educational needs and fit in with their personal learning styles.Such a link would avoid the need to introduce sanctions as, with audit as the monitoring instrument, participation and the attainment of satisfactory standards of performance would be documented.The emphasis on local provision would also help to overcome the conflict of interests that might arise when a royal college both approved or accredited continuing medical education programmes and also provided continuing medical education. ConclusionsIt is and always has been a fundamental requirement for any professional to keep up to date in his or her profession.IJke breast milk and a high fibre diet, continuing medical education is without doubt good for use.Why then has activity erupted among those who wish to manage, control, and codify continuing medical education?Britain is rapidly moving down the road, well trodden in other countries, towards a rigid, formalised, and policed continuing medical education industry.Continuing medical education is in danger of becoming a behemoth, a lumbering, unbending monster, and this burgeoning industry is based on assumptions that remain unproved.A shift from centralised to local provision linked to peer review and audit will avoid these hazards.* Making customers' needs a priority for everyone * Defining quality in terms of customers' needs * Recognising the existence of intemal customers and suppliers * Examining the process of production rather than individual performance for explanations of flaws or poor quality * Using sound measurement to understand how to improve quality * Removing barriers between staff and promoting effective team work * Promoting training for everyone * Involving the whole work force in the task of improving quality * Understanding that quality improvement is a con- tinuous process Key point summary * Quality improvement is on the agenda * Total quality management has a role in the NHS * Problems with quality are often the result of flawed processes rather than incompetent individuals * Sound management underpins clinical activity, and the two combined effect improvements in quality * A collective view of care requires input from all relevant professionals * Good, reliable data on the processes of work are vital * Improving quality is a continual process