tbuckley/cabot-search huggingface dataset:
Italians celebrate success of treatment no longer legal in Italy
Authors: Fabio Turone
Journal: BMJ (2004)

A 5 year old child with Cooley's anaemia has been successfully treated in Italy using cord blood stem cells from his new born twin brothers.

The case has been controversial in Italy because the parents initially went to Turkey to have in vitro fertilisation; preimplantation diagnosis of the fetus to ensure that the baby would not have his or her brother's condition; and tissue typing to ensure a good match for the transplant. Italy has a restrictive law on assisted reproduction (3 January, p 9 and 5 June, p 1334), and the initial procedure which the parents chose to have in Turkey (because they are Turkish) is no longer legal in Italy.

The couple had a …
Monitoring adverse events of low-dose glucocorticoid therapy: EULAR recommendations for clinical trials and daily practice
Authors: M C van der Goes, J W G Jacobs, M Boers, T Andrews, M A M Blom-Bakkers, F Buttgereit, N Caeyers, M Cutolo, J A P Da Silva, L Guillevin, J R Kirwan, J Rovensky, G Severijns, S Webber, R Westhovens, J W J Bijlsma
Journal: Annals of the Rheumatic Diseases (2010)

Objective To develop recommendations on monitoring for adverse events (AEs) of low-dose glucocorticoid (GC) therapy (≤7.5 mg prednisone or equivalent daily) in clinical trials and daily practice. Methods Literature was searched for articles containing information on incidence and monitoring of GC-related AEs using PubMed, EMBASE and Cochrane databases. Second, the authors searched for broad accepted guidelines on the monitoring of certain AEs (eg, WHO guidelines on screening for diabetes). Available data were summarised and discussed among experts (rheumatologists and patients) of the EULAR Task Force to decide which potential AEs should be monitored, how and at which interval. Results Data on monitoring proved to be scarce; most articles were focused on therapeutic effects of GCs, not on occurrence and monitoring of AEs. Most recommendations had to be based on consensus. Those for clinical trials aimed at getting insights into incidence, prevalence and clinical relevance of AEs to create a comprehensive and valid AE-profile of GC therapy. The set of AEs to monitor is therefore more extensive, and often consists of assessments at baseline and at end of trials. Recommendations for daily practice are meant to protect patients from real dangers, which can be prevented or treated. Standard care monitoring needs NOT be extended for patients on low-dose GC therapy, except for osteoporosis (follow national guidelines), and baseline assessments of ankle edema, fasting blood glucose and risk factors for glaucoma. Conclusion Given the incompleteness of literature data, consensus-based recommendations on monitoring for GC-related AEs were created, separately for daily practice and clinical trials.
Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5
Authors: Roland Züst, Luisa Cervantes-Barragan, Matthias Habjan, Reinhard Maier, Benjamin W Neuman, John Ziebuhr, Kristy J Szretter, Susan C Baker, Winfried Barchet, Michael S Diamond, Stuart G Siddell, Burkhard Ludewig, Volker Thiel
Journal: Nature Immunology (2011)
Mechanism of Action of Sulforaphane: Inhibition of p38 Mitogen-Activated Protein Kinase Isoforms Contributing to the Induction of Antioxidant Response Element–Mediated Heme Oxygenase-1 in Human Hepatoma HepG2 Cells
Authors: Young-Sam Keum, Siwang Yu, Peter Pil-Jae Chang, Xiaoling Yuan, Jung-Hwan Kim, Changjiang Xu, Jiahuai Han, Anupam Agarwal, Ah-Ng Tony Kong
Journal: Cancer Research (2006)

Abstract Exposure of sulforaphane to HepG2 cells increased heme oxygenase-1 (HO-1) expression by activating antioxidant response element (ARE) through induction of Nrf2 and suppression of Kelch-like ECH-associated protein 1 (Keap1). Using human HO-1 promoter reporter plasmids and ChIP assay, we have identified that sulforaphane transcriptionally activated the upstream ARE-rich enhancer region, located at −9.0 kb upstream human HO-1 promoter. Induction of HO-1 by sulforaphane was attenuated by overexpression of mutant Nrf2 plasmid in HepG2 cells and totally abolished in Nrf2 knockout mouse embryonic keratinocytes and fibroblasts. Overexpression of individual p38 mitogen-activated protein (MAP) kinase (MAPK) isoforms also suppressed constitutive as well as sulforaphane- or Nrf2-induced ARE-dependent gene expression. Among the upstream kinases, although MKK3 was not involved in suppression of ARE by any of p38 MAPK isoforms, MKK6 selectively suppressed ARE by p38γ or p38δ, but not by p38α or p38β. Importantly, sulforaphane not only activated MAP/extracellular signal-regulated kinase (ERK) kinases 1/2 and ERK1/2, but also strongly suppressed anisomycin-induced activation of p38 MAPK isoforms by blocking phosphorylation of upstream kinases, MKK3/6. Finally, we found that stimulation of p38 MAPK isoforms phosphorylated purified Nrf2 protein and caused an increase in the interaction between Nrf2 and Keap1 in vitro and the suppression of Nrf2 translocation into the nucleus. Collectively, our results indicate that transcriptional activation of Nrf2/ARE is critical in sulforaphane-mediated induction of HO-1, which can be modulated in part by the blockade of p38 MAPK signaling pathway. In addition, our study shows that p38 MAPK can phosphorylate Nrf2 and promotes the association between Nrf2 and Keap1 proteins, thereby potentially inhibiting nuclear translocation of Nrf2. (Cancer Res 2006; 66(17): 8804-13)
Challenging Dogma: Thresholds for Genotoxic Carcinogens? The Case of Vinyl Acetate
Authors: J.G. Hengstler, M.S. Bogdanffy, H.M. Bolt, F. Oesch
Journal: The Annual Review of Pharmacology and Toxicology (2003)

Although many questions remain unanswered, the general principle of the sequence of events leading to cancer after exposure to genotoxic carcinogens has become increasingly clear. This helps to understand the parameters that influence the shape of the dose-effect curve for carcinogenesis, including metabolic activation and inactivation of carcinogens, DNA repair, cell cycle control, apoptosis, and control by the immune system. A linear dose-response relationship with no observable threshold seems to be a conservative but adequate description for the carcinogenic activity of many genotoxic carcinogens, such as aflatoxin B1, the tobacco-specific nitrosoketone NNK, and probably N,N-diethylnitrosamine. However, extrapolation models connecting the high-level risk to the zero intercept have clearly resulted in overestimations of risk. Vinyl acetate is an example that is discussed extensively in this review. At extremely high and toxic doses, vinyl acetate is carcinogenic in rats and mice and causes chromosomal aberrations. In tissues of contact, vinyl acetate is converted to acetic acid and acetaldehyde. Only when threshold levels are achieved do critical steps in the mechanism ultimately leading to cancer become active, namely pH reduction in exposed cells of more than 0.15 units leading to cytotoxicity, damage to DNA, and regenerative proliferation. Consistent with the known exposure to endogenous acetic acid and acetaldehyde, tissues sustain a certain level of exposure without adverse effects. Physiological modeling shows that the conditions necessary for carcinogenesis are in place only when threshold levels of vinyl acetate are exceeded. The example of vinyl acetate underlines the importance of toxicological research that unequivocally identifies genotoxic carcinogens acting through a threshold process.
Is lung function really a good parameter in evaluating the long-term effects of inhaled corticosteroids in COPD?
Authors: C.P. van Schayck
Journal: European Respiratory Journal (2000)

Recently several large trials evaluating the effects of long-term medication in chronic obstructive pulmonary disease (COPD) have appeared and there are still several which will be published in the coming years.The primary outcome of these trials was the decline in lung function.The long-term medication investigated was mainly inhaled corticosteroids.In contrast to asthma, COPD is a progressive and, to a large extent, irreversible pulmonary disease.One of the consequences is that the effectiveness of (for instance) inhaled corticosteroids in COPD can probably be measured to a limited extent on the basis of the lung function.Which parameters should be used to evaluate whether or not long-term medication in COPD is justified?
Functional Compensation of Primary and Secondary Metabolites by Duplicate Genes in Arabidopsis thaliana
Authors: K. Hanada, Y. Sawada, T. Kuromori, R. Klausnitzer, K. Saito, T. Toyoda, K. Shinozaki, W.-H. Li, M. Y. Hirai
Journal: Molecular Biology and Evolution (2010)

It is well known that knocking out a gene in an organism often causes no phenotypic effect. One possible explanation is the existence of duplicate genes; that is, the effect of knocking out a gene is compensated by a duplicate copy. Another explanation is the existence of alternative pathways. In terms of metabolic products, the relative roles of the two mechanisms have been extensively studied in yeast but not in any multi-cellular organisms. Here, to address the functional compensation of metabolic products by duplicate genes, we quantified 35 metabolic products from 1,976 genes in knockout mutants of Arabidopsis thaliana by a high-throughput Liquid chromatography-Mass spectrometer (LC-MS) analysis. We found that knocking out either a singleton gene or a duplicate gene with distant paralogs in the genome tends to induce stronger metabolic effects than knocking out a duplicate gene with a close paralog in the genome, indicating that only duplicate genes with close paralogs play a significant role in functional compensation for metabolic products in A. thaliana. To extend the analysis, we examined metabolic products with either high or low connectivity in a metabolic network. We found that the compensatory role of duplicate genes is less important when the metabolite has a high connectivity, indicating that functional compensation by alternative pathways is common in the case of high connectivity. In conclusion, recently duplicated genes play an important role in the compensation of metabolic products only when the number of alternative pathways is small.
Measuring Local Gradients of Intramitochondrial [Ca <sup>2+</sup> ] in Cardiac Myocytes During Sarcoplasmic Reticulum Ca <sup>2+</sup> Release
Authors: Xiyuan Lu, Kenneth S. Ginsburg, Sarah Kettlewell, Julie Bossuyt, Godfrey L. Smith, Donald M. Bers
Journal: Circulation Research (2012)

Mitochondrial [Ca(2+)] ([Ca(2+)](mito)) regulates mitochondrial energy production, provides transient Ca(2+) buffering under stress, and can be involved in cell death. Mitochondria are near the sarcoplasmic reticulum (SR) in cardiac myocytes, and evidence for crosstalk exists. However, quantitative measurements of [Ca(2+)](mito) are limited, and spatial [Ca(2+)](mito) gradients have not been directly measured.To directly measure local [Ca(2+)](mito) during normal SR Ca release in intact myocytes, and evaluate potential subsarcomeric spatial [Ca(2+)](mito) gradients.Using the mitochondrially targeted inverse pericam indicator Mitycam, calibrated in situ, we directly measured [Ca(2+)](mito) during SR Ca(2+) release in intact rabbit ventricular myocytes by confocal microscopy. During steady state pacing, Δ[Ca(2+)](mito) amplitude was 29±3 nmol/L, rising rapidly (similar to cytosolic free [Ca(2+)]) but declining much more slowly. Taking advantage of the structural periodicity of cardiac sarcomeres, we found that [Ca(2+)](mito) near SR Ca(2+) release sites (Z-line) versus mid-sarcomere (M-line) reached a high peak amplitude (37±4 versus 26±4 nmol/L, respectively P<0.05) which occurred earlier in time. This difference was attributed to ends of mitochondria being physically closer to SR Ca(2+) release sites, because the mitochondrial Ca(2+) uniporter was homogeneously distributed, and elevated [Ca(2+)] applied laterally did not produce longitudinal [Ca(2+)](mito) gradients.We developed methods to measure spatiotemporal [Ca(2+)](mito) gradients quantitatively during excitation-contraction coupling. The amplitude and kinetics of [Ca(2+)](mito) transients differ significantly from those in the cytosol and are respectively higher and faster near the Z-line versus M-line. This approach will help clarify SR-mitochondrial Ca(2+) signaling.
Improved Detection of Prostate Cancer Using Classification and Regression Tree Analysis
Authors: Mark Garzotto, Tomasz M. Beer, R. Guy Hudson, Laura Peters, Yi-Ching Hsieh, Eduardo Barrera, Thomas Klein, Motomi Mori
Journal: Journal of Clinical Oncology (2005)

To build a decision tree for patients suspected of having prostate cancer using classification and regression tree (CART) analysis.Data were uniformly collected on 1,433 referred men with a serum prostate-specific antigen (PSA) levels of < or = 10 ng/mL who underwent a prostate biopsy. Factors analyzed included demographic, laboratory, and ultrasound data (ie, hypoechoic lesions and PSA density [PSAD]). Twenty percent of the data was randomly selected and reserved for study validation. CART analysis was performed in two steps, initially using PSA and digital rectal examination (DRE) alone and subsequently using the remaining variables.CART analysis selected a PSA cutoff of more than 1.55 ng/mL for further work-up, regardless of DRE findings. CART then selected the following subgroups at risk for a positive biopsy: (1) PSAD more than 0.165 ng/mL/cc; (2) PSAD < or = 0.165 ng/mL/cc and a hypoechoic lesion; (3) PSAD < or = 0.165 ng/mL/cc, no hypoechoic lesions, age older than 55.5 years, and prostate volume < or = 44.0 cc; and (4) PSAD < or = 0.165 ng/mL/cc, no hypoechoic lesions, age older than 55.5 years, and 50.25 cc less than prostate volume < or = 80.8 cc. In the validation data set, specificity and sensitivity were 31.3% and 96.6%, respectively. Cancers that were missed by the CART were Gleason score 6 or less in 93.4% of cases. Receiver operator characteristic curve analysis showed that CART and logistic regression models had similar accuracy (area under the curve = 0.74 v 0.72, respectively).Application of CART analysis to the prostate biopsy decision results in a significant reduction in unnecessary biopsies while retaining a high degree of sensitivity when compared with the standard of performing a biopsy of all patients with an abnormal PSA or DRE.
Aberrations of <i>EZH2</i> in Cancer
Authors: Andrew Chase, Nicholas C.P. Cross
Journal: Clinical Cancer Research (2011)

Control of gene expression is exerted at a number of different levels, one of which is the accessibility of genes and their controlling elements to the transcriptional machinery. Accessibility is dictated broadly by the degree of chromatin compaction, which is influenced in part by polycomb group proteins. EZH2, together with SUZ12 and EED, forms the polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3). PRC2 may recruit other polycomb complexes, DNA methyltransferases, and histone deacetylases, resulting in additional transcriptional repressive marks and chromatin compaction at key developmental loci. Overexpression of EZH2 is a marker of advanced and metastatic disease in many solid tumors, including prostate and breast cancer. Mutation of EZH2 Y641 is described in lymphoma and results in enhanced activity, whereas inactivating mutations are seen in poor prognosis myeloid neoplasms. No histone demethylating agents are currently available for treatment of patients, but 3-deazaneplanocin (DZNep) reduces EZH2 levels and H3K27 trimethylation, resulting in reduced cell proliferation in breast and prostate cancer cells in vitro. Furthermore, synergistic effects are seen for combined treatment with DNA demethylating agents and histone deacetylation inhibitors, opening up the possibility of refined epigenetic treatments in the future.
EVALUATION OF A STROMA-FREE HEMOGLOBIN SOLUTION FOR USE AS A PLASMA EXPANDER
Authors: S. Frederick Rabiner, J. Raymond Helbert, Harry Lopas, Lila H. Friedman
Journal: The Journal of Experimental Medicine (1967)

The preparation of large quantities of a stable, stroma-free hemoglobin solution without coagulant activity is described. Following infusion of this solution into phlebotomized dogs, there is no methemoglobin formation, no adverse effects on vital signs, and no demonstrable activation of blood coagulation. The hemoglobin maintains its oxygen-carrying capacity and liberates oxygen into tissues. Acute and chronic effects on renal function following infusion of this preparation were also studied and no effect on clearance of urea, creatinine, or P.A.H. could be demonstrated. There was no change in urinary output and histological sections revealed no lesions attributable to hemoglobin toxicity. It is concluded that a stroma-free hemoglobin solution may have use as a plasma expander.
Treatment Disparities in the Care of Patients With and Without Diabetes Presenting With Non–ST-Segment Elevation Acute Coronary Syndromes
Authors: Gerard X. Brogan, Eric D. Peterson, Jyotsna Mulgund, Deepak L. Bhatt, E. Magnus Ohman, W. Brian Gibler, Charles V. Pollack, Michael E. Farkouh, Matthew T. Roe
Journal: Diabetes Care (2006)

The objective of this study was to characterize treatment patterns among patients with diabetes presenting with non-ST-segment elevation (NSTE) acute coronary syndromes (ACSs).We compared adherence to treatment recommendations from the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for NSTE ACS among 46,410 patients from 413 U.S. hospitals that were included in the Can Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) quality improvement initiative. Patients were stratified as nondiabetic, non-insulin-dependent diabetic (type 2 diabetic), and insulin-treated diabetic.Insulin-treated diabetic patients were less likely than nondiabetic patients to receive aspirin (adjusted odds ratio 0.83 [95% CI 0.74-0.93]), beta-blockers (0.89 [0.83-0.96]), heparin (0.90 [0.83-0.98]), and glycoprotein IIb/IIIa inhibitors (0.86 [0.79-0.93]). Type 2 diabetic patients were treated similarly to nondiabetic patients. After adjustment for differences in clinical characteristics, insulin-treated diabetic patients were significantly less likely than nondiabetic patients to receive cardiac catheterization within 48 h of presentation (0.80 [0.74-0.86]) or percutaneous coronary intervention (0.87 [0.82-0.94]). Compared with nondiabetic patients, insulin-treated diabetic and type 2 diabetic patients were more likely to undergo coronary artery bypass grafting (1.34 [1.21-1.49] and 1.35 [1.26-1.44]). In-hospital mortality rates were higher in insulin-treated diabetic (6.8%) and type 2 diabetic (5.4%) than in nondiabetic (4.4%) patients.Diabetic patients have a higher risk of mortality than nondiabetic patients, yet physicians adhere to the ACC/AHA NSTE ACS guidelines less often when treating diabetic patients, particularly insulin-treated diabetic patients. Increased use of guideline-recommended therapies and early invasive management strategies in diabetic patients may improve their outcomes.
Oestrogen receptors and survival in early breast cancer.
Authors: T Cooke
Journal: BMJ (1982)

Oestrogen receptor status was related to survival in 414 patients with primary breast cancer. Women with oestrogen receptors in their tumours survived significantly longer than those without receptors; this was true for both premenopausal and postmenopausal women and also when the patients were subdivided into those with and without axillary metastases. Patients with axillary metastases and no oestrogen receptors in their tumours had the worst prognosis, while women with axillary metastases and oestrogen receptors had a death rate similar to that of women with no axillary metastases and no receptors. Patients without oestrogen receptors and with no axillary metastases were identified as a high-risk group, and it would seem appropriate to include such patients in future trials for adjuvant therapy in early breast cancer.
Separation of primary and secondary cardiovascular events in systemic anaphylaxis.
Authors: J H Zavecz, R Levi
Journal: Circulation Research (1977)

The purpose of this investigation was to differentiate primary cardiac participation in systemic anaphylaxis from a cardiac reaction secondary to respiratory distress. Hemocyaninsensitized guinea pigs were anesthetized with sodium pentobarbital and artifically ventilated. The chest was opened and the left ventricle cannulated. The electrocardiogram, bronchial resistance, arterial blood pressure, and left ventricular pressure and its first derivative were recorded. Following intravenous administration of antigen, the sinus rate increased by about 50-60 beats/min, left ventricular dP/dt increased by a factor of 3, and mean arterial pressure doubled. Conduction disturbances occurred in all of the experiments and ventricular fibrillation in four of six. These changes were concomitant with a 4-fold rise in bronchial resistance. To separate the cardiac and respiratory components, antigen was administered directly into the left ventricle to expose the heart to antigen before the lungs. The intracardiac challenge resulted in increases in sinus rate and left ventricular and arterial pressure quantitatively similar to changes recorded from guinea pigs after the intravenous challenge. However, all these changes preceded the rise in bronchial resistance by 60 seconds. Arrhythmias occurred as frequently as with the intravenous challenge. Our findings show that by use of an appropriate route for administration of antigen, cardiovascular and respiratory components of systemic anaphylaxis can be separated. Our data also indicate that anaphylactic cardiovascular changes can be dissociated temporally into two sets of events: an initial primary cardiac reaction caused by intracardiac release of histamine and a subsequent cardiovascular reaction secondary to systemic release of mediator.
744 TREATMENT OF MULTIRESISTANT HBV PATIENTS WITH ENTECAVIR PLUS TENOFOVIR. 2 YEARS SAFETY AND EFFICACY ANALYSIS. AN INTERNATIONAL MULTICENTER COHORT STUDY
Authors: J. Petersen, M. Lutgehetmann, M. Buti, H. Janssen, A. Brown, P. Lampertico, F. Zoulim, H. Wedemeyer, M. Sterneck, T. Berg, C. Sarrazin, V. Ratziu, P. Buggisch
Journal: Journal of Hepatology (2011)