WT1 is a transcription factor expressed in hematopoietic stem cells and in most cases of myeloid leukemia. We investigated the roles of hypoxia and epigenetics in the regulation of WT1 expression in ...myeloid leukemia cells. WT1 expression correlates with hypomethylation of the CpG island in Intron 1, and pharmacologic demethylation of this CpG island induces WT1 mRNA expression. Hypoxia causes decreases in DNMT expression and activity and increased expression and activity of TET2 and TET3, resulting in demethylation of this CpG island and expression of WT1 mRNA. Demethylation of the CpG island, either from pharmacologic treatment or induction of hypoxia, results in transcription of an antisense-oriented lncRNA, and inhibiting lncRNA expression with shRNA blocks WT1 mRNA expression. These results reveal a novel model of hypoxia-mediated epigenetic gene regulation. In addition, this is the first report that TET2 and TET3, increasingly recognized as important epigenetic regulators of gene expression in stem cells and in cancer cells, can be regulated by hypoxia, providing a solid mechanistic link between hypoxia and epigenetic regulation of gene expression with important implications for the role of hypoxia in stem cell function.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The authors argue that quality measures in health care should be based on strong evidence that a care process directly improves outcomes, should capture the actual performance of a process, should ...address a process proximate to the desired outcome, and should not have unintended adverse consequences.
Measuring the quality of health care and using those measurements to promote improvements in the delivery of care, to influence payment for services, and to increase transparency are now commonplace. These activities, which now involve virtually all U.S. hospitals, are migrating to ambulatory and other care settings and are increasingly evident in health care systems worldwide. Many constituencies are pressing for continued expansion of programs that rely on quality measurement and reporting.
In this article, we review the origins of contemporary standardized quality measurement, with a focus on hospitals, where such programs have reached their most highly developed state. We . . .
Aliment Pharmacol Ther 31, 1165–1177
Summary
Background Observational studies examining the association between proton pump inhibitor (PPI) use and risk of community‐acquired pneumonia are ...conflicting.
Aim To assess systematically the association between risk of community‐acquired pneumonia and PPI use in adults.
Methods We searched MEDLINE, EMBASE and CINAHL databases between 1988 and January 2010. Two reviewers independently selected studies based on eligibility criteria and extracted data. Included studies evaluated adults (≥18 years) who took PPIs as an out‐patient. The primary outcome was community‐acquired pneumonia. Only observational studies with a comparison arm were included.
Results Over 2600 citations were reviewed. Six studies were included. All were nested case‐control studies. Meta‐analysis found an increased risk of community‐acquired pneumonia associated with PPI use OR 1.36 (95% CI 1.12–1.65); significant heterogeneity remained (I2 92%, P < 0.001). In exploratory subgroup analysis, short duration of use was associated with an increased odds of community‐acquired pneumonia OR 1.92 (95% CI 1.40–2.63), I2 75%, P = 0.003, whereas chronic use was not OR 1.11 (95% CI 0.90–1.38), I2 91%, P < 0.001, a significant interaction (P < 0.005).
Conclusions Heterogeneity precluded interpretation of the summary statistic. Exploratory analysis revealed that duration of PPI use may impact the risk of community‐acquired pneumonia, a finding that should be explored in future studies.
The CBFA2T3-GLIS2 (C/G) fusion is a product of a cryptic translocation primarily seen in infants and early childhood and is associated with dismal outcome. Here, we demonstrate that the expression of ...the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem and progenitor cells (CB HSPCs) in an endothelial cell coculture system that recapitulates the transcriptome, morphology, and immunophenotype of C/G acute myeloid leukemia (AML) and induces highly aggressive leukemia in xenograft models. Interrogating the transcriptome of C/G-CB cells and primary C/G AML identified a library of C/G-fusion-specific genes that are potential targets for therapy. We developed chimeric antigen receptor (CAR) T cells directed against one of the targets, folate receptor α (FOLR1), and demonstrated their preclinical efficacy against C/G AML using in vitro and xenograft models. FOLR1 is also expressed in renal and pulmonary epithelium, raising concerns for toxicity that must be addressed for the clinical application of this therapy. Our findings underscore the role of the endothelial niche in promoting leukemic transformation of C/G-transduced CB HSPCs. Furthermore, this work has broad implications for studies of leukemogenesis applicable to a variety of oncogenic fusion-driven pediatric leukemias, providing a robust and tractable model system to characterize the molecular mechanisms of leukemogenesis and identify biomarkers for disease diagnosis and targets for therapy.
Objective To evaluate risk factors for severe outcomes in patients with seasonal and pandemic influenza. Design Systematic review. Study selection Observational studies reporting on risk ...factor-outcome combinations of interest in participants with influenza. Outcomes included death, ventilator support, admission to hospital, admission to an intensive care unit, pneumonia, and composite outcomes. Data sources Medline, Embase, CINAHL, Global Health, and the Cochrane Central Register of Controlled Trials to March 2011. Risk of bias assessment Newcastle-Ottawa scale to assess the risk of bias. GRADE framework to evaluate the quality of evidence. Results 63 537 articles were identified of which 234 with a total of 610 782 participants met the inclusion criteria. The evidence supporting risk factors for severe outcomes of influenza ranged from being limited to absent. This was particularly relevant for the relative lack of data for non-2009 H1N1 pandemics and for seasonal influenza studies. Limitations in the published literature included lack of power and lack of adjustment for confounders was widespread: adjusted risk estimates were provided for only 5% of risk factor-outcome comparisons in 39 of 260 (15%) studies. The level of evidence was low for “any risk factor” (odds ratio for mortality 2.77, 95% confidence interval 1.90 to 4.05 for pandemic influenza and 2.04, 1.74 to 2.39 for seasonal influenza), obesity (2.74, 1.56 to 4.80 and 30.1, 1.74 to 2.39), cardiovascular diseases (2.92, 1.76 to 4.86 and 1.97, 1.06 to 3.67), and neuromuscular disease (2.68, 1.91 to 3.75 and 3.21, 1.84 to 5.58). The level of evidence was very low for all other risk factors. Some well accepted risk factors such as pregnancy and belonging to an ethnic minority group could not be identified as risk factors. In contrast, women who were less than four weeks post partum had a significantly increased risk of death from pandemic influenza (4.43, 1.24 to 15.81). Conclusion The level of evidence to support risk factors for influenza related complications is low and some well accepted risk factors, including pregnancy and ethnicity, could not be confirmed as risks. Rigorous and adequately powered studies are needed.
Patients with metastatic or recurrent and refractory sarcomas have a dismal prognosis. Therefore, new targeted therapies are urgently needed. This study was designed to evaluate chimeric antigen ...receptor (CAR) T cells targeting the type I insulin-like growth factor receptor (IGF1R) or tyrosine kinase-like orphan receptor 1 (ROR1) molecules for their therapeutic potential against sarcomas. Here, we report that IGF1R (15/15) and ROR1 (11/15) were highly expressed in sarcoma cell lines including Ewing sarcoma, osteosarcoma, alveolar or embryonal rhabdomyosarcoma, and fibrosarcoma. IGF1R and ROR1 CAR T cells derived from eight healthy donors using the Sleeping Beauty (SB) transposon system were cytotoxic against sarcoma cells and produced high levels of IFN-γ, TNF-α and IL-13 in an antigen-specific manner. IGF1R and ROR1 CAR T cells generated from three sarcoma patients released significant amounts of IFN-γ in response to sarcoma stimulation. The adoptive transfer of IGF1R and ROR1 CAR T cells derived from a sarcoma patient significantly reduced tumor growth in pre-established, systemically disseminated and localized osteosarcoma xenograft models in NSG mice. Infusion of IGF1R and ROR1 CAR T cells also prolonged animal survival in a localized sarcoma model using NOD/scid mice. Our data indicate that both IGF1R and ROR1 can be effectively targeted by SB modified CAR T cells and that such CAR T cells may be useful in the treatment of high risk sarcoma patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
AbstractObjective To examine differences in the characteristics of adverse events between English speaking patients and patients with limited English proficiency in US hospitals. Setting Six Joint ...Commission accredited hospitals in the USA. Method Adverse event data on English speaking patients and patients with limited English proficiency were collected from six hospitals over 7 months in 2005 and classified using the National Quality Forum endorsed Patient Safety Event Taxonomy. Results About 49.1% of limited English proficient patient adverse events involved some physical harm whereas only 29.5% of adverse events for patients who speak English resulted in physical harm. Of those adverse events resulting in physical harm, 46.8% of the limited English proficient patient adverse events had a level of harm ranging from moderate temporary harm to death, compared with 24.4% of English speaking patient adverse events. The adverse events that occurred to limited English proficient patients were also more likely to be the result of communication errors (52.4%) than adverse events for English speaking patients (35.9%). Conclusions Language barriers appear to increase the risks to patient safety. It is important for patients with language barriers to have ready access to competent language services. Providers need to collect reliable language data at the patient point of entry and document the language services provided during the patient–provider encounter.
In 2002, the JCAHO began requiring hospitals to report their performance on standardized measures of the quality of health care and began providing hospitals with feedback on their performance. This ...study documented substantial improvement between 2002 and 2004 in hospitals' performance for myocardial infarction, congestive heart failure, and pneumonia. Hospitals with a low level of performance at baseline had the largest improvements.
This study documented substantial improvement between 2002 and 2004 in hospitals' performance for myocardial infarction, congestive heart failure, and pneumonia.
The 2001 report of the Institute of Medicine,
Crossing the Quality Chasm,
indicated that the American health care system “is currently functioning at far lower levels than it could and should.”
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To address shortcomings in the health care system, the report called for the “establishment of monitoring and tracking processes for use in evaluating the progress of the health system.” The report emphasized the need to improve the effectiveness of health care through the consistent provision of services that are based on current scientific knowledge.
In 2003, the Agency for Healthcare Research and Quality (AHRQ) released the National Healthcare Quality . . .
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