Forced homo-oligomerization of RARα leads to transformation of primary hematopoietic cells

SummaryAlmost 100% of APL patients carry chimeric transcripts encoding truncated RARα fused to homo-oligomerization domains from partner proteins. To gain further insights into the cellular transformation mechanisms mediated by RARα fusion proteins, thorough structure/function analyses have been performed and identified the POZ homo-oligomerization domain as the minimal transformation domain that is necessary and sufficient for PLZF-RARα-mediated in vitro transformation of primary hematopoietic cells. A transformation-incompetent PLZF-RARα mutant defective in homo-oligomerization but not corepressor interaction could be rescued by synthetic FKBP-oligomerization domains. Furthermore, an artificial FKBP-RARα construct not only mimicked various biochemical properties of bona fide RARα fusion proteins but also mediated an ATRA-dependent transformation. Taken together, these findings endorse an oligomerization-dependent mechanism for RARα-mediated transformation and suggest a potential avenue for molecular therapy

Impact of incomplete percutaneous revascularization in patients With multivessel coronary artery disease: a systematic review and meta-analysis

Background: Up to half of patients undergoing percutaneous coronary intervention have multivessel coronary artery disease (MVD) with conflicting data regarding optimal revascularization strategy in such patients. This paper assesses the evidence for complete revascularization (CR) versus incomplete revascularization in patients undergoing percutaneous coronary intervention, and its prognostic impact using meta‐analysis. Methods and Results: A search of PubMed, EMBASE, MEDLINE, Current Contents Connect, Google Scholar, Cochrane library, Science Direct, and Web of Science was conducted to identify the association of CR in patients with multivessel coronary artery disease undergoing percutaneous coronary intervention with major adverse cardiac events and mortality. Random‐effects meta‐analysis was used to estimate the odds of adverse outcomes. Meta‐regression analysis was conducted to assess the relationship with continuous variables and outcomes. Thirty‐eight publications that included 156 240 patients were identified. Odds of death (OR 0.69, 95% CI 0.61‐0.78), repeat revascularization (OR 0.60, 95% CI 0.45‐0.80), myocardial infarction (OR 0.64, 95% CI 0.50‐0.81), and major adverse cardiac events (OR 0.63, 95% CI 0.50‐0.79) were significantly lower in the patients who underwent CR. These outcomes were unchanged on subgroup analysis regardless of the definition of CR. Similar findings were recorded when CR was studied in the chronic total occlusion (CTO) subgroup (OR 0.65, 95% CI 0.53‐0.80). A meta‐regression analysis revealed a negative relationship between the OR for mortality and the percentage of CR. Conclusion: CR is associated with reduced risk of mortality and major adverse cardiac events, irrespective of whether an anatomical or a score‐based definition of incomplete revascularization is used, and this magnitude of risk relates to degree of CR. These results have important implications for the interventional management of patients with multivessel coronary artery disease

Semi-quantitative mass spectrometry in AML cells identifies new non-genomic targets of the EZH2 methyltransferase

Alterations to the gene encoding the EZH2 (KMT6A) methyltransferase, including both gain-of-function and loss-of-function, have been linked to a variety of haematological malignancies and solid tumours, suggesting a complex, context-dependent role of this methyltransferase. The successful implementation of molecularly targeted therapies against EZH2 requires a greater understanding of the potential mechanisms by which EZH2 contributes to cancer. One aspect of this effort is the mapping of EZH2 partner proteins and cellular targets. To this end we performed affinity-purification mass spectrometry in the FAB-M2 HL-60 acute myeloid leukaemia (AML) cell line before and after all-transretinoic acid-induced differentiation. These studies identified new EZH2 interaction partners and potential non-histone substrates for EZH2-mediated methylation. Our results suggest that EZH2 is involved in the regulation of translation through interactions with a number of RNA binding proteins and by methylating key components of protein synthesis such as eEF1A1. Given that deregulated mRNA translation is a frequent feature of cancer and that eEF1A1 is highly expressed in many human tumours, these findings present new possibilities for the therapeutic targeting of EZH2 in AML

Stroke following percutaneous coronary intervention : type-specific incidence, outcomes and determinants seen by the British Cardiovascular Intervention Society 2007-12

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: [email protected] reviewedPostprin

Acute renal impairment in coronavirus-associated severe acute respiratory syndrome

Acute renal impairment in coronavirus-associated severe acute respiratory syndrome.BackgroundSevere acute respiratory syndrome (SARS) is a newly emerged infection from a novel coronavirus (SARS-CoV). Apart from fever and respiratory complications, acute renal impairment has been observed in some patients with SARS. Herein, we describe the clinical, pathologic, and laboratory features of the acute renal impairment complicating this new viral infection.MethodsWe conducted a retrospective analysis of the plasma creatinine concentration and other clinical parameters of the 536 SARS patients with normal plasma creatinine at first clinical presentation, admitted to two regional hospitals following a major outbreak in Hong Kong in March 2003. Kidney tissues from seven other patients with postmortem examinations were studied by light microscopy and electron microscopy.ResultsAmong these 536 patients with SARS, 36 (6.7%) developed acute renal impairment occurring at a median duration of 20 days (range 5–48 days) after the onset of viral infection despite a normal plasma creatinine level at first clinical presentation. The acute renal impairment reflected the different prerenal and renal factors that exerted renal insult occurring in the context of multiorgan failure. Eventually, 33 SARS patients (91.7%) with acute renal impairment died. The mortality rate was significantly higher among patients with SARS and acute renal impairment compared with those with SARS and no renal impairment (91.7% vs. 8.8%) (P < 0.0001). Renal tissues revealed predominantly acute tubular necrosis with no evidence of glomerular pathology. The adjusted relative risk of mortality associated with the development of acute renal impairment was 4.057 (P < 0.001). By multivariate analysis, acute respiratory distress syndrome and age were the most significant independent risk factors predicting the development of acute renal impairment in SARS.ConclusionAcute renal impairment is uncommon in SARS but carries a high mortality. The acute renal impairment is likely to be related to multi-organ failure rather than the kidney tropism of the virus. The development of acute renal impairment is an important negative prognostic indicator for survival with SARS

Percutaneous coronary intervention and 30-day unplanned readmission with chest pain in the United States (nationwide readmissions database)

Percutaneous coronary intervention (PCI) improves anginal chest pain in most, but not all, treated patients. PCI is associated with unplanned readmission for angina and non‐specific chest pain within 30‐days of index PCI. Patients with an index hospitalization for PCI between January–November in each of the years 2010–2014 were included from the United States Nationwide Readmissions Database. Of 2 723 455 included patients, the 30‐day unplanned readmission rate was 7.2% (n = 196 581, 42.3% female). This included 9.8% (n = 19 183) with angina and 11.1% (n = 21 714) with non‐specific chest pain. The unplanned readmission group were younger (62.2 vs 65.1 years; P &lt; 0.001), more likely to be females (41.0% vs 34.2%; P &lt; 0.001), from the lowest quartile of household income (32.9% vs 31.2%; P &lt; 0.001), have higher prevalence of cardiovascular risk factors or have index PCI performed for non‐acute coronary syndromes (ACS) (OR:3.46, 95%CI 3.39–3.54). Factors associated with angina readmissions included female sex (OR:1.28, 95%CI 1.25–1.32), history of ischemic heart disease (IHD) (OR:3.28, 95%CI 2.95–3.66), coronary artery bypass grafts (OR:1.79, 95%CI 1.72–2.86), anaemia (OR:1.16, 95%CI 1.11–1.21), hypertension (OR:1.13, 95%CI 1.09, 1.17), and dyslipidemia (OR:1.10, 95%CI 1.06–1.14). Non‐specific chest pain compared with angina readmissions were younger (mean difference 1.25 years, 95% CI 0.99, 1.50), more likely to be females (RR:1.13, 95%CI 1.10, 1.15) and have undergone PCI for non‐ACS (RR:2.17, 95%CI 2.13, 2.21). Indications for PCI other than ACS have a greater likelihood of readmission with angina or non‐specific chest pain at 30‐days. Readmissions are more common in patients with modifiable risk factors, previous history of IHD and anaemia

Does shear wave ultrasound independently predict axillary lymph node metastasis in women with invasive breast cancer?

Shear wave elastography (SWE) shows promise as an adjunct to greyscale ultrasound examination in assessing breast masses. In breast cancer, higher lesion stiffness on SWE has been shown to be associated with features of poor prognosis. The purpose of this study was to assess whether lesion stiffness at SWE is an independent predictor of lymph node involvement. Patients with invasive breast cancer treated by primary surgery, who had undergone SWE examination were eligible. Data were retrospectively analysed from 396 consecutive patients. The mean stiffness values were obtained using the Aixplorer(®) ultrasound machine from SuperSonic Imagine Ltd. Measurements were taken from a region of interest positioned over the stiffest part of the abnormality. The average of the mean stiffness value obtained from each of two orthogonal image planes was used for analysis. Associations between lymph node involvement and mean lesion stiffness, invasive cancer size, histologic grade, tumour type, ER expression, HER-2 status and vascular invasion were assessed using univariate and multivariate logistic regression. At univariate analysis, invasive size, histologic grade, HER-2 status, vascular invasion, tumour type and mean stiffness were significantly associated with nodal involvement. Nodal involvement rates ranged from 7 % for tumours with mean stiffness <50 kPa to 41 % for tumours with a mean stiffness of >150 kPa. At multivariate analysis, invasive size, tumour type, vascular invasion, and mean stiffness maintained independent significance. Mean stiffness at SWE is an independent predictor of lymph node metastasis and thus can confer prognostic information additional to that provided by conventional preoperative tumour assessment and staging

Annexin II-binding immunoglobulins in patients with lupus nephritis and their correlation with disease manifestations

Correspondence: Tak Mao Chan ([email protected]) and Susan Yung ([email protected]) Annexin II on mesangial cell surface mediates the binding of anti-dsDNA antibodies and consequent downstream inflammatory and fibrotic processes. We investigated the clinical relevance of circulating annexin II-binding immunoglobulins (Igs) in patients with severe proliferative lupus nephritis, and renal annexin II expression in relation to progression of nephritis in New Zealand Black and White F1 mice (NZBWF1/J) mice. Annexin II-binding Igs in serum were measured by ELISA. Ultrastructural localization of annexin II was determined by electron microscopy. Seropositivity rates for annexin II-binding IgG and IgM in patients with active lupus nephritis were significantly higher compared with controls (8.9%, 1.3% and 0.9% for annexin II-binding IgG and 11.1%, 4.0% and 1.9% for annexin II-binding IgM for patients with active lupus nephritis, patients with non-lupus renal disease and healthy subjects respectively). In lupus patients, annexin II-binding IgM level was higher at disease flare compared with remission. Annexin II-binding IgG and IgM levels were associated with that of anti-dsDNA and disease activity. Annexin II-binding IgG and IgM levels correlated with histological activity index in lupus nephritis biopsy samples. In NZBWF1/J mice, serum annexin II-binding IgG and IgM levels and glomerular annexin II and p11 expression increased with progression of active nephritis. Annexin II expression was present on mesangial cell surface and in the mesangial matrix, and co-localized with electron-dense deposits along the glomerular basement membrane. Our results show that circulating annexin II-binding IgG and IgM levels are associated with clinical and histological disease activity in proliferative lupus nephritis. The co-localization of annexin II and p11 expression with immune deposition in the kidney suggests pathogenic relevance

Sharing voxelwise neuroimaging results from rhesus monkeys and other species with Neurovault

© 2020 The Authors Animal neuroimaging studies can provide unique insights into brain structure and function, and can be leveraged to bridge the gap between animal and human neuroscience. In part, this power comes from the ability to combine mechanistic interventions with brain-wide neuroimaging. Due to their phylogenetic proximity to humans, nonhuman primate neuroimaging holds particular promise. Because nonhuman primate neuroimaging studies are often underpowered, there is a great need to share data amongst translational researchers. Data sharing efforts have been limited, however, by the lack of standardized tools and repositories through which nonhuman neuroimaging data can easily be archived and accessed. Here, we provide an extension of the Neurovault framework to enable sharing of statistical maps and related voxelwise neuroimaging data from other species and template-spaces. Neurovault, which was previously limited to human neuroimaging data, now allows researchers to easily upload and share nonhuman primate neuroimaging results. This promises to facilitate open, integrative, cross-species science while affording researchers the increased statistical power provided by data aggregation. In addition, the Neurovault code-base now enables the addition of other species and template-spaces. Together, these advances promise to bring neuroimaging data sharing to research in other species, for supplemental data, location-based atlases, and data that would otherwise be relegated to a file-drawer . As increasing numbers of researchers share their nonhuman neuroimaging data on Neurovault, this resource will enable novel, large-scale, cross-species comparisons that were previously impossible

IgE to epitopes of Ara h 2 enhance the diagnostic accuracy of Ara h 2‐specific IgE

© 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background: Understanding the discrepancy between IgE sensitization and allergic reactions to peanut could facilitate diagnosis and lead to novel means of treating peanut allergy. Objective: To identify differences in IgE and IgG4 binding to peanut peptides between peanut-allergic (PA) and peanut-sensitized but tolerant (PS) children. Methods: PA (n = 56), PS (n = 42) and nonsensitized nonallergic (NA, n = 10) patients were studied. Synthetic overlapping 15-mer peptides of peanut allergens (Ara h 1-11) were spotted onto microarray slides, and patients' samples were tested for IgE and IgG4 binding using immunofluorescence. IgE and IgG4 levels to selected peptides were quantified using ImmunoCAP. Diagnostic model comparisons were performed using likelihood-ratio tests between each specified nominal logistic regression models. Results: Seven peptides on Ara h 1, Ara h 2, and Ara h 3 were bound more by IgE of PA compared to PS patients on the microarray. IgE binding to one peptide on Ara h 5 and IgG4 binding to one Ara h 9 peptide were greater in PS than in PA patients. Using ImmunoCAP, IgE to the Ara h 2 peptides enhanced the diagnostic accuracy of Ara h 2-specific IgE. Ratios of IgG4/IgE to 4 out of the 7 peptides were higher in PS than in PA subjects. Conclusions: Ara h 2 peptide-specific IgE added diagnostic value to Ara h 2-specific IgE. Ability of peptide-specific IgG4 to surmount their IgE counterpart seems to be important in established peanut tolerance.This work was supported by the Medical Research Council (MRC Clinical Research Training Fellowship G090218, MRC Centenary Early Career Award and MRC Clinician Scientist Fellowship MR/M008517/1, all awarded to A. F. Santos), the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust; the US Department of Agriculture, Agricultural Research Service (USDA-ARS6054-43440-046-00D; USDA-NIFA) and the National Peanut Board (GRANT12229460).info:eu-repo/semantics/publishedVersio